5% blasts in the \n\nbone marrow and either relapse at any time after allogeneic HSCT, untreated first relapse with first \n\nremission duration < 12 months, or refractory to last therapy). \n\n \n\nPatients were randomised 2:1 to receive BLINCYTO or 1 of 4 prespecified, investigator-selected, \n\nSOC backbone chemotherapy regimens. Randomisation was stratified by age (< 35 years versus \n\n≥ 35 years of age), prior salvage therapy (yes versus no), and prior allogeneic HSCT (yes versus no) \n\nas assessed at the time of consent. The demographics and baseline characteristics were well-balanced \n\nbetween the two arms (see table 1). \n\n \n\nTable 1. Demographics and baseline characteristics in phase III study \n\n \n\nCharacteristic \nBLINCYTO \n\n(N = 271) \n\nSOC chemotherapy \n\n(N = 134) \n\nAge \n\n Median, years (min, max) 37 (18, 80) 37 (18, 78) \n\n Mean, years (SD) 40.8 (17.1) 41.1 (17.3) \n\n ≥ 65 Years, n (%) 33 (12.2) 15 (11.2) \n\nPrior salvage therapy 164 (60.5) 80 (59.7) \n\n 0 114 (42.1) 65 (48.5) \n\n 1 91 (33.6) 43 (32.1) \n\n ≥ 2 66 (24.3) 26 (19.4) \n\nPrior alloHSCT 94 (34.7) 46 (34.3) \n\nECOG status - n (%) \n\n0 96 (35.4) 52 (38.8) \n\n1 134 (49.4) 61 (45.5) \n\n2 41 (15.1) 20 (14.9) \n\nRefractory status - n (%) \n\n Primary refractory 46 (17.0) 27 (20.1) \n\n Refractory to salvage therapy 87 (32.1) 34 (25.4) \n\nMaximum of central/local bone marrow \n\nblasts - n (%) \n \n\n ≥ 50% 201 (74.2) 104 (77.6) \nAlloHSCT = allogeneic haematopoietic stem cell transplantation \n\nSOC = standard of care \n\n \n\nBLINCYTO was administered as a continuous intravenous infusion. In the first cycle, the initial dose \n\nwas 9 mcg/day for week 1, then 28 mcg/day for the remaining 3 weeks. The target dose of \n\n28 mcg/day was administered in cycle 2 and subsequent cycles starting on day 1 of each cycle. Dose \n\nadjustment was possible in case of adverse events. Of the 267 patients who received BLINCYTO, \n\nthe mean number of completed treatment cycles was 2.0; of the 109 patients who received SOC \n\nchemotherapy, the mean number of treatment cycles was 1.3. \n\n \n\n\n\n18 \n\nThe primary endpoint was overall survival (OS). The median OS was 4.0 months (95% CI: 2.9, 5.3) \n\nin the SOC chemotherapy arm compared with 7.7 months (95% CI: 5.6, 9.6) in the BLINCYTO arm. \n\nThe hazard ratio (95% CI) was 0.71 (0.55, 0.93) between treatment arms favouring BLINCYTO, \n\nindicated a 29% reduction in hazard rate in the BLINCYTO arm (p-value = 0.012 (stratified log-rank \n\ntest)), see figure 1. Consistency in OS results was shown in subgroups by stratification factors. \n\n \n\nConsistent results were observed after censoring at the time of HSCT; median OS, censored at the \n\ntime of HSCT, was 6.9 months (95% CI: 5.3, 8.8) in the BLINCYTO group and 3.9 months \n\n(95% CI: 2.8, 4.9) in the SOC group (HR, 0.66; 95% CI: 0.50, 0.88; p value = 0.004). The mortality \n\nrate following alloHSCT among all responders who did not receive anti-leukemic therapy was \n\n10/38 (26.3%; 95% CI: 13.4, 43.1) in the BLINCYTO group and 3/12 (25%; 95% CI: 5.5, 57.2) in \n\nthe SOC group; such mortality rate at 100 days post alloHSCT was 4/38 (12.4%; 95% CI: 4.8%, \n\n29.9%) in the BLINCYTO group and 0/12 (0%; 95% CI: not estimable) in the SOC group. Efficacy \n\nresults from other key endpoints in the study are summarised in table 2. \n\n \n\nFigure 1. Kaplan-Meier curve of overall survival \n\n \n\n \n \n\n \n\n \n\nTable 2. Efficacy results in patients ≥ 18 years of age with Philadelphia chromosome negative \n\nrelapsed or refractory B-cell precursor ALL \n\n \n\n BLINCYTO \n\n(N = 271) \n\nSOC chemotherapy \n\n(N = 134) \n\nComplete remission (CR) \n\nCRa/CRh*b/CRic, n (%) [95% CI] \n119 (43.9) (37.9, 50.0) 33 (24.6) (17.6, 32.8) \n\nTreatment difference [95% CI] 19.3 (9.9, 28.7) \n\np-value < 0.001 \n\nCR, n (%) [95% CI] 91 (33.6) (28.0, 39.5) 21 (15.7) (10.0, 23.0) \n\nTreatment difference [95% CI] 17.9 (9.6 - 26.2) \n\np-value < 0.001 \n\nEvent-free survivald \n\n6-month estimate % [95% CI] 30.7 (25.0, 36.5) 12.5 (7.2, 19.2) \n\n18-months estimate % [95% CI] 9.5 (5.1, 15.6) 7.9 (3.7, 14.2) \n\nHR [95% CI] 0.55 (0.43, 0.71) \n\n \n\nNumber of subjects at Risk \n\nMonths \n\n1.0 \n\n0.9 \n\n0.8 \n\n0.7 \n\n0.6 \n\n0.5 \n\n0.4 \n\n0.3 \n\n0.2 \n\n0.1 \n\n0.0 \n\n \n\nS\nur\n\nvi\nva\n\nl P\nro\n\nba\nbi\n\nlit\ny \n\nMedian OS, mo 7.7 (5.6, 9.6) 4.0 (2.9, 5.3) \nHR (BLINCYTO/SOC Chemo) (95% CI) 0.71 (0.55, 0.93) \np-value (2-sided) 0.012 \n\n \n\nBLINCYTO 271 176 124 79 45 27 9 4 0 0 \n\nSOC Chemo 134 71 41 27 17 7 4 1 0 0 \n\n \n\n0 3 6 9 12 15 18 21 24 27 \n\n \n\nBLINCYTO (N=271) SOC Chemo (N=134) \n\n BLINCYTO SOC Chemo \n\nA censored subject is indicated by a Vertical Bar l. GRH0358 v1 \n\n\n\n19 \n\n BLINCYTO \n\n(N = 271) \n\nSOC chemotherapy \n\n(N = 134) \n\nDuration of haematological response- \n\nMedian time to event [95% CI] \n\nCR 8.3 (5.7, 10.7) 7.8 (2.2, 19.0) \n\nCR/CRh*/CRi 7.3 (5.8, 9.9) 4.6 (1.8, 19.0) \n\nMRDe response for CR/CRh*/CRi \n\nMRD evaluable patients (%) \n\n[95% CI]f \n74/97 (76.3) (66.6, 84.3) \n\n16/33 (48.5) (30.8, \n\n66.5) \n\nDuration of MRD response- \n\nMedian time to event [95% CI] \n4.5 months (3.6, 9.0) 3.8 months (1.9, 19.0) \n\nPostbaseline alloHSCT - n (%) \n\nOverall subjects 65 (24) 32 (23.9) \n\nHematological responders \n\n(CR/CRh*/CRi) \n50 (42.0) 18 (54.5) \n\nTime to alloHSCT among all \n\ntransplanted patients \n\nMedian time to event \n\n(Interquartile range) \n\n3.7 months (3.0, 5.3) \n\n(N = 65) \n\n3.1 months (2.6, 4.3) \n\n(N = 32) \n\nTime to alloHSCT among \n\nCR/CRh*/CRi responders \n\nMedian time to event [95% CI] \n\n(KM estimate) \n\n11.3 months (5.2, NE) \n\n(N = 119) \n\n3.6 months (2.3, 7.2) \n\n(N = 33) \n\n100 day mortality after alloHSCT \n\nn/N (%), [95% CI] 4/38, 12.4% (4.8, 29.9) 0/12, 0.0% (0.0, NE) \na. CR was defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral \n\nblood counts (platelets > 100,000/microlitre and absolute neutrophil counts [ANC] > 1,000/microlitre). \nb. CRh* (complete remission with partial haematologic recovery) was defined as ≤ 5% blasts in the bone \n\nmarrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50,000/microlitre \n\nand ANC > 500/microlitre). \nc. CRi (complete remission with incomplete haematologic recovery) was defined as ≤ 5% blasts in the bone \n\nmarrow, no evidence of disease, and incomplete recovery of peripheral blood counts (platelets \n\n> 100,000/microlitre or ANC > 1,000/microlitre). \nd. EFS time was calculated from the time of randomisation until the date of disease assessment indicating a \n\nrelapse after achieving a CR/CRh*/CRi or death, whichever is earlier. Subjects who fail to achieve a \n\nCR/CRh*/CRi within 12 weeks of treatment initiation are considered treatment failures and assigned an EFS \n\nduration of 1 day. \ne. MRD (minimum residual disease) response was defined as MRD by PCR or flow cytometry < 1 x 10-4. \nf. Patients who achieved CR/CRh*/CRi and had an evaluable post baseline MRD assessment. \n \n\nHealth related quality of life \n\n \n\nIn this open-label study, Health related quality of life (HRQoL) reported by patients were measured \n\nusing the European Organisation for Research and Treatment of Cancer Quality of Life \n\nQuestionnaire - Core 30 (EORTC QLQ-C30). In a post-hoc sensitivity analysis, compared to SOC, \n\nBLINCYTO consistently delayed the time to clinically meaningful deterioration of HRQoL \n\n(≥ 10-point worsening from baseline) for global health status [median BLINCYTO versus SOC: \n\n8.1 months versus 1.0 month; HR = 0.60 (95% CI = 0.42, 0.85)], functional scales, symptom scales \n\nand individual items. Because the health-related quality of life results are based on a post-hoc \n\nsensitivity analysis, the results should be interpreted with caution. \n\n \n\nBLINCYTO was also evaluated in an open-label, multicentre, single-arm phase II study of \n\n189 patients. Eligible patients were ≥ 18 years of age with Philadelphia chromosome negative \n\nrelapsed or refractory B-precursor ALL (relapsed with first remission duration of ≤ 12 months in first \n\nsalvage, or relapsed or refractory after first salvage therapy, or relapsed within 12 months of \n\nallogeneic HSCT, and had ≥ 10% blasts in bone marrow). \n\n \n\n\n\n20 \n\nPremedication, BLINCYTO dose per treatment cycle and route of administration were identical to \n\nthose in the phase III study. Patients were premedicated with a mandatory cerebrospinal fluid \n\nprophylaxis consisting of an intrathecal regimen according to institutional or national guidelines \n\nwithin 1 week prior to start of BLINCYTO treatment. BLINCYTO was administered as a continuous \n\nintravenous infusion. In the first cycle, the initial dose was 9 mcg/day for week 1, then 28 mcg/day \n\nfor the remaining 3 weeks. The target dose of 28 mcg/day was administered in cycle 2 and \n\nsubsequent cycles starting on day 1 of each cycle. Dose adjustment was possible in the case of \n\nadverse events. The treated population included 189 patients who received at least 1 infusion of \n\nBLINCYTO; the mean number of cycles per patient was 1.6. Patients who responded to BLINCYTO \n\nbut later relapsed had the option to be retreated with BLINCYTO. Among treated patients, the \n\nmedian age was 39 years (range: 18 to 79 years, including 25 patients ≥ 65 years of age), 64 of \n\n189 (33.9%) had undergone HSCT prior to receiving BLINCYTO and 32 of 189 (16.9%) had \n\nreceived more than 2 prior salvage therapies. \n\n \n\nThe primary endpoint was the complete remission/complete remission with partial haematological \n\nrecovery (CR/CRh*) rate within 2 cycles of treatment with BLINCYTO. Eighty-one of 189 (42.9%) \n\npatients achieved CR/CRh* within the first 2 treatment cycles with the majority of responses (64 of \n\n81) occurring within 1 cycle of treatment. In the elderly population (≥ 65 years of age) 11 of \n\n25 patients (44.0%) achieved CR/CRh* within the first 2 treatment cycles (see section 4.8 for safety \n\nin elderly). Four patients achieved CR during consolidation cycles, resulting in a cumulative CR rate \n\nof 35.4% (67/189; 95% CI: 28.6% - 42.7%). Thirty-two of 189 (17%) patients underwent allogeneic \n\nHSCT in CR/CRh* induced with BLINCYTO (see table 3). \n\n \n\nTable 3. Efficacy results in patients ≥ 18 years of age with Philadelphia chromosome negative \n\nrelapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL) \n \n\n n (%) \n\nn = 189 \n\n95% CI \n\nComplete remission (CR)1/Complete remission \n\nwith partial haematological recovery (CRh*)2 \n\n81 (42.9%) [35.7% - 50.2%] \n\nCR 63 (33.3%) [26.7% - 40.5%] \n\nCRh* 18 (9.5%) [5.7% - 14.6%] \n\nBlast free hypoplastic or aplastic bone marrow3 17 (9%) [5.3% - 14.0%] \n\nPartial remission4 5 (2.6%) [0.9% - 6.1%] \n\nRelapse5-free survival (RFS) for CR/CRh* 5.9 months [4.8 to 8.3 months] \n\nOverall survival 6.1 months [4.2 to 7.5 months] \n1. CR was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheral \n\nblood counts (platelets > 100,000/microlitre and absolute neutrophil counts [ANC] > 1,000/microlitre). \n2. CRh* was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and partial recovery of \n\nperipheral blood counts (platelets > 50,000/microlitre and ANC > 500/microlitre). \n3. Blast free hypoplastic or aplastic bone marrow was defined as bone marrow blasts ≤ 5%, no evidence of \n\ndisease, insufficient recovery of peripheral blood counts: platelets ≤ 50,000/microlitre and/or ANC \n\n≤ 500/microlitre. \n4. Partial remission was defined as bone marrow blasts 6% to 25% with at least a 50% reduction from baseline. \n5. Relapse was defined as haematological relapse (blasts in bone marrow greater than 5% following CR) or an \n\nextramedullary relapse. \n \n\nIn a prespecified exploratory analysis, 60 of 73 MRD evaluable patients with CR/CRh* (82.2%) also \n\nhad a MRD response (defined as MRD by PCR < 1 x 10-4). \n\n \n\nPatients with prior allogeneic HSCT had similar response rates to those without prior HSCT, older \n\npatients had similar response rates to younger patients, and no substantial difference was observed in \n\nremission rates based on the number of lines of prior salvage treatment. \n\n \n\nIn patients with non-CNS/non-testes extramedullary disease (defined as at least 1 lesion ≥ 1.5 cm) at \n\nscreening (N = 8/189) clinical response rates (25% [95% CI: 3.2-65.1] were lower compared with \n\npatients with no evidence of extramedullary disease (N = 181, 43.6% [95% CI: 36.3 - 51.2]) (see \n\nfigure 2). \n\n\n\n21 \n\n \n\nPatients with the highest tumour burden as measured by the percentage of bone marrow blast cells at \n\nbaseline (≥ 90%) still had a clinically meaningful response with a CR/CRh* rate of 21.6% (CI \n\n12.9 - 32.7) (see figure 2). Patients with low tumour burden (< 50%) responded best to BLINCYTO \n\ntreatment with CR/CRh* rate of 72.9% (CI 59.7 - 83.6). \n\n \n\nFigure 2. Forest plot of CR/CRh* rate during the first two cycles for study MT103-211 \n\n(primary analysis set) \n\n \n\n \nn = number of patients who achieved CR or CRh* in the first two cycles of treatment in the specified subgroup. \n\nN = total number of patients in the specified subgroup. \n\n \n\nThere is limited data in patients with late first relapse of B-precursor ALL defined as a relapse \n\noccurring more than 12 months after first remission or more than 12 months after HSCT in the first \n\nremission. In clinical phase II studies, 88.9% (8/9) of patients with late first relapse as defined in the \n\nindividual studies achieved CR/CRh* within the first 2 treatment cycles with 62.5% (6/9) achieving \n\nMRD response and 37.5% (3/9) undergoing allogeneic HSCT after treatment with BLINCYTO. The \n\nmedian overall survival (OS) was 17.7 months (CI 3.1 - not estimable). \n\n \n\nIn the randomised, open-label, multicentre, phase III study, 70% (7/10) of post-transplant patients in \n\nlate first relapse treated with BLINCYTO compared to 20% (1/5) treated with SOC chemotherapy \n\nachieved CR/CRh* within the first 2 treatment cycles. Fifty percent (5/10) compared to 0% (0/5) \n\nachieved MRD response and 20% (2/10) compared to 40% (2/5) underwent allogeneic HSCT after \n\ntreatment. The median OS was 15.6 months (CI 5.5 – not estimable) for the BLINCYTO group and \n\n5.3 months (CI 1.1 – not estimable) for the SOC chemotherapy group. \n\n \n\nMRD positive B-precursor ALL \n\n \n\nThe safety and efficacy of BLINCYTO in adult patients with MRD positive B-precursor ALL were \n\nevaluated in an open-label, multicentre, single-arm study. Eligible patients were ≥ 18 years of age \n\nwith no prior HSCT, had received at least 3 blocks of standard ALL induction therapy, were in \n\ncomplete haematologic remission (defined as < 5% blasts in bone marrow, absolute neutrophil count \n\n≥ 1,000/microlitres, platelets ≥ 50,000/microlitres, and haemoglobin level ≥ 9 g/dL) and had \n\nmolecular failure or molecular relapse (defined as MRD ≥ 10-3), see table 4. MRD status at screening \n\nwas determined from bone marrow aspirations using flow cytometry or polymerase chain reaction \n\n(PCR) at a minimum sensitivity of 10-4 based on local site evaluations. A central laboratory \n\nsubsequently confirmed MRD levels by PCR. Final interpretation of MRD results followed \n\nEuroMRD Consortium guidelines. \n\n0 20 40 60 80 100 \n\n \n\nSubgroup \n\nBone Marrow Blast Infiltration \n(Central Lab) \n\n<50% \n\n≥50% to <75% \n \n\n≥75% to <90% \n \n\n≥90% \n\nExtramedullary Disease at Baseline \n\nYes \n\nNo \n\n \n\nOverall \n\n \n\nPercent Achieving CR/CRh* \n\nRate and 95% Confidence Interval (CI) n/N Rate (95% CI) \n\n \n\n43/59 72.9% (59.7%-83.6%) \n\n8/25 32.0% (14.9%-53.5%) \n \n\n14/31 45.2% (27.3%-64.0%) \n \n\n16/74 21.6% (12.9%-32.7%) \n\n \n\n2/8 25.0% (3.2%-65.1%) \n\n79/181 43.6% (36.3%-51.2%) \n\n \n\n81/189 42.9% (35.7%-50.2%) \n\n \n\nGRH0148v2 \n\n\n\n22 \n\n \n\nTable 4. Demographics and baseline characteristics in MRD study \n\n \n\nCharacteristic \nBLINCYTO \n\n(N = 116) \n\nAge \n\nMedian, years (min, max) 45 (18, 76) \n\nMean, years (SD) 44.6 (16.4) \n\n≥ 65 years, n (%) 15 (12.9) \n\nMales, n (%) 68 (58.6) \n\nRace, n (%) \n\n Asian 1 (0.9) \n\n Other (mixed) 1 (0.9) \n\n White 102 (87.9) \n\n Unknown 12 (10.3) \n\nRelapse history n (%) \n\nPatients in 1st CR 75 (64.7) \n\nPatients in 2nd CR 39 (33.6) \n\nPatients in 3rd CR 2 (1.7) \n\nMRD level at baseline* n (%) \n\n≥ 10-1 and < 1 9 (7.8) \n\n≥ 10-2 and < 10-1 45 (38.8) \n\n≥ 10-3 and < 10-2 52 (44.8) \n\n< 10-3 3 (2.6) \n\nBelow lower limit of quantification 5 (4.3) \n\nUnknown 2 (1.7) \n* Centrally assessed in an assay with minimum sensitivity of 10-4 \n\n \n\nBLINCYTO was administered as a continuous intravenous infusion. Patients received BLINCYTO \n\nat a constant dose of 15 mcg/m2/day (equivalent to the recommended dosage of 28 mcg/day) for all \n\ntreatment cycles. Patients received up to 4 cycles of treatment. Dose adjustment was possible in case \n\nof adverse events. The treated population included 116 patients who received at least one infusion of \n\nBLINCYTO; the mean number of completed treatment cycles was 1.8 (range: 1 to 4). \n\n \n\nThe primary endpoint was the proportion of patients who achieved a complete MRD response within \n\none cycle of BLINCYTO treatment. Eighty-eight out of 113 (77.9%) evaluable patients achieved a \n\ncomplete MRD response after one cycle of treatment; see table 5. Two subjects achieved a complete \n\nMRD response with 1 additional cycle of BLINCYTO. MRD response rates by age and MRD level \n\nat baseline subgroups were consistent with the results in the overall population. RFS in patients with \n\nPhiladelphia chromosome negative B-precursor ALL at 18 months censored at HSCT or post-\n\nBLINCYTO chemotherapy was 54% (33%, 70%). RFS at 18 months not censored at HSCT or post-\n\nBLINCYTO chemotherapy was 53% (44%, 62%). \n\n \n\nTable 5. Efficacy results in patients ≥ 18 years of age with MRD positive B-precursor ALL \n\n \n\nComplete MRD responsea, n/N (%), [95% CI] 88/113b (77.9) [69.1, 85.1] \n\n≥ 65 years old 12/15 (80.0) [51.9-95.7] \n\nPatients in 1st CR 60/73 (82.2) [71.5-90.2] \n\nPatients in 2nd CR 27/38 (71.1) [54.1-84.6] \n\nPatients in 3rd CR 1/2 (50.0) [1.3-98.7] \n\nDuration of complete MRD response [95% CI] 17.3 months [12.6, 23.3] \na Complete MRD response was defined as the absence of detectable MRD confirmed in an assay with minimum sensitivity \n\nof 10-4 \nb One hundred thirteen patients (97.4%; 113/116) were included in the primary endpoint full analysis set \n\n \n\n\n\n23 \n\nPaediatric population \n\n \n\nThe safety and efficacy of BLINCYTO were evaluated in an open-label, multicentre, single-arm \n\nstudy in 93 paediatric patients with relapsed or refractory B-precursor ALL (second or later bone \n\nmarrow relapse, in any marrow relapse after allogeneic HSCT, or refractory to other treatments, and \n\nalso with > 25% blasts in bone marrow). This was a two-part study, a dose-finding part to determine \n\nthe appropriate dosing regimen, followed by a single-arm efficacy part using this regimen. \n\n \n\nBLINCYTO was administered as a continuous intravenous infusion. In the dose-finding part of the \n\nstudy, doses of up to 30 mcg/m2/day were evaluated. The recommended dose for the PK expansion \n\nand efficacy parts of the study was determined to be 5 mcg/m2/day on days 1-7 and 15 mcg/m2/day \n\non days 8-28 for cycle 1, and 15 mcg/m2/day on days 1-28 for subsequent cycles. Dose adjustment \n\nwas possible in case of adverse events. Patients who responded to BLINCYTO but later relapsed had \n\nthe option to be retreated with BLINCYTO. \n\n \n\nThe treated population (in the dose-finding, PK expansion, and efficacy parts) included 70 patients \n\nwho received at least 1 infusion of BLINCYTO at the recommended dose; the mean number of \n\ntreatment cycles was 1.5. Among treated patients, the median age was 8 years (range: 7 months to \n\n17 years), 40 out of 70 (57.1%) had undergone allogeneic HSCT prior to receiving BLINCYTO, and \n\n39 out of 70 (55.7%) had refractory disease. Most patients had a high tumour burden (≥ 50% \n\nleukaemic blasts in bone marrow) at baseline with a median of 75.5% bone marrow blasts. \n\n \n\nTwenty out of 70 (28.6%) patients achieved CR/CRh* within the first 2 treatment cycles with 17 out \n\nof 20 (85%) occurring within cycle 1 of treatment. Four patients achieved M1 bone marrow but did \n\nnot meet the peripheral blood count recovery criteria for CR or CRh*. Eleven of the 20 patients \n\n(55%) who achieved CR/CRh* received an allogeneic HSCT. The CR/CRh* for patients less than \n\n2 years of age was 40% (4/10), for patients 2 to 6 years was 30.0% (6/20); and for patients aged 7 to \n\n17 years was 25% (10/40). 3 patients < 1 year of age refractory to prior treatment and without prior \n\nalloHSCT received one cycle of Blincyto at a dose of 5-15 µg/m2/day. None of the 3 subjects \n\n< 1 year old achieved a CR/CRh*, 1 patient had progressive disease (OS 2.3 months) and 2 were \n\nnon-responders (OS 1.1 months and 8.7 months, respectively). The type of adverse events observed \n\nin infants were similar to those observed in the overall paediatric population. See table 6 for the \n\nefficacy results. \n\n \n\nTable 6. Efficacy results in patients < 18 years of age with relapsed or refractory B-cell \n\nprecursor ALL \n\n \n\n N = 70 \n\nCRa/CRh*b, n (%) [95% CI] 20 (28.6%) [18.4% – 40.6%] \n\nCR, n (%) [95% CI] 11 (15.7%) [8.1% – 26.4%] \n\nCRh*, n (%) [95% CI] 9 (12.9%) [6.1% – 23.0%] \n\nComplete MRD response for CR /CRh*c, n1/n2d (%) [95% CI] 11/20 (55.0%) [31.5 – 76.9] \n\nCR, n1/n2d (%) [95% CI] 6/11 (54.5%) [23.4 – 83.3] \n\nCRh*, n1/n2d (%) [95% CI] 5/9 (55.6%) [21.2 – 86.3] \n\nMedian relapsee-free survival (RFS)e for CR /CRh* [95% CI] 6.8 months [2.2 to 12.0 months] \n\nMedian overall survival [95% CI] 7.5 months [4.0 to 11.8 months] \n\n100-day mortality after alloHSCTf \n\nn/N (%), [95% CI] 1/6 (16.7%) [2.5% – 72.7%] \na. CR was defined as M1 marrow (≤ 5% of blasts in the bone marrow), no evidence of circulating blasts or extramedullary \n\ndisease, and full recovery of peripheral blood counts (platelets > 100,000/microlitre and absolute neutrophil counts [ANC] \n\n> 1,000/microlitre) and no relapse within 28 days. \nb. CRh*was defined as M1 marrow (≤ 5% of blasts in the bone marrow), no evidence of circulating blasts or extramedullary \n\ndisease, and partial recovery of peripheral blood counts (platelets > 50,000/microlitre and ANC > 500/microlitre) and no \n\nrelapse within 28 days. \nc. Complete MRD response No detectable signal for leukemic cells either by PCR or flow cytometry. \n\n\n\n24 \n\nd. n1: number of patients who achieved MRD response and the respective remission status; n2: number of patients who \n\nachieved the respective remission status. One CR /CRh*responder with missing MRD data was considered as a MRD-\n\nnonresponder. \n\ne. Relapse was defined as haematological relapse (blasts in bone marrow greater than 25% following CR) or an \n\nextramedullary relapse. \n\nf. Only patients with HSCT in CR/CRh* remission (with no anti-leukemia agents used prior to HSCT) are included. \n\n \n\n5.2 Pharmacokinetic properties \n\n \n\nThe pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 90 mcg/m2/day \n\n(approximately equivalent to 9-162 mcg/day) in adult patients. Following continuous intravenous \n\ninfusion, the steady state serum concentration (Css) was achieved within a day and remained stable \n\nover time. The increase in mean Css values was approximately proportional to the dose in the range \n\ntested. At the clinical doses of 9 mcg/day and 28 mcg/day for the treatment of relapsed/refractory \n\nALL, the mean (SD) Css was 230 (359) pg/mL and 612 (532) pg/mL, respectively. The \n\npharmacokinetics of blinatumomab in patients with MRD positive B-precursor ALL was similar to \n\npatients with relapsed or refractory ALL. \n\n \n\nDistribution \n\n \n\nThe estimated mean (SD) volume of distribution based on terminal phase (Vz) was 4.52 (2.89) L \n\nwith the continuous intravenous infusion of blinatumomab. \n\n \n\nBiotransformation \n\n \n\nThe metabolic pathway of blinatumomab has not been characterised. Like other protein therapeutics, \n\nblinatumomab is expected to be degraded into small peptides and amino acids via catabolic \n\npathways. \n\n \n\nElimination \n\n \n\nThe estimated mean (SD) systemic clearance with continuous intravenous infusion in patients \n\nreceiving blinatumomab in clinical studies was 2.92 (2.83) L/hour. The mean (SD) half-life was \n\n2.11 (1.42) hours. Negligible amounts of blinatumomab were excreted in the urine at the tested \n\nclinical doses. \n\n \n\nBody surface area, gender and age \n\n \n\nA population pharmacokinetic analysis was performed to evaluate the effects of demographic \n\ncharacteristics on blinatumomab pharmacokinetics. Results suggest that age (7 months to 80 years) \n\nand gender do not influence the pharmacokinetics of blinatumomab. Body surface area (0.37 to \n\n2.70 m2) influences the pharmacokinetics of blinatumomab. However the influence is negligible in \n\nadults and body surface area based dosing is recommended in the paediatric population. \n\n \n\nRenal impairment \n\n \n\nNo formal pharmacokinetic studies of blinatumomab have been conducted in patients with renal \n\nimpairment. \n\n \n\nPharmacokinetic analyses showed an approximately 2-fold difference in mean blinatumomab \n\nclearance values between patients with moderate renal dysfunction and normal renal function. \n\nHowever high inter-patient variability was discerned (CV% up to 95.6%), and clearance values in \n\nrenal impaired patients were essentially within the range observed in patients with normal renal \n\nfunction, no clinically meaningful impact of renal function on clinical outcomes is expected. \n\n \n\n\n\n25 \n\nHepatic impairment \n\n \n\nNo formal pharmacokinetic studies of blinatumomab have been conducted in patients with hepatic \n\nimpairment. Baseline ALT and AST levels were used to assess the effect of hepatic impairment on \n\nthe clearance of blinatumomab. Population pharmacokinetic analysis suggested that there was no \n\nassociation between ALT or AST levels and the clearance of blinatumomab. \n\n \n\nPaediatric population \n\n \n\nThe pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 30 mcg/m2/day in \n\npaediatric patients. At the recommended doses, the mean (SD) steady state concentration (Css) \n\nvalues were 162 (179) and 533 (392) pg/mL at 5 and 15 mcg/m2/day doses, respectively. The \n\nestimated mean (SD) volume of distribution (Vz), clearance (CL) and terminal half-life (t1/2,z) were \n\n3.91 (3.36) L/m2, 1.88 (1.90) L/hr/m2 and 2.19 (1.53) hours, respectively. \n\n \n\n5.3 Preclinical safety data \n\n \n\nRepeat-dose toxicity studies conducted with blinatumomab and the murine surrogate revealed the \n\nexpected pharmacologic effects (including release of cytokines, decreases in leukocyte counts, \n\ndepletion of B-cells, decreases in T-cells, decreased cellularity in lymphoid tissues). These changes \n\nreversed after cessation of treatment. \n\n \n\nReproductive toxicity studies have not been conducted with blinatumomab. In an embryo-foetal \n\ndevelopmental toxicity study performed in mice, the murine surrogate crossed the placenta to a limited \n\nextent (foetal-to-maternal serum concentration ratio < 1%) and did not induce embryo-foetal toxicity or \n\nteratogenicity. The expected depletions of B- and T-cells were observed in the pregnant mice but \n\nhaematological effects were not assessed in foetuses. No studies have been conducted to evaluate \n\ntreatment-related effects on fertility. There were no effects on male or female reproductive organs in \n\ntoxicity studies with the murine surrogate. \n\n \n\n \n\n6. PHARMACEUTICAL PARTICULARS \n\n \n\n6.1 List of excipients \n\n \n\nPowder \n\n \n\nCitric acid monohydrate (E330) \n\nTrehalose dihydrate \n\nLysine hydrochloride \n\nPolysorbate 80 \n\nSodium hydroxide (for pH-adjustment) \n\n \n\nSolution (stabiliser) \n\n \n\nCitric acid monohydrate (E330) \n\nLysine hydrochloride \n\nPolysorbate 80 \n\nSodium hydroxide (for pH-adjustment) \n\nWater for injections \n\n \n\n6.2 Incompatibilities \n\n \n\nThis medicinal product must not be mixed with other medicinal products except those mentioned in \n\nsection 6.6. \n\n \n\n\n\n26 \n\n6.3 Shelf life \n\n \n\nUnopened vials \n\n \n\n5 years \n\n \n\nReconstituted solution \n\n \n\nChemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C or 4 hours at \n\nor below 27°C. \n\n \n\nFrom a microbiological point of view, unless the method of reconstituting precludes the risks of \n\nmicrobial contamination, the reconstituted solution should be diluted immediately. If not diluted \n\nimmediately, in-use storage times and conditions are the responsibility of the user. \n\n \n\nDiluted solution (prepared infusion bag) \n\n \n\nChemical and physical in-use stability has been demonstrated for 10 days at 2°C - 8°C or 96 hours at \n\nor below 27°C. \n\n \n\nFrom a microbiological point of view, the prepared infusion bags should be used immediately. If not \n\nused immediately, in-use storage times and conditions prior to use are the responsibility of the user \n\nand would normally not be longer than 24 hours at 2°C - 8°C, unless dilution has taken place in \n\ncontrolled and validated aseptic conditions. \n\n \n\n6.4 Special precautions for storage \n\n \n\nStore and transport refrigerated (2°C - 8°C). \n\nDo not freeze. \n\nStore the vials in the original package in order to protect from light. \n\n \n\nFor storage conditions after reconstitution and dilution of the medicinal product, see section 6.3. \n\n \n\n6.5 Nature and contents of container \n\n \n\nEach BLINCYTO pack contains 1 vial of powder for concentrate for solution for infusion and 1 vial \n\nof solution (stabiliser): \n\n• 38.5 micrograms blinatumomab powder in a vial (type I glass) with a stopper (elastomeric \nrubber), seal (aluminium) and a flip off cap and \n\n• 10 mL solution in a vial (type I glass) with a stopper (elastomeric rubber), seal (aluminium) \nand a flip off cap. \n\n \n\n6.6 Special precautions for disposal and other handling \n\n \n\nAseptic preparation \n \n\nAseptic handling must be ensured when preparing the infusion. Preparation of BLINCYTO should \n\nbe: \n- performed under aseptic conditions by trained personnel in accordance with good practice \n\nrules especially with respect to the aseptic preparation of parenteral products. \n- prepared in a laminar flow hood or biological safety cabinet using standard precautions for the \n\nsafe handling of intravenous agents. \n\n \n\nIt is very important that the instructions for preparation and administration provided in this section \n\nare strictly followed to minimise medication errors (including underdose and overdose). \n\n \n\n\n\n27 \n\nSpecial instructions to support accurate preparation \n\n \n\n• A solution (stabiliser) is provided inside the BLINCYTO package and is used to coat the pre-\nfilled infusion bag prior to addition of reconstituted BLINCYTO. Do not use this solution \n\n(stabiliser) for reconstitution of BLINCYTO powder for concentrate. \n\n• The entire volume of the reconstituted and diluted BLINCYTO will be more than the volume \nto be administered to the patient (240 mL). This is to account for intravenous infusion line loss \n\nand to assure that the patient will receive the full dose of BLINCYTO. \n\n• When preparing an infusion bag, remove all air from infusion bag. This is particularly \nimportant when using an ambulatory infusion pump. \n\n• Use the specific volumes described in the reconstitution and dilution instructions below to \nminimise errors in calculation. \n\n \n\nOther instructions \n\n \n\n• BLINCYTO is compatible with polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or \nethyl vinyl acetate (EVA) infusion bags/pump cassettes. \n\n• Pump specifications: The infusion pump to administer BLINCYTO solution for infusion \nshould be programmable, lockable and have an alarm. Elastomeric pumps should not be used. \n\n• Any unused medicinal product or waste material should be disposed of in accordance with \nlocal requirements. \n\n \n\nPreparation of the solution for infusion \n\n \n\nSpecific reconstitution and dilution instructions are provided for each dose and infusion time. Verify \n\nthe prescribed dose and infusion time of BLINCYTO and identify the appropriate dosing preparation \n\nsection listed below. Table 7 provides instructions for patients weighing greater than or equal to \n\n45 kg, whereas table 8 and table 9 provide instructions for patients weighing less than 45 kg. Follow \n\nthe steps for reconstituting BLINCYTO and preparing the infusion bag detailed below table 9. \n\n \n\nTable 7. For patients weighing greater than or equal to 45 kg: volumes of sodium chloride \n\n9 mg/mL (0.9%) solution for injection, solution (stabiliser), and reconstituted BLINCYTO to \n\nadd to infusion bag \n\n \n\nSodium chloride 9 mg/mL (0.9%) solution for injection (starting volume) \n\n250 mL \n\n(usual overfill \n\nvolume of 265 to \n\n275 mL) \n\nSolution (stabiliser) 5.5 mL \n\nDose Infusion duration Infusion rate \n\nReconstituted \n\nBLINCYTO \n\n(number of \n\npackages) \n\n9 mcg/day \n\n24 hours 10 mL/hour 0.83 mL (1) \n\n48 hours 5 mL/hour 1.7 mL (1) \n\n72 hours 3.3 mL/hour 2.5 mL (1) \n\n96 hours 2.5 mL/hour 3.3 mL (2) \n\n28 mcg/day \n\n24 hours 10 mL/hour 2.6 mL (1) \n\n48 hours 5 mL/hour 5.2 mL (2) \n\n72 hours 3.3 mL/hour 8 mL (3) \n\n96 hours 2.5 mL/hour 10.7 mL (4) \n\n \n\n\n\n28 \n\nTable 8. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) \n\nsolution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion \n\nbag for 5 mcg/m2/day dose \n\n \n\nSodium chloride 9 mg/mL (0.9%) solution for injection (starting \n\nvolume) \n\n250 mL (usual overfill volume \n\nof 265 to 275 mL) \n\nSolution (stabiliser) 5.5 mL \n\nDose Infusion duration Infusion rate BSA (m2) \nReconstituted BLINCYTO \n\n(number of packages) \n\n5 mcg/m2/day \n\n24 hours 10 mL/hour \n\n1.50 – 1.59 0.70 mL (1) \n\n1.40 – 1.49 0.66 mL (1) \n\n1.30 – 1.39 0.61 mL (1) \n\n1.20 – 1.29 0.56 mL (1) \n\n1.10 – 1.19 0.52 mL (1) \n\n1.00 – 1.09 0.47 mL (1) \n\n0.90 – 0.99 0.43 mL (1) \n\n0.80 – 0.89 0.38 mL (1) \n\n0.70 – 0.79 0.33 mL (1) \n\n0.60 – 0.69 0.29 mL (1) \n\n0.50 – 0.59 0.24 mL (1) \n\n0.40 – 0.49 0.20 mL (1) \n\n \n\n48 hours 5 mL/hour \n\n1.50 – 1.59 1.4 mL (1) \n\n1.40 – 1.49 1.3 mL (1) \n\n1.30 – 1.39 1.2 mL (1) \n\n1.20 – 1.29 1.1 mL (1) \n\n1.10 – 1.19 1.0 mL (1) \n\n1.00 – 1.09 0.94 mL (1) \n\n0.90 – 0.99 0.85 mL (1) \n\n0.80 – 0.89 0.76 mL (1) \n\n0.70 – 0.79 0.67 mL (1) \n\n0.60 – 0.69 0.57 mL (1) \n\n0.50 – 0.59 0.48 mL (1) \n\n0.40 – 0.49 0.39 mL (1) \n\n \n\n72 hours 3.3 mL/hour \n\n1.50 – 1.59 2.1 mL (1) \n\n1.40 – 1.49 2.0 mL (1) \n\n1.30 – 1.39 1.8 mL (1) \n\n1.20 – 1.29 1.7 mL (1) \n\n1.10 – 1.19 1.6 mL (1) \n\n1.00 – 1.09 1.4 mL (1) \n\n0.90 – 0.99 1.3 mL (1) \n\n0.80 – 0.89 1.1 mL (1) \n\n0.70 – 0.79 1 mL (1) \n\n0.60 – 0.69 0.86 mL (1) \n\n0.50 – 0.59 0.72 mL (1) \n\n0.40 – 0.49 0.59 mL (1) \n\n \n\n96 hours 2.5 mL/hour \n\n1.50 – 1.59 2.8 mL (1) \n\n1.40 – 1.49 2.6 mL (1) \n\n1.30 – 1.39 2.4 mL (1) \n\n1.20 – 1.29 2.3 mL (1) \n\n1.10 – 1.19 2.1 mL (1) \n\n1.00 – 1.09 1.9 mL (1) \n\n0.90 – 0.99 1.7 mL (1) \n\n0.80 – 0.89 1.5 mL (1) \n\n0.70 – 0.79 1.3 mL (1) \n\n0.60 – 0.69 1.2 mL (1) \n\n0.50 – 0.59 0.97 mL (1) \n\n0.40 – 0.49 0.78 mL (1) \n\n\n\n29 \n\nTable 9. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) \n\nsolution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion \n\nbag for 15 mcg/m2/day dose \n\n \n\nSodium chloride 9 mg/mL (0.9%) (starting volume) 250 mL (usual overfill volume \n\nof 265 to 275 mL) \n\nSolution (stabiliser) 5.5 mL \n\nDose Infusion duration Infusion rate BSA (m2) \nReconstituted BLINCYTO \n\n(number of packages) \n\n15 mcg/m2/day \n\n24 hours 10 mL/hour \n\n1.50 – 1.59 2.1 mL (1) \n\n1.40 – 1.49 2.0 mL (1) \n\n1.30 – 1.39 1.8 mL (1) \n\n1.20 – 1.29 1.7 mL (1) \n\n1.10 – 1.19 1.6 mL (1) \n\n1.00 – 1.09 1.4 mL (1) \n\n0.90 – 0.99 1.3 mL (1) \n\n0.80 – 0.89 1.1 mL (1) \n\n0.70 – 0.79 1.00 mL (1) \n\n0.60 – 0.69 0.86 mL (1) \n\n0.50 – 0.59 0.72 mL (1) \n\n0.40 – 0.49 0.59 mL (1) \n\n \n\n48 hours 5 mL/hour \n\n1.50 – 1.59 4.2 mL (2) \n\n1.40 – 1.49 3.9 mL (2) \n\n1.30 – 1.39 3.7 mL (2) \n\n1.20 – 1.29 3.4 mL (2) \n\n1.10 – 1.19 3.1 mL (2) \n\n1.00 – 1.09 2.8 mL (1) \n\n0.90 – 0.99 2.6 mL (1) \n\n0.80 – 0.89 2.3 mL (1) \n\n0.70 – 0.79 2.0 mL (1) \n\n0.60 – 0.69 1.7 mL (1) \n\n0.50 – 0.59 1.4 mL (1) \n\n0.40 – 0.49 1.2 mL (1) \n\n \n\n72 hours 3.3 mL/hour \n\n1.50 – 1.59 6.3 mL (3) \n\n1.40 – 1.49 5.9 mL (3) \n\n1.30 – 1.39 5.5 mL (2) \n\n1.20 – 1.29 5.1 mL (2) \n\n1.10 – 1.19 4.7 mL (2) \n\n1.00 – 1.09 4.2 mL (2) \n\n0.90 – 0.99 3.8 mL (2) \n\n0.80 – 0.89 3.4 mL (2) \n\n0.70 – 0.79 3.0 mL (2) \n\n0.60 – 0.69 2.6 mL (1) \n\n0.50 – 0.59 2.2 mL (1) \n\n0.40 – 0.49 1.8 mL (1) \n\n \n\n96 hours 2.5 mL/hour \n\n1.50 – 1.59 8.4 mL (3) \n\n1.40 – 1.49 7.9 mL (3) \n\n1.30 – 1.39 7.3 mL (3) \n\n1.20 – 1.29 6.8 mL (3) \n\n1.10 – 1.19 6.2 mL (3) \n\n1.00 – 1.09 5.7 mL (3) \n\n0.90 – 0.99 5.1 mL (2) \n\n0.80 – 0.89 4.6 mL (2) \n\n0.70 – 0.79 4.0 mL (2) \n\n0.60 – 0.69 3.4 mL (2) \n\n0.50 – 0.59 2.9 mL (2) \n\n0.40 – 0.49 2.3 mL (1) \n\n\n\n30 \n\nBSA = body surface area \n\n \n\nThese supplies are also required, but not included in the package \n\n• Sterile single-use disposable syringes \n\n• 21-23 gauge needle(s) (recommended) \n\n• Water for injections \n\n• Infusion bag with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection; \no To minimise the number of aseptic transfers, use a 250 mL pre-filled infusion bag. \n\nBLINCYTO dose calculations are based on a usual overfill volume of 265 to \n\n275 mL sodium chloride 9 mg/mL (0.9%) solution for injection. \n\no Use only polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl \nacetate (EVA) infusion bags/pump cassettes. \n\n• Polyolefin, PVC non-DEHP, or EVA intravenous tubing with a sterile, non-pyrogenic, low \nprotein-binding 0.2 micrometre in-line filter. \n\no Ensure that the tubing is compatible with the infusion pump. \n \n\nReconstitution and preparation of BLINCYTO solution for infusion using an infusion bag pre-filled \n\nwith 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection \n\n \n\n1. Use an infusion bag pre-filled with 250 mL sodium chloride 9 mg/mL (0.9%) solution for \ninjection that usually contains a total volume of 265 to 275 mL. \n\n2. To coat the infusion bag, using a syringe, aseptically transfer 5.5 mL of the solution \n(stabiliser) to the infusion bag. Gently mix the contents of the bag to avoid foaming. Discard \n\nthe remaining solution (stabiliser) vial. \n\n3. Using a syringe, reconstitute each vial of BLINCYTO powder for concentrate using 3 mL of \nwater for injections. Direct the water for injections toward the side of the vial during \n\nreconstitution. Gently swirl contents to avoid excess foaming. Do not shake. \n\n• Do not reconstitute BLINCYTO powder for concentrate with the solution \n(stabiliser). \n\n• The addition of water for injections to the powder for concentrate results in a total \nvolume of 3.08 mL for a final BLINCYTO concentration of 12.5 mcg/mL. \n\n4. Visually inspect the reconstituted solution for particulate matter and discolouration during \nreconstitution and prior to infusion. The resulting solution should be clear to slightly \n\nopalescent, colourless-to-slightly yellow. Do not use if the solution is cloudy or has \n\nprecipitated. \n\n5. Using a syringe, aseptically transfer reconstituted BLINCYTO into the infusion bag (refer to \ntable 7 to table 9 for the specific volume of reconstituted BLINCYTO). Gently mix the \n\ncontents of the bag to avoid foaming. Discard any remaining BLINCYTO reconstituted \n\nsolution. \n\n6. Under aseptic conditions, attach the intravenous tubing to the infusion bag with the sterile \n0.2 micron in-line filter. \n\n7. Remove air from the infusion bag and prime the intravenous infusion line only with the \nprepared solution for infusion. Do not prime with sodium chloride 9 mg/mL (0.9%) \n\nsolution for injection. \n\n8. Store at 2°C - 8°C if not used immediately. \n \n\n \n\n7. MARKETING AUTHORISATION HOLDER \n\n \n\nAmgen Europe B.V. \n\nMinervum 7061 \n\n4817 ZK Breda \n\nThe Netherlands \n\n \n\n \n\n\n\n31 \n\n8. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/15/1047/001 \n\n \n\n \n\n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n\n \n\nDate of first authorisation: 23 November 2015 \n\nDate of last renewal: 19 April 2018 \n\n \n\n \n\n10. DATE OF REVISION OF THE TEXT \n\n \n\n \n\n \n\nDetailed information on this medicinal product is available on the website of the European \n\nMedicines Agency http://www.ema.europa.eu. \n\n \n\nhttp://www.ema.europa.eu/\nhttp://www.ema.europa.eu/\n\n\n32 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX II \n\n \n\nA. MANUFACTURER OF THE BIOLOGICAL ACTIVE \n\nSUBSTANCE AND MANUFACTURERS RESPONSIBLE \n\nFOR BATCH RELEASE \n\n \n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY \n\nAND USE \n\n \n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE \n\nMARKETING AUTHORISATION \n\n \n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO \n\nTHE SAFE AND EFFECTIVE USE OF THE MEDICINAL \n\nPRODUCT \n\n \n\n\n\n33 \n\nA. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND \n\nMANUFACTURERS RESPONSIBLE FOR BATCH RELEASE \n\n \n\nName and address of the manufacturer of the biological active substance \n\n \n\nLonza Biologics plc \n\n228 Bath Road \n\nSlough \n\nBerkshire, SL1 4DX \n\nUK \n\n \n\nName and address of the manufacturers responsible for batch release \n\n \n\nAmgen Europe B.V. \n\nMinervum 7061 \n\n4817 ZK Breda \n\nThe Netherlands \n\n \n\nAmgen NV \n\nTelecomlaan 5-7 \n\n1831 Diegem \n\nBelgium \n\n \n\n \n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n\n \n\nMedicinal product subject to restricted medical prescription (see Annex I: Summary of Product \n\nCharacteristics, section 4.2). \n\n \n\n \n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n\n \n\n• Periodic Safety Update Reports \n \n\nThe requirements for submission of periodic safety update reports for this medicinal product \n\nare set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) \n\nof Directive 2001/83/EC and any subsequent updates published on the European medicines \n\nweb-portal. \n\n \n\nThe marketing authorisation holder shall submit the first periodic safety update report for this \n\nproduct within 6 months following authorisation. \n\n \n\n \n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n\n \n\n• Risk Management Plan (RMP) \n \n\nThe MAH shall perform the required pharmacovigilance activities and interventions detailed \n\nin the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed \n\nsubsequent updates of the RMP. \n\n \n\n\n\n34 \n\nAn updated RMP should be submitted: \n\n• At the request of the European Medicines Agency; \n\n• Whenever the risk management system is modified, especially as the result of new information \nbeing received that may lead to a significant change to the benefit/risk profile or as the result \n\nof an important (pharmacovigilance or risk minimisation) milestone being reached. \n\n \n\n• Additional risk minimisation measures \n \n\nPrior to launch of BLINCYTO in each Member State, the Marketing Authorisation Holder (MAH) \n\nmust agree about the content and format of the educational programme, including communication \n\nmedia, distribution modalities, and any other aspects of the programme, with the National Competent \n\nAuthority. \n\n \n\nThe MAH shall ensure that in each Member State where BLINCYTO is marketed, all healthcare \n\nprofessionals (HCP) and patients / caregivers who are expected to prescribe, dispense and use \n\nBLINCYTO are provided with the following educational packages: \n\n• Physician educational material \n\n• Pharmacist educational material \n\n• Nurse educational material \n\n• Patient / caregivers educational material \n\n• Patient alert card \n \n\nThe physician educational material should contain: \n\n1. A link to the Summary of Product Characteristics (SmPC) \n2. The guide for physicians shall contain the following key elements: \n\n• Remarks on the importance of reporting ADRs \n\n• Information on treatment with BLINCYTO, administration and posology, duration of \nhospitalisation, interruption and / or permanent discontinuation of the treatment \n\nMedication errors (ME) \n\n• Data from clinical trials, causes of ME, frequency, severity and outcomes. \n\n• Reminder to counsel the patients on how to reduce the risk of ME while using the \ninfusion pump. \n\nNeurologic events \n\n• Data from clinical trials, frequency and severity (grade 3 and 4 neurological toxicities \nwere observed) \n\n• Recommendation to monitor patients for signs and symptoms of neurotoxicity \n\n• Management of neurotoxicity (including dose adjustment and dose interruption) \n\n• Recommendation for patients not to drive while receiving BLINCYTO and to contact \nimmediately the treating physician if they experience neurological symptoms \n\n \n\nThe pharmacist educational material should contain: \n\n1. A link to the Summary of Product Characteristics (SmPC) \n2. The guide for pharmacists, containing the following key elements: \n\n• Remarks on the importance of reporting ADRs \n\n• Detailed description of the reconstitution and preparation procedures of BLINCYTO \ninfusion solution for intravenous administration under aseptic conditions, using aseptic \n\ntechniques. \n\n \n\nThe nurse educational material should contain: \n\n1. A link to the Summary of Product Characteristics (SmPC) \n2. The nurse educational guide, including the following key elements: \n\n• Remarks on the importance of reporting ADRs \n\n• Description of the administration procedures of BLINCYTO \n\n\n\n35 \n\n• Description on patient’s monitoring and management of early signs and symptoms of \nneurological events \n\n• Recommendation for patients not to drive while receiving BLINCYTO and to contact \nimmediately the treating physician/nurse if they experience neurological symptoms \n\n \n\nThe patient (including caregivers) educational material should contain: \n\n1. The patient information guide, including the following key elements: \n\n• Remarks on the importance of reporting ADRs \n\n• Description of the administration procedures of BLINCYTO and how to reduce the risk \nof ME while using the infusion pump. \n\n• Description of the main signs and / or symptoms of neurologic events and the \nimportance of notifying the treating physician or nurse immediately if symptoms occur \n\n• Recommendation for patients not to drive while receiving BLINCYTO \n2. A link to the package leaflet \n \n\nThe patient alert card should contain: \n\n• A warning message for HCPs treating the patient at any time, including emergency \nconditions, that the patient is using BLINCYTO \n\n• Contact details of the BLINCYTO prescriber \n\n• BLINCYTO treatment start date \n\n• Remarks on the importance of reporting ADRs \n \n\n• Obligation to complete post-authorisation measures \n \n\nThe MAH shall complete, within the stated timeframe, the below measures: \n\n \n\nDescription Due date \n\nNon-interventional post-authorisation safety study (PASS): Study 20150136: an \n\nobservational study of blinatumomab safety and effectiveness, utilisation, and \n\ntreatment practices* \n\nQ42021 \n\n* The study protocol needs to be developed and presented for PRAC review within 2 months after the EU \n\nCommission Decision. \n\n \n\nDescription Due date \n\nNon-interventional post-authorisation safety study (PASS): The applicant \n\nshould submit the final results of a follow-up observational study to further \n\ncharacterise the long-term safety of BLINCYTO including developmental \n\naspects, HSCT and secondary malignancy in high-risk paediatric patients \n\nenrolled in Study 20120215*. \n\nQ42036 \n\n* The study protocol needs to be developed and presented for PRAC review within 3 months after the EU \n\nCommission Decision. \n\n \n\n \n\n\n\n36 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX III \n\n \n\nLABELLING AND PACKAGE LEAFLET \n\n \n\n\n\n37 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nA. LABELLING \n\n \n\n\n\n38 \n\n \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n\n \n\nCARTON \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nBLINCYTO 38.5 micrograms powder for concentrate and solution for solution for infusion \n\nblinatumomab \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nOne vial of powder contains 38.5 micrograms of blinatumomab. \n\nAfter reconstitution with water for injections each vial contains 12.5 micrograms/mL of \n\nblinatumomab. \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\nPowder: citric acid monohydrate (E330), trehalose dihydrate, lysine hydrochloride, polysorbate 80 \n\nand sodium hydroxide. \n\nSolution (stabiliser): citric acid monohydrate (E330), lysine hydrochloride, polysorbate 80, sodium \n\nhydroxide and water for injections. \n\nSee leaflet for further information. \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\nPowder for concentrate and solution for solution for infusion \n\n1 vial of powder. \n\n1 vial of solution (stabiliser). Add to the sodium chloride bag only. \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nRead the package leaflet before use. \n\nIntravenous use after reconstitution and dilution. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\nDo not shake the reconstituted solution. \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\n\n\n39 \n\n \n\n \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\nStore and transport refrigerated. \n\nDo not freeze. \n\nStore in the original carton in order to protect from light. \n\n \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nAmgen Europe B.V. \n\nMinervum 7061 \n\n4817 ZK Breda \n\nThe Netherlands \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/15/1047/001 \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nJustification for not including Braille accepted. \n\n \n\n \n\n17. UNIQUE IDENTIFIER – 2D BARCODE \n\n \n\n2D barcode carrying the unique identifier included. \n\n \n\n \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n\n \n\nPC \n\nSN \n\nNN \n\n\n\n40 \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n\n \n\nPOWDER VIAL \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n\n \n\nBLINCYTO 38.5 mcg powder for concentrate \n\nblinatumomab \n\nIV after reconstitution and dilution \n\n \n\n \n\n2. METHOD OF ADMINISTRATION \n\n \n\n \n\n3. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n4. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n\n \n\n \n\n6. OTHER \n\n \n\n \n\n \n\n \n\n\n\n41 \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n\n \n\nSOLUTION (STABILISER) VIAL \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n\n \n\nSolution (stabiliser). \n\nBLINCYTO \n\n \n\n \n\n2. METHOD OF ADMINISTRATION \n\n \n\n \n\n3. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n4. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n\n \n\n10 ml \n\n \n\n \n\n6. OTHER \n\n \n\nAdd to the sodium chloride bag only. \n\n \n\n\n\n42 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nB. PACKAGE LEAFLET \n\n \n\n\n\n43 \n\nPackage leaflet: Information for the patient \n\n \n\nBLINCYTO 38.5 micrograms powder for concentrate and solution for solution for infusion \n\nblinatumomab \n\n \n\nThis medicine is subject to additional monitoring. This will allow quick identification of new \n\nsafety information. You can help by reporting any side effects you may get. See the end of section 4 \n\nfor how to report side effects. \n\n \n\nRead all of this leaflet carefully before you start using this medicine because it contains \n\nimportant information for you. \n\n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor, pharmacist or nurse. \n- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible \n\nside effects not listed in this leaflet. See section 4. \n\n \n\nWhat is in this leaflet \n\n \n\n1. What BLINCYTO is and what it is used for \n2. What you need to know before you use BLINCYTO \n3. How to use BLINCYTO \n4. Possible side effects \n5. How to store BLINCYTO \n6. Contents of the pack and other information \n \n\n \n\n1. What BLINCYTO is and what it is used for \n\n \n\nThe active ingredient in BLINCYTO is blinatumomab. This belongs to a group of medicines called \n\nantineoplastic agents which target cancer cells. \n\n \n\nBLINCYTO is used to treat adults with acute lymphoblastic leukaemia. Acute lymphoblastic \n\nleukaemia is a cancer of the blood in which a particular kind of white blood cell called \n\n“B-lymphocyte” is growing out of control. This medicine works by enabling your immune system to \n\nattack and destroy these abnormal white blood cancer cells. BLINCYTO is used when acute \n\nlymphoblastic leukaemia has come back or has not responded to previous treatment (referred to as \n\nrelapsed/refractory acute lymphoblastic leukaemia). \n\n \n\nIt is also used in patients with acute lymphoblastic leukaemia who still have a small number of \n\ncancer cells remaining after previous treatment (referred to as minimal residual disease). \n\n \n\nBLINCYTO is used to treat children (≥ 1 year old), teenagers and young adults with acute \n\nlymphoblastic leukaemia (ALL) when previous treatments have not worked or have stopped \n\nworking. \n\n \n\n \n\n2. What you need to know before you use BLINCYTO \n\n \n\nDo not use BLINCYTO: \n\n- if you are allergic to blinatumomab or any of the other ingredients of this medicine (listed in \nsection 6). \n\n- if you are breast-feeding. \n \n\n\n\n44 \n\nWarnings and precautions \n\n \n\nTalk to your doctor, pharmacist or nurse before using BLINCYTO if any of these apply to you. \n\nBLINCYTO may not be suitable for you: \n\n• if you have ever had neurological problems, for example, shaking (or tremor), abnormal \nsensations, seizures, memory loss, confusion, disorientation, loss of balance, or difficulty in \n\nspeaking. If you are still suffering from active neurological problems or conditions, tell your \n\ndoctor. If your leukaemia has spread to your brain and/or spinal cord, your doctor may have to \n\ntreat this first before you can start treatment with BLINCYTO. Your doctor will assess your \n\nnervous system and conduct tests before deciding if you should receive BLINCYTO. Your \n\ndoctor may need to take special care of you during your treatment with BLINCYTO. \n• if you have an active infection. \n\n• if you have ever had an infusion reaction after previously using BLINCYTO. Symptoms may \ninclude wheezing, flushing, face swelling, difficulty breathing, low or high blood pressure. \n\n• if you think you may need any vaccinations in the near future, including those needed to travel \nto other countries. Some vaccines must not be given within two weeks before, at the same time \n\nas or in the months after you receive treatment with BLINCYTO. Your doctor will check if \n\nyou should have the vaccination. \n\n \n\nTell your doctor, pharmacist or nurse immediately if you experience any of the following \n\nreactions whilst receiving BLINCYTO as these may need to be treated and your dose adjusted: \n\n• if you experience seizures, difficulty in speaking or slurred speech, confusion and \ndisorientation, or loss of balance. \n\n• if you develop chills or shivering, or feel warm; you should take your temperature as you may \nhave a fever - these may be symptoms of an infection. \n\n• if you develop a reaction at any time during your infusion, which may include dizziness, \nfeeling faint, nauseated, face swelling, difficulty breathing, wheezing, or rash. \n\n• if you have severe and persistent stomach pain, with or without nausea and vomiting, as these \nmay be symptoms of a serious and potentially fatal condition known as pancreatitis \n\n(inflammation of the pancreas). \n\n \n\nYour doctor or nurse will monitor you for signs and symptoms of these reactions. \n\n \n\nTell your doctor, pharmacist or nurse immediately if you became pregnant whilst receiving \n\nBLINCYTO. Your doctor will talk to you about precautions in using vaccinations for your baby. \n\n \n\nBefore each infusion cycle of BLINCYTO, you will be given medicines which help reduce a \n\npotentially life-threatening complication known as tumour lysis syndrome, which is caused by \n\nchemical disturbances in the blood due to the breakdown of dying cancer cells. You may also be \n\ngiven medicines to reduce fever. \n\n \n\nDuring treatment, especially in the first few days after treatment start, you may experience a severe \n\nlow white blood cell count (neutropenia), severe low white blood cell count with a fever (febrile \n\nneutropenia), elevated liver enzymes, or elevated uric acid. Your doctor will take regular blood tests \n\nto monitor your blood counts during treatment with BLINCYTO. \n\n \n\nChildren and adolescents \n\n \n\nBLINCYTO should not be used in children below 1 year of age. \n\n \n\nOther medicines and BLINCYTO \n\n \n\nTell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other \n\nmedicines. \n\n \n\n\n\n45 \n\nPregnancy and breast-feeding \n\n \n\nIf you are pregnant, are breast-feeding, think you may be pregnant or are planning to have a baby, \n\nask your doctor or nurse for advice before taking this medicine. \n\n \n\nContraception \n\n \n\nWomen who are able to become pregnant have to use effective contraception during treatment and \n\nfor at least 48 hours after your last treatment. Talk to your doctor or nurse about suitable methods of \n\ncontraception. \n\n \n\nPregnancy \n\n \n\nThe effects of BLINCYTO in pregnant women are not known but based on its mechanism of action, \n\nBLINCYTO may harm your unborn baby. You should not use BLINCYTO during pregnancy, unless \n\nyour doctor thinks that it is the best medicine for you. \n\n \n\nIf you become pregnant during BLINCYTO treatment, please inform your doctor or nurse. Your \n\ndoctor will talk to you about precautions in using vaccinations for your baby. \n\n \n\nBreast-feeding \n\n \n\nYou must not breast-feed during and for at least 48 hours after your last treatment. It is not known \n\nwhether BLINCYTO is excreted in breast milk but a risk for suckling baby cannot be excluded. \n\n \n\nDriving and using machines \n\n \n\nDo not drive, use heavy machines, or engage in hazardous activities while you are being given \n\nBLINCYTO. BLINCYTO can cause neurological problems such as dizziness, seizures, confusion, \n\ncoordination and balance disorders. \n\n \n\nBLINCYTO contains sodium \n\n \n\nThis medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially ‘sodium-free’. \n\n \n\n \n\n3. How to use BLINCYTO \n\n \n\nAlways use this medicine exactly as your doctor, pharmacist or nurse have told you. Check with \n\nyour doctor, pharmacist or nurse if you are not sure. \n\n \n\nHow BLINCYTO is given \n\n \n\nBLINCYTO will be given to you through a vein (intravenous) continuously for 4 weeks using an \n\ninfusion pump (this is 1 treatment cycle). You will then have a 2-week break where you will not be \n\ngiven the infusion. Your infusion catheter will be attached to you at all times during each cycle of \n\nyour treatment. \n\n \n\nBLINCYTO is usually given for 2 treatment cycles if you have relapsed/refractory acute \n\nlymphoblastic leukaemia, or for 1 treatment cycle if you have minimal residual disease acute \n\nlymphoblastic leukaemia. If you respond to this treatment, your doctor may decide to give you up to \n\n3 additional cycles of treatment. The number of treatment cycles and the dose which you will be \n\ngiven will depend on how you tolerate and respond to BLINCYTO. Your doctor will discuss with \n\nyou how long your treatment will last. Your treatment may also be interrupted depending on how \n\nyou tolerate BLINCYTO. \n\n \n\n\n\n46 \n\nIf you have relapsed/refractory acute lymphoblastic leukaemia it is recommended that the first 9 days \n\nof treatment and the first two days of the second cycle will be given to you in a hospital or clinic \n\nunder the supervision of a doctor or nurse experienced in the use of anti-cancer medicines. \n\n \n\nIf you have minimal residual disease acute lymphoblastic leukaemia, it is recommended that the first \n\n3 days of treatment and the first 2 days of subsequent cycles will be given to you in a hospital or \n\nclinic under the supervision of a doctor or nurse experienced in the use of anti-cancer medicines. \n\n \n\nIf you have or had neurological problems, it is recommended that the first 14 days of treatment will \n\nbe given to you in a hospital or clinic. Your doctor will discuss with you if you can continue \n\ntreatment at home after your initial hospital stay. Treatment may include a bag change by a nurse. \n\n \n\nYour doctor will determine when your BLINCYTO infusion bag will be changed, which may range \n\nfrom every day to every 4 days. The infusion rate may be faster or slower depending on how often \n\nthe bag is changed. \n\n \n\nYour first cycle \n\n \n\nIf you have relapsed/refractory acute lymphoblastic leukaemia and your body weight is greater than \n\nor equal to 45 kilograms the recommended initial dose in your first cycle is 9 micrograms per day for \n\n1 week. Your doctor may decide to then increase your dose to 28 micrograms per day for weeks 2, 3, \n\nand 4 of your treatment. \n\n \n\nIf your body weight is less than 45 kilograms, the recommended initial dose in your first cycle will \n\nbe based on your weight and height. Your doctor may decide to then increase your dose for weeks 2, \n\n3, and 4 of your treatment. \n\n \n\nIf you have minimal residual disease acute lymphoblastic leukaemia, your dose of BLINCYTO will \n\nbe 28 micrograms per day throughout the first cycle. \n\n \n\nYour next cycles \n\n \n\nIf your doctor determines that you should be given more cycles of BLINCYTO and if your body \n\nweight is greater than or equal to 45 kilograms, your pump will be set to infuse a dose of \n\n28 micrograms per day. \n\n \n\nIf your doctor determines that you should be given more cycles of BLINCYTO and if your body \n\nweight is less than 45 kilograms, your pump will be set to infuse a dose based on your weight and \n\nheight. \n\n \n\nMedicines given before each cycle of BLINCYTO \n\n \n\nBefore your treatment with BLINCYTO, you will be given other medicines (pre-medication) to help \n\nreduce infusion reactions and other possible side effects. These may include corticosteroids (e.g. \n\ndexamethasone). \n\n \n\nInfusion catheter \n\n \n\nIf you have a catheter for infusion, it is very important to keep the area around the catheter clean; \n\notherwise you could get an infection. Your doctor or nurse will show you how to care for your \n\ncatheter site. \n\n \n\nInfusion pump and intravenous tubing \n\n \n\nDo not adjust the settings on the pump, even if there is a problem or the pump alarm sounds. Any \n\nchanges to the pump settings may result in a dose that is too high or too low. \n\n \n\n\n\n47 \n\nContact your doctor or nurse immediately if: \n\n• there is a problem with the pump or the pump alarm sounds \n\n• the infusion bag empties before the scheduled bag change \n\n• if the infusion pump stops unexpectedly. Do not try to restart your pump. \n \n\nYour doctor or nurse will advise you on how to manage your daily activities around your infusion \n\npump. Contact your doctor or nurse if you have questions. \n\n \n\n \n\n4. Possible side effects \n\n \n\nLike all medicines, this medicine can cause side effects, although not everybody gets them. Some of \n\nthese side effects may be serious. \n\n \n\nTell your doctor immediately if you get any of the following or combination of the following side \n\neffects: \n\n• chills, shivering, fever, rapid heart rate, decreased blood pressure, aching muscles, feeling \ntired, coughing, difficulty breathing, confusion, redness, swelling or discharge in the affected \n\narea or at the site of the infusion line - these may be signs of an infection. \n\n• neurologic events: shaking (or tremor), confusion, disturbances of brain function \n(encephalopathy), difficulty in communicating (aphasia), seizure (convulsion). \n\n• fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may \nbecome severe - these may be signs of a so-called cytokine release syndrome. \n\n• if you have severe and persistent stomach pain, with or without nausea and vomiting, as these \nmay be symptoms of a serious and potentially fatal condition known as pancreatitis \n\n(inflammation of the pancreas). \n\n \n\nTreatment with BLINCYTO can cause a decrease in the levels of certain white blood cells with or \n\nwithout fever (febrile neutropenia or neutropenia) or can lead to increased blood levels of potassium, \n\nuric acid, and phosphate and decreased blood levels of calcium (tumour lysis syndrome). Your \n\ndoctor will take regular blood tests during treatment with BLINCYTO. \n\n \n\nOther side effects include: \n\n \n\nVery common side effects (may affect more than 1 in 10 people): \n\n• infections in the blood including bacteria, fungi, viruses, or other types of infection \n\n• decreased levels of certain white blood cells with or without fever ((febrile) neutropenia, \nleukopenia), decreased levels of red blood cells, decreased levels of platelets \n\n• fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may \nbecome severe (cytokine release syndrome) \n\n• not being able to sleep \n\n• headache, shaking (or tremor) \n\n• rapid heart rate (tachycardia) \n\n• low blood pressure \n\n• cough \n\n• nausea, diarrhoea, vomiting, constipation, abdominal pain \n\n• rash \n\n• back pain, pain in extremity \n\n• fever (pyrexia), swelling of the face, lips, mouth, tongue or throat which may cause difficulty \nin swallowing or breathing (oedema), chills \n\n• low levels of antibodies called “immunoglobulins” which help the immune system fight \ninfection (decreased immunoglobulins) \n\n• increased levels of liver enzymes (ALT, AST, GGT) \n\n• reactions related to infusion may include, wheezing, flushing, face swelling, difficulty \nbreathing, low blood pressure, high blood pressure. \n\n \n\n\n\n48 \n\nCommon side effects (may affect up to 1 in 10 people): \n\n• serious infection which can result in organ failure, shock or can be fatal (sepsis) \n\n• lung infection (pneumonia) \n\n• increased levels of white blood cell count (leucocytosis), decreased levels of certain white \nblood cells (lymphopenia) \n\n• allergic reaction \n\n• complications occurring after cancer treatment leading to increased blood levels of potassium, \nuric acid, and phosphate and decreased blood levels of calcium (tumour lysis syndrome) \n\n• confusion, disorientation \n\n• disturbances of brain function (encephalopathy) such as difficulty in communicating (aphasia), \ntingling of skin (paraesthesia), seizure, difficulty thinking or processing thoughts, difficulty \n\nremembering, difficulty in controlling movement (ataxia) \n\n• feeling sleepy (somnolence), numbness, dizziness \n\n• nerve problems affecting the head and neck such as visual disturbances, drooping eyelid \nand/or sagging muscles on one side of the face, difficulty hearing or trouble swallowing \n\n(cranial nerve disorders) \n\n• wheezing or difficulty in breathing (dyspnoea), breathlessness (respiratory failure) \n\n• high blood pressure (hypertension) \n\n• flushing \n\n• coughing with phlegm \n\n• increased bilirubin in the blood \n\n• bone pain \n\n• chest pain or other pain \n\n• high levels of some enzymes including blood enzymes \n\n• increase in your weight \n \n\nUncommon side effects (may affect up to 1 in 100 people): \n\n• excessive activation of white blood cells associated with inflammation (hemophagocytic \nhistiocytosis) \n\n• swollen lymph nodes (lymphadenopathy) \n\n• fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may \nbe severe and can be fatal (cytokine storm) \n\n• a condition which causes fluid to leak from the small blood vessels into your body (capillary \nleak syndrome) \n\n• difficulty in speaking \n \n\nAdditionally, the side effects that happened more often in adolescents and children include: \n\n• decreased levels of red blood cells (anaemia), decreased levels of platelets \n(thrombocytopenia), decreased levels of certain white blood cells (leukopenia) \n\n• fever (pyrexia) \n\n• reactions related to infusion may include face swelling, low blood pressure, high blood \npressure (infusion-related reaction) \n\n• increase in your weight \n\n• high blood pressure (hypertension) \n \n\nReporting of side effects \n\n \n\nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \n\neffects not listed in this leaflet. You can also report side effects directly via the national reporting \n\nsystem listed in Appendix V. By reporting side effects you can help provide more information on the \n\nsafety of this medicine. \n\n \n\n \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n49 \n\n5. How to store BLINCYTO \n\n \n\nKeep this medicine out of the sight and reach of children. \n\n \n\nDo not use this medicine after the expiry date which is stated on the label and carton after EXP. The \n\nexpiry date refers to the last day of that month. \n\n \n\nUnopened vials: \n\n- Store and transport refrigerated (2°C - 8°C). \n- Do not freeze. \n- Store in the original carton in order to protect from light. \n \n\nReconstituted solution (BLINCYTO solution): \n\n- When refrigerated, the reconstituted solution must be used within 24 hours. Alternatively the \nvials can be stored at room temperature (up to 27°C) for up to 4 hours. \n\n \n\nDiluted solution (prepared infusion bag): \n\nIf your infusion bag is changed at home: \n\n- Infusion bags containing BLINCYTO solution for infusion will arrive in special packaging \ncontaining cooling packs. \n\n• Do not open the package. \n\n• Store the package at room temperature (up to 27°C). \n\n• Do not refrigerate or freeze the package. \n- The package will be opened by your nurse and the infusion bags will be stored in a refrigerator \n\nuntil infusion. \n\n- When refrigerated, the infusion bags must be used within 10 days of preparation. \n- Once at room temperature (up to 27°C) the solution will be infused within 96 hours. \n \n\nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \n\nthrow away medicines you no longer use. These measures will help protect the environment. \n\n \n\n \n\n6. Contents of the pack and other information \n\n \n\nWhat BLINCYTO contains \n\n \n\n- The active substance is blinatumomab. Each vial of powder contains 38.5 micrograms of \nblinatumomab. Reconstitution with water for injections results in a final blinatumomab \n\nconcentration of 12.5 micrograms/mL. \n\n- The other ingredients in the powder are citric acid monohydrate (E330), trehalose dihydrate, \nlysine hydrochloride, polysorbate 80, and sodium hydroxide. \n\n- The solution (stabiliser) contains citric acid monohydrate (E330), lysine hydrochloride, \npolysorbate 80, sodium hydroxide and water for injections. \n\n \n\nWhat BLINCYTO looks like and contents of the pack \n\n \n\nBLINCYTO is a powder for concentrate and solution for solution for infusion. \n\nEach pack of BLINCYTO contains: \n\n• 1 glass vial containing a white to off-white powder. \n\n• 1 glass vial containing a colourless-to-slightly yellow, clear solution. \n \n\nMarketing Authorisation Holder and Manufacturer \n\nAmgen Europe B.V. \n\nMinervum 7061 \n\n4817 ZK Breda \n\nThe Netherlands \n\n \n\n\n\n50 \n\nMarketing Authorisation Holder \n\nAmgen Europe B.V. \n\nMinervum 7061 \n\n4817 ZK Breda \n\nThe Netherlands \n\n \n\nManufacturer \n\nAmgen NV \n\nTelecomlaan 5-7 \n\n1831 Diegem \n\nBelgium \n\n \n\nFor any information about this medicine, please contact the local representative of the Marketing \n\nAuthorisation Holder. \n\n \n\nBelgië/Belgique/Belgien \n\ns.a. Amgen n.v. \n\nTel/Tél: +32 (0)2 7752711 \n\n \n\nLietuva \n\nAmgen Switzerland AG Vilniaus filialas \n\nTel: +370 5 219 7474 \n\n \n\nБългария \n\nАмджен България ЕООД \n\nТел.: +359 (0)2 424 7440 \n\n \n\nLuxembourg/Luxemburg \n\ns.a. Amgen \n\nBelgique/Belgien \n\nTel/Tél: +32 (0)2 7752711 \n\n \n\nČeská republika \n\nAmgen s.r.o. \n\nTel: +420 221 773 500 \n\n \n\nMagyarország \n\nAmgen Kft. \n\nTel.: +36 1 35 44 700 \n\n \n\nDanmark \n\nAmgen, filial af Amgen AB, Sverige \n\nTlf: +45 39617500 \n\n \n\nMalta \n\nAmgen B.V. \n\nThe Netherlands \n\nTel: +31 (0)76 5732500 \n\n \n\nDeutschland \n\nAMGEN GmbH \n\nTel.: +49 89 1490960 \n\n \n\nNederland \n\nAmgen B.V. \n\nTel: +31 (0)76 5732500 \n\n \n\nEesti \n\nAmgen Switzerland AG Vilniaus filialas \n\nTel: +372 586 09553 \n\n \n\nNorge \n\nAmgen AB \n\nTel: +47 23308000 \n\n \n\nΕλλάδα \n\nAmgen Ελλάς Φαρμακευτικά Ε.Π.Ε. \n\nΤηλ.: +30 210 3447000 \n\n \n\nÖsterreich \n\nAmgen GmbH \n\nTel: +43 (0)1 50 217 \n\n \n\nEspaña \n\nAmgen S.A. \n\nTel: +34 93 600 18 60 \n \n\nPolska \n\nAmgen Biotechnologia Sp. z o.o. \n\nTel.: +48 22 581 3000 \n\n \n\nFrance \n\nAmgen S.A.S. \n\nTél: +33 (0)9 69 363 363 \n\n \n\nPortugal \n\nAmgen Biofarmacêutica, Lda. \n\nTel: +351 21 422 0606 \n\n \n\nHrvatska \n\nAmgen d.o.o. \n\nTel: +385 (0)1 562 57 20 \n\n \n\nRomânia \n\nAmgen România SRL \n\nTel: +4021 527 3000 \n\n \n\n\n\n51 \n\nIreland \n\nAmgen Ireland Limited \n\nTel: +353 1 8527400 \n \n\nSlovenija \n\nAMGEN zdravila d.o.o. \n\nTel: +386 (0)1 585 1767 \n\n \n\nÍsland \n\nVistor hf. \n\nSími: +354 535 7000 \n\n \n\nSlovenská republika \n\nAmgen Slovakia s.r.o. \n\nTel: +421 2 321 114 49 \n\n \n\nItalia \n\nAmgen S.r.l. \n\nTel: +39 02 6241121 \n\n \n\nSuomi/Finland \n\nAmgen AB, sivuliike Suomessa/Amgen AB, filial \n\ni Finland \n\nPuh/Tel: +358 (0)9 54900500 \n\n \n\nKύπρος \n\nC.A. Papaellinas Ltd \n\nΤηλ.: +357 22741 741 \n\n \n\nSverige \n\nAmgen AB \n\nTel: +46 (0)8 6951100 \n\n \n\nLatvija \n\nAmgen Switzerland AG Rīgas filiāle \n\nTel: +371 257 25888 \n\n \n\nUnited Kingdom \n\nAmgen Limited \n\nTel: +44 (0)1223 420305 \n\n \n\n \n\nThis leaflet was last revised in \n\n \n\nOther sources of information \n\n \n\nDetailed information on this medicine is available on the European Medicines Agency web site: \n\nhttp://www.ema.europa.eu. \n\n \n\n \n\nThe following information is intended for healthcare professionals only: \n\n \n\nBLINCYTO solution for infusion is administered as a continuous intravenous infusion delivered at a \n\nconstant flow rate using an infusion pump, over a period of up to 96 hours. \n\n \n\nPhiladelphia chromosome negative relapsed or refractory B-precursor ALL \n\n \n\nRecommended daily dose by patient weight. Patients greater than or equal to 45 kg receive a \n\nfixed-dose and for patients less than 45 kg, the dose is calculated using the patient’s body surface \n\narea (BSA). \n\n \n\nhttp://www.ema.europa.eu/\nhttp://www.ema.europa.eu/\n\n\n52 \n\nPatient \n\nweight \n\nCycle 1 Subsequent cycles \n\nDays 1-7 Days 8-28 Days 29-42 Days 1-28 Days 29-42 \n\nGreater than \n\nor equal to \n\n45 kg \n\n(fixed-dose) \n\n9 mcg/day via \n\ncontinuous \n\ninfusion \n\n \n\n28 mcg/day via \n\ncontinuous \n\ninfusion \n\n \n\n14 day \n\ntreatment free \n\ninterval \n\n28 mcg/day \n\nvia \n\ncontinuous \n\ninfusion \n\n \n\n14 day \n\ntreatment \n\nfree interval \n\nLess than \n\n45 kg \n\n(BSA-based \n\ndose) \n\n5 mcg/m2/day \n\nvia \n\ncontinuous \n\ninfusion \n\n(not to exceed \n\n9 mcg/day) \n\n15 mcg/m2/day \n\nvia continuous \n\ninfusion \n\n(not to exceed \n\n28 mcg/day) \n\n \n\n15 mcg/m2/da\n\ny via \n\ncontinuous \n\ninfusion \n\n(not to exceed \n\n28 mcg/day) \n\n \n\n \n\nMRD positive B-precursor ALL \n\n \n\nThe recommended dose of BLINCYTO throughout each 4-week treatment cycle is 28 mcg/day. \n\n \n\nThe starting volume (270 mL) is more than the volume administered to the patient (240 mL) to \n\naccount for the priming of the intravenous tubing and to ensure that the patient will receive the full \n\ndose of BLINCYTO. \n\n \n\nInfuse BLINCYTO solution according to the instructions on the pharmacy label on the prepared bag \n\nat one of the following constant infusion rates: \n\n• Infusion rate of 10 mL/h for a duration of 24 hours \n\n• Infusion rate of 5 mL/h for a duration of 48 hours \n\n• Infusion rate of 3.3 mL/h for a duration of 72 hours \n\n• Infusion rate of 2.5 mL/h for a duration of 96 hours \n \n\nThe choice of the infusion duration should be made by the treating physician considering the \n\nfrequency of the infusion bag changes. The target therapeutic dose of BLINCYTO delivered does not \n\nchange. \n\n \n\nAseptic preparation \n \n\nAseptic handling must be ensured when preparing the infusion. Preparation of BLINCYTO should \n\nbe: \n- performed under aseptic conditions by trained personnel in accordance with good practice \n\nrules especially with respect to the aseptic preparation of parenteral products. \n- prepared in a laminar flow hood or biological safety cabinet using standard precautions for the \n\nsafe handling of intravenous agents. \n\n \n\nIt is very important that the instructions for preparation and administration provided in this section \n\nare strictly followed to minimise medication errors (including underdose and overdose). \n\n \n\nSpecial instructions to support accurate preparation \n\n \n\n• A solution (stabiliser) is provided inside the BLINCYTO package and is used to coat the \npre-filled infusion bag prior to addition of reconstituted BLINCYTO. Do not use this solution \n\n(stabiliser) for reconstitution of BLINCYTO powder for concentrate. \n\n• The entire volume of the reconstituted and diluted BLINCYTO will be more than the volume \nto be administered to the patient (240 mL). This is to account for intravenous infusion line loss \n\nand to assure that the patient will receive the full dose of BLINCYTO. \n\n\n\n53 \n\n• When preparing an infusion bag, remove all air from infusion bag. This is particularly \nimportant when using an ambulatory infusion pump. \n\n• Use the specific volumes described in the reconstitution and dilution instructions below to \nminimise errors in calculation. \n\n \n\nOther instructions \n\n \n\n• BLINCYTO is compatible with polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or \nethyl vinyl acetate (EVA) infusion bags/pump cassettes. \n\n• Pump specifications: The infusion pump to administer BLINCYTO solution for infusion \nshould be programmable, lockable and have an alarm. Elastomeric pumps should not be used. \n\n• Any unused medicinal product or waste material should be disposed of in accordance with \nlocal requirements. \n\n \n\nPreparation of the solution for infusion \n\n \n\nSpecific reconstitution and dilution instructions are provided for each dose and infusion time. Verify \n\nthe prescribed dose and infusion time of BLINCYTO and identify the appropriate dosing preparation \n\nin the relevant table below. Table 1 provides instructions for patients weighing greater than or equal \n\nto 45 kg whereas table 2 and table 3 provide instructions for patients weighing less than 45 kg. \n\nFollow the steps for reconstituting BLINCYTO and preparing the infusion bag detailed below \n\ntable 3. \n\n \n\nTable 1. For patients weighing greater than or equal to 45 kg: volumes of sodium chloride \n\n9 mg/mL (0.9%) solution for injection, solution (stabiliser), and reconstituted BLINCYTO to \n\nadd to infusion bag \n\n \n\nPre-filled bag containing sodium chloride 9 mg/mL (0.9%) solution for \n\ninjection \n\n250 mL \n\n(usual overfill volume \n\nof 265 to 275 mL) \n\nSolution (stabiliser) 5.5 mL \n\n \n\nDose \nInfusion duration \n\n(hours) \n\nInfusion rate \n\n(mL/hour) \n\nReconstituted \n\nBLINCYTO \n\n(number of \n\npackages) \n\n9 mcg/day \n\n24 10 0.83 mL (1) \n\n48 5 1.7 mL (1) \n\n72 3.3 2.5 mL (1) \n\n96 2.5 3.3 mL (2) \n\n28 mcg/day \n\n24 10 2.6 mL (1) \n\n48 5 5.2 mL (2) \n\n72 3.3 8 mL (3) \n\n96 2.5 10.7 mL (4) \n\n \n\n\n\n54 \n\nTable 2. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) \n\nsolution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion \n\nbag for 5 mcg/m2/day dose \n\n \n\nSodium chloride 9 mg/mL (0.9%) solution for injection (starting \n\nvolume) \n\n250 mL (usual overfill volume \n\nof 265 to 275 mL) \n\nSolution (stabiliser) 5.5 mL \n\nDose Infusion duration Infusion rate BSA (m2) \nReconstituted BLINCYTO \n\n(number of packages) \n\n5 mcg/m2/day \n\n24 hours 10 mL/hour \n\n1.50 – 1.59 0.70 mL (1) \n\n1.40 – 1.49 0.66 mL (1) \n\n1.30 – 1.39 0.61 mL (1) \n\n1.20 – 1.29 0.56 mL (1) \n\n1.10 – 1.19 0.52 mL (1) \n\n1.00 – 1.09 0.47 mL (1) \n\n0.90 – 0.99 0.43 mL (1) \n\n0.80 – 0.89 0.38 mL (1) \n\n0.70 – 0.79 0.33 mL (1) \n\n0.60 – 0.69 0.29 mL (1) \n\n0.50 – 0.59 0.24 mL (1) \n\n0.40 – 0.49 0.20 mL (1) \n\n \n\n48 hours 5 mL/hour \n\n1.50 – 1.59 1.4 mL (1) \n\n1.40 – 1.49 1.3 mL (1) \n\n1.30 – 1.39 1.2 mL (1) \n\n1.20 – 1.29 1.1 mL (1) \n\n1.10 – 1.19 1.0 mL (1) \n\n1.00 – 1.09 0.94 mL (1) \n\n0.90 – 0.99 0.85 mL (1) \n\n0.80 – 0.89 0.76 mL (1) \n\n0.70 – 0.79 0.67 mL (1) \n\n0.60 – 0.69 0.57 mL (1) \n\n0.50 – 0.59 0.48 mL (1) \n\n0.40 – 0.49 0.39 mL (1) \n\n \n\n72 hours 3.3 mL/hour \n\n1.50 – 1.59 2.1 mL (1) \n\n1.40 – 1.49 2.0 mL (1) \n\n1.30 – 1.39 1.8 mL (1) \n\n1.20 – 1.29 1.7 mL (1) \n\n1.10 – 1.19 1.6 mL (1) \n\n1.00 – 1.09 1.4 mL (1) \n\n0.90 – 0.99 1.3 mL (1) \n\n0.80 – 0.89 1.1 mL (1) \n\n0.70 – 0.79 1 mL (1) \n\n0.60 – 0.69 0.86 mL (1) \n\n0.50 – 0.59 0.72 mL (1) \n\n0.40 – 0.49 0.59 mL (1) \n\n \n\n96 hours 2.5 mL/hour \n\n1.50 – 1.59 2.8 mL (1) \n\n1.40 – 1.49 2.6 mL (1) \n\n1.30 – 1.39 2.4 mL (1) \n\n1.20 – 1.29 2.3 mL (1) \n\n1.10 – 1.19 2.1 mL (1) \n\n1.00 – 1.09 1.9 mL (1) \n\n0.90 – 0.99 1.7 mL (1) \n\n0.80 – 0.89 1.5 mL (1) \n\n0.70 – 0.79 1.3 mL (1) \n\n0.60 – 0.69 1.2 mL (1) \n\n0.50 – 0.59 0.97 mL (1) \n\n0.40 – 0.49 0.78 mL (1) \n\n\n\n55 \n\nTable 3. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%) \n\nsolution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion \n\nbag for 15 mcg/m2/day dose \n\n \n\nSodium chloride 9 mg/mL (0.9%) solution for injection (starting \n\nvolume) \n\n250 mL (usual overfill volume \n\nof 265 to 275 mL) \n\nSolution (stabiliser) 5.5 mL \n\nDose Infusion duration Infusion rate BSA (m2) \nReconstituted BLINCYTO \n\n(number of packages) \n\n15 mcg/m2/day \n\n24 hours 10 mL/hour \n\n1.50 – 1.59 2.1 mL (1) \n\n1.40 – 1.49 2.0 mL (1) \n\n1.30 – 1.39 1.8 mL (1) \n\n1.20 – 1.29 1.7 mL (1) \n\n1.10 – 1.19 1.6 mL (1) \n\n1.00 – 1.09 1.4 mL (1) \n\n0.90 – 0.99 1.3 mL (1) \n\n0.80 – 0.89 1.1 mL (1) \n\n0.70 – 0.79 1.00 mL (1) \n\n0.60 – 0.69 0.86 mL (1) \n\n0.50 – 0.59 0.72 mL (1) \n\n0.40 – 0.49 0.59 mL (1) \n\n \n\n48 hours 5 mL/hour \n\n1.50 – 1.59 4.2 mL (2) \n\n1.40 – 1.49 3.9 mL (2) \n\n1.30 – 1.39 3.7 mL (2) \n\n1.20 – 1.29 3.4 mL (2) \n\n1.10 – 1.19 3.1 mL (2) \n\n1.00 – 1.09 2.8 mL (1) \n\n0.90 – 0.99 2.6 mL (1) \n\n0.80 – 0.89 2.3 mL (1) \n\n0.70 – 0.79 2.0 mL (1) \n\n0.60 – 0.69 1.7 mL (1) \n\n0.50 – 0.59 1.4 mL (1) \n\n0.40 – 0.49 1.2 mL (1) \n\n \n\n72 hours 3.3 mL/hour \n\n1.50 – 1.59 6.3 mL (3) \n\n1.40 – 1.49 5.9 mL (3) \n\n1.30 – 1.39 5.5 mL (2) \n\n1.20 – 1.29 5.1 mL (2) \n\n1.10 – 1.19 4.7 mL (2) \n\n1.00 – 1.09 4.2 mL (2) \n\n0.90 – 0.99 3.8 mL (2) \n\n0.80 – 0.89 3.4 mL (2) \n\n0.70 – 0.79 3.0 mL (2) \n\n0.60 – 0.69 2.6 mL (1) \n\n0.50 – 0.59 2.2 mL (1) \n\n0.40 – 0.49 1.8 mL (1) \n\n \n\n96 hours 2.5 mL/hour \n\n1.50 – 1.59 8.4 mL (3) \n\n1.40 – 1.49 7.9 mL (3) \n\n1.30 – 1.39 7.3 mL (3) \n\n1.20 – 1.29 6.8 mL (3) \n\n1.10 – 1.19 6.2 mL (3) \n\n1.00 – 1.09 5.7 mL (3) \n\n0.90 – 0.99 5.1 mL (2) \n\n0.80 – 0.89 4.6 mL (2) \n\n0.70 – 0.79 4.0 mL (2) \n\n0.60 – 0.69 3.4 mL (2) \n\n0.50 – 0.59 2.9 mL (2) \n\n0.40 – 0.49 2.3 mL (1) \n\n\n\n56 \n\n \n\nThese supplies are also required, but not included in the package \n\n• Sterile single-use disposable syringes \n\n• 21-23 gauge needle(s) (recommended) \n\n• Water for injections \n\n• Infusion bag with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection; \no To minimise the number of aseptic transfers, use a 250 mL pre-filled infusion bag. \n\nBLINCYTO dose calculations are based on a usual overfill volume of 265 to \n\n275 mL sodium chloride 9 mg/mL (0.9%) solution for injection. \n\no Use only polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl \nacetate (EVA) infusion bags/pump cassettes. \n\n• Polyolefin, PVC non-DEHP, or EVA intravenous tubing with a sterile, non-pyrogenic, low \nprotein-binding 0.2 micrometre in-line filter. \n\no Ensure that the tubing is compatible with the infusion pump. \n \n\nReconstitution and preparation of BLINCYTO solution for infusion using an infusion bag pre-filled \n\nwith 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection \n\n \n\n1. Use an infusion bag pre-filled with 250 mL sodium chloride 9 mg/mL (0.9%) solution for \ninjection that usually contains a total volume of 265 to 275 mL. \n\n2. To coat the infusion bag, using a syringe, aseptically transfer 5.5 mL of the solution \n(stabiliser) to the infusion bag. Gently mix the contents of the bag to avoid foaming. Discard \n\nthe remaining solution (stabiliser) vial. \n\n3. Using a syringe, reconstitute each vial of BLINCYTO powder for concentrate using 3 mL of \nwater for injections. Direct the water for injections toward the side of the vial during \n\nreconstitution. Gently swirl contents to avoid excess foaming. Do not shake. \n\n• Do not reconstitute BLINCYTO powder for concentrate with the solution \n(stabiliser). \n\n• The addition of water for injections to the powder for concentrate results in a total \nvolume of 3.08 mL for a final BLINCYTO concentration of 12.5 mcg/mL. \n\n4. Visually inspect the reconstituted solution for particulate matter and discolouration during \nreconstitution and prior to infusion. The resulting solution should be clear to slightly \n\nopalescent, colourless-to-slightly yellow. Do not use if the solution is cloudy or has \n\nprecipitated. \n\n5. Using a syringe, aseptically transfer reconstituted BLINCYTO into the infusion bag (refer to \ntable 1 to table 3 for the specific volume of reconstituted BLINCYTO). Gently mix the \n\ncontents of the bag to avoid foaming. Discard any remaining BLINCYTO reconstituted \n\nsolution. \n\n6. Under aseptic conditions, attach the intravenous tubing to the infusion bag with the sterile \n0.2 micron in-line filter. \n\n7. Remove air from the infusion bag and prime the intravenous infusion line only with the \nprepared solution for infusion. Do not prime with sodium chloride 9 mg/mL (0.9%) \n\nsolution for injection. \n\n8. Store at 2°C – 8°C if not used immediately. \n \n\nFor instructions on administration, see Summary of Product Characteristics section 4.2. \n \n\nMethod of administration \n\n \n\nImportant Note: Do not flush the BLINCYTO infusion line or intravenous catheter, especially \n\nwhen changing infusion bags. Flushing when changing bags or at completion of infusion can \n\nresult in excess dosage and complications thereof. When administering via multi-lumen venous \n\ncatheter, BLINCYTO should be infused through a dedicated lumen. \n\n \n\nBLINCYTO solution for infusion is administered as a continuous intravenous infusion delivered at a \n\nconstant flow rate using an infusion pump over a period of up to 96 hours. \n\n \n\n\n\n57 \n\nThe BLINCYTO solution for infusion must be administered using intravenous tubing that contains a \n\nsterile, non-pyrogenic, low protein-binding 0.2 micrometre in-line filter. \n\n \n\nThe infusion bag must be changed at least every 96 hours by a healthcare professional for sterility \n\nreasons. \n\n \n\nStorage conditions and shelf life \n\n \n\nUnopened vials: \n\n \n\n5 years (2°C - 8°C) \n\n \n\nReconstituted solution: \n\n \n\nChemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C or 4 hours at \n\nor below 27°C. \n\n \n\nFrom a microbiological point of view, unless the method of reconstituting precludes the risks of \n\nmicrobial contamination, the reconstituted solution should be diluted immediately. If not diluted \n\nimmediately, in-use storage times and conditions are the responsibility of the user. \n\n \n\nDiluted solution (prepared infusion bag) \n\n \n\nChemical and physical in-use stability has been demonstrated for 10 days at 2°C - 8°C or 96 hours at \n\nor below 27°C. \n\n \n\nFrom a microbiological point of view, the prepared infusion bags should be used immediately. If not \n\nused immediately, in-use storage times and conditions prior to use are the responsibility of the user \n\nand would normally not be longer than 24 hours at 2°C - 8°C, unless dilution has taken place in \n\ncontrolled and validated aseptic conditions. \n\n \n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. PACKAGE LEAFLET"},"Section_1":{"kind":"string","value":"{'Title': '1. what blincyto is and what it is used for', 'Section_Content': 'the active ingredient in blincyto is blinatumomab. this belongs to a group of medicines called antineoplastic agents which target cancer cells. blincyto is used to treat adults with acute lymphoblastic leukaemia. acute lymphoblastic leukaemia is a cancer of the blood in which a particular kind of white blood cell called \"b-lymphocyte\" is growing out of control. this medicine works by enabling your immune system to attack and destroy these abnormal white blood cancer cells. blincyto is used when acute lymphoblastic leukaemia has come back or has not responded to previous treatment (referred to as relapsed/refractory acute lymphoblastic leukaemia). it is also used in patients with acute lymphoblastic leukaemia who still have a small number of cancer cells remaining after previous treatment (referred to as minimal residual disease). blincyto is used to treat children (≥ 1 year old), teenagers and young adults with acute lymphoblastic leukaemia (all) when previous treatments have not worked or have stopped working.', 'Entity_Recognition': [{'Text': 'blincyto', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 25, 'EndOffset': 33, 'Score': 0.39556774497032166, 'Text': 'blincyto', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 37, 'EndOffset': 49, 'Score': 0.9883153438568115, 'Text': 'blinatumomab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a group of medicines', 'Type': 'TREATMENT', 'BeginOffset': 67, 'EndOffset': 87}, {'Id': 17, 'BeginOffset': 95, 'EndOffset': 116, 'Score': 0.5930503010749817, 'Text': 'antineoplastic agents', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'target cancer cells', 'Type': 'PROBLEM', 'BeginOffset': 123, 'EndOffset': 142}, {'Text': 'acute lymphoblastic leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 182, 'EndOffset': 211}, {'Text': 'acute lymphoblastic leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 213, 'EndOffset': 242}, {'Text': 'a cancer', 'Type': 'PROBLEM', 'BeginOffset': 246, 'EndOffset': 254}, {'Text': 'the blood', 'Type': 'PROBLEM', 'BeginOffset': 258, 'EndOffset': 267}, {'Text': 'white blood cell', 'Type': 'TEST', 'BeginOffset': 298, 'EndOffset': 314}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 364, 'EndOffset': 377}, {'Text': 'these abnormal white blood cancer cells', 'Type': 'PROBLEM', 'BeginOffset': 437, 'EndOffset': 476}, {'Text': 'acute lymphoblastic leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 500, 'EndOffset': 529}, {'Text': 'previous treatment', 'Type': 'TREATMENT', 'BeginOffset': 568, 'EndOffset': 586}, {'Id': 10, 'BeginOffset': 603, 'EndOffset': 652, 'Score': 0.4433751404285431, 'Text': 'relapsed/refractory acute lymphoblastic leukaemia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9565421938896179}]}, {'Text': 'acute lymphoblastic leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 688, 'EndOffset': 717}, {'Text': 'cancer cells', 'Type': 'PROBLEM', 'BeginOffset': 751, 'EndOffset': 763}, {'Text': 'previous treatment', 'Type': 'TREATMENT', 'BeginOffset': 780, 'EndOffset': 798}, {'Text': 'minimal residual disease)', 'Type': 'PROBLEM', 'BeginOffset': 815, 'EndOffset': 840}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 880, 'EndOffset': 881}, {'Text': 'acute lymphoblastic leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 925, 'EndOffset': 954}, {'Text': 'previous treatments', 'Type': 'TREATMENT', 'BeginOffset': 966, 'EndOffset': 985}]}"},"Section_2":{"kind":"string","value":"{'Title': '2. what you need to know before you use blincyto', 'Section_Content': \"do not use blincyto: - if you are allergic to blinatumomab or any of the other ingredients of this medicine (listed in section 6). - if you are breast-feeding. warnings and precautions talk to your doctor, pharmacist or nurse before using blincyto if any of these apply to you. blincyto may not be suitable for you: if you have ever had neurological problems, for example, shaking (or tremor), abnormal sensations, seizures, memory loss, confusion, disorientation, loss of balance, or difficulty in speaking. if you are still suffering from active neurological problems or conditions, tell your doctor. if your leukaemia has spread to your brain and/or spinal cord, your doctor may have to treat this first before you can start treatment with blincyto. your doctor will assess your nervous system and conduct tests before deciding if you should receive blincyto. your doctor may need to take special care of you during your treatment with blincyto. if you have an active infection. if you have ever had an infusion reaction after previously using blincyto. symptoms may include wheezing, flushing, face swelling, difficulty breathing, low or high blood pressure. if you think you may need any vaccinations in the near future, including those needed to travel to other countries. some vaccines must not be given within two weeks before, at the same time as or in the months after you receive treatment with blincyto. your doctor will check if you should have the vaccination. tell your doctor, pharmacist or nurse immediately if you experience any of the following reactions whilst receiving blincyto as these may need to be treated and your dose adjusted: if you experience seizures, difficulty in speaking or slurred speech, confusion and disorientation, or loss of balance. if you develop chills or shivering, or feel warm; you should take your temperature as you may have a fever - these may be symptoms of an infection. if you develop a reaction at any time during your infusion, which may include dizziness, feeling faint, nauseated, face swelling, difficulty breathing, wheezing, or rash. if you have severe and persistent stomach pain, with or without nausea and vomiting, as these may be symptoms of a serious and potentially fatal condition known as pancreatitis (inflammation of the pancreas). your doctor or nurse will monitor you for signs and symptoms of these reactions. tell your doctor, pharmacist or nurse immediately if you became pregnant whilst receiving blincyto. your doctor will talk to you about precautions in using vaccinations for your baby. before each infusion cycle of blincyto, you will be given medicines which help reduce a potentially life-threatening complication known as tumour lysis syndrome, which is caused by chemical disturbances in the blood due to the breakdown of dying cancer cells. you may also be given medicines to reduce fever. during treatment, especially in the first few days after treatment start, you may experience a severe low white blood cell count (neutropenia), severe low white blood cell count with a fever (febrile neutropenia), elevated liver enzymes, or elevated uric acid. your doctor will take regular blood tests to monitor your blood counts during treatment with blincyto. children and adolescents blincyto should not be used in children below 1 year of age. other medicines and blincyto tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines. pregnancy and breast-feeding if you are pregnant, are breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or nurse for advice before taking this medicine. contraception women who are able to become pregnant have to use effective contraception during treatment and for at least 48 hours after your last treatment. talk to your doctor or nurse about suitable methods of contraception. pregnancy the effects of blincyto in pregnant women are not known but based on its mechanism of action, blincyto may harm your unborn baby. you should not use blincyto during pregnancy, unless your doctor thinks that it is the best medicine for you. if you become pregnant during blincyto treatment, please inform your doctor or nurse. your doctor will talk to you about precautions in using vaccinations for your baby. breast-feeding you must not breast-feed during and for at least 48 hours after your last treatment. it is not known whether blincyto is excreted in breast milk but a risk for suckling baby cannot be excluded. driving and using machines do not drive, use heavy machines, or engage in hazardous activities while you are being given blincyto. blincyto can cause neurological problems such as dizziness, seizures, confusion, coordination and balance disorders. blincyto contains sodium this medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 'sodium-free'.\", 'Entity_Recognition': [{'Text': 'blincyto', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 3, 'BeginOffset': 11, 'EndOffset': 19, 'Score': 0.43430274724960327, 'Text': 'blincyto', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 34, 'EndOffset': 42}, {'Id': 4, 'BeginOffset': 46, 'EndOffset': 58, 'Score': 0.9744138717651367, 'Text': 'blinatumomab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 94, 'EndOffset': 107}, {'Id': 5, 'BeginOffset': 239, 'EndOffset': 247, 'Score': 0.5667914152145386, 'Text': 'blincyto', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 14, 'BeginOffset': 278, 'EndOffset': 286, 'Score': 0.33402347564697266, 'Text': 'blincyto', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 15, 'BeginOffset': 337, 'EndOffset': 358, 'Score': 0.9303174018859863, 'Text': 'neurological problems', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8834717273712158}]}, {'Id': 16, 'BeginOffset': 373, 'EndOffset': 380, 'Score': 0.9379701018333435, 'Text': 'shaking', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9449137449264526}]}, {'Id': 17, 'BeginOffset': 385, 'EndOffset': 391, 'Score': 0.9817041754722595, 'Text': 'tremor', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.948353111743927}]}, {'Id': 18, 'BeginOffset': 394, 'EndOffset': 413, 'Score': 0.8776080012321472, 'Text': 'abnormal sensations', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9548762440681458}]}, {'Id': 19, 'BeginOffset': 415, 'EndOffset': 423, 'Score': 0.9983270764350891, 'Text': 'seizures', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9668914675712585}]}, {'Id': 20, 'BeginOffset': 425, 'EndOffset': 436, 'Score': 0.9922711849212646, 'Text': 'memory loss', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9577546119689941}]}, {'Id': 21, 'BeginOffset': 438, 'EndOffset': 447, 'Score': 0.9991570711135864, 'Text': 'confusion', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9775951504707336}]}, {'Id': 22, 'BeginOffset': 449, 'EndOffset': 463, 'Score': 0.9982446432113647, 'Text': 'disorientation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9631183743476868}]}, {'Id': 23, 'BeginOffset': 465, 'EndOffset': 480, 'Score': 0.9957316517829895, 'Text': 'loss of balance', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9348769783973694}]}, {'Id': 24, 'BeginOffset': 485, 'EndOffset': 507, 'Score': 0.9506481885910034, 'Text': 'difficulty in speaking', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8143515586853027}]}, {'Text': 'active neurological problems', 'Type': 'PROBLEM', 'BeginOffset': 541, 'EndOffset': 569}, {'Text': 'your leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 606, 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how you tolerate and respond to blincyto. your doctor will discuss with you how long your treatment will last. your treatment may also be interrupted depending on how you tolerate blincyto. if you have relapsed/refractory acute lymphoblastic leukaemia it is recommended that the first 9 days of treatment and the first two days of the second cycle will be given to you in a hospital or clinic under the supervision of a doctor or nurse experienced in the use of anti-cancer medicines. if you have minimal residual disease acute lymphoblastic leukaemia, it is recommended that the first 3 days of treatment and the first 2 days of subsequent cycles will be given to you in a hospital or clinic under the supervision of a doctor or nurse experienced in the use of anti-cancer medicines. if you have or had neurological problems, it is recommended that the first 14 days of treatment will be given to you in a hospital or clinic. your doctor will discuss with you if you can continue treatment at home after your initial hospital stay. treatment may include a bag change by a nurse. your doctor will determine when your blincyto infusion bag will be changed, which may range from every day to every 4 days. the infusion rate may be faster or slower depending on how often the bag is changed. your first cycle if you have relapsed/refractory acute lymphoblastic leukaemia and your body weight is greater than or equal to 45 kilograms the recommended initial dose in your first cycle is 9 micrograms per day for 1 week. your doctor may decide to then increase your dose to 28 micrograms per day for weeks 2, 3, and 4 of your treatment. if your body weight is less than 45 kilograms, the recommended initial dose in your first cycle will be based on your weight and height. your doctor may decide to then increase your dose for weeks 2, 3, and 4 of your treatment. if you have minimal residual disease acute lymphoblastic leukaemia, your dose of blincyto will be 28 micrograms per day throughout the first cycle. your next cycles if your doctor determines that you should be given more cycles of blincyto and if your body weight is greater than or equal to 45 kilograms, your pump will be set to infuse a dose of 28 micrograms per day. if your doctor determines that you should be given more cycles of blincyto and if your body weight is less than 45 kilograms, your pump will be set to infuse a dose based on your weight and height. medicines given before each cycle of blincyto before your treatment with blincyto, you will be given other medicines (pre-medication) to help reduce infusion reactions and other possible side effects. these may include corticosteroids (e.g. dexamethasone). infusion catheter if you have a catheter for infusion, it is very important to keep the area around the catheter clean; otherwise you could get an infection. your doctor or nurse will show you how to care for your catheter site. infusion pump and intravenous tubing do not adjust the settings on the pump, even if 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effects: chills, shivering, fever, rapid heart rate, decreased blood pressure, aching muscles, feeling tired, coughing, difficulty breathing, confusion, redness, swelling or discharge in the affected area or at the site of the infusion line - these may be signs of an infection. neurologic events: shaking (or tremor), confusion, disturbances of brain function (encephalopathy), difficulty in communicating (aphasia), seizure (convulsion). fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may become severe - these may be signs of a so-called cytokine release syndrome. if you have severe and persistent stomach pain, with or without nausea and vomiting, as these may be symptoms of a serious and potentially fatal condition known as pancreatitis (inflammation of the pancreas). treatment with blincyto can cause a decrease in the levels of certain white blood cells with or without fever (febrile neutropenia or neutropenia) or can lead to increased blood levels of potassium, uric acid, and phosphate and decreased blood levels of calcium (tumour lysis syndrome). your doctor will take regular blood tests during treatment with blincyto. other side effects include: very common side effects (may affect more than 1 in 10 people): infections in the blood including bacteria, fungi, viruses, or other types of infection decreased levels of certain white blood cells with or without fever ((febrile) neutropenia, leukopenia), decreased levels of red blood cells, decreased levels of platelets fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may become severe (cytokine release syndrome) not being able to sleep headache, shaking (or tremor) rapid heart rate (tachycardia) low blood pressure cough nausea, diarrhoea, vomiting, constipation, abdominal pain rash back pain, pain in extremity fever (pyrexia), swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing (oedema), chills low levels of antibodies called \"immunoglobulins\" which help the immune system fight infection (decreased immunoglobulins) increased levels of liver enzymes (alt, ast, ggt) reactions related to infusion may include, wheezing, flushing, face swelling, difficulty breathing, low blood pressure, high blood pressure. common side effects (may affect up to 1 in 10 people): serious infection which can result in organ failure, shock or can be fatal (sepsis) lung infection (pneumonia) increased levels of white blood cell count (leucocytosis), decreased levels of certain white blood cells (lymphopenia) allergic reaction complications occurring after cancer treatment leading to increased blood levels of potassium, uric acid, and phosphate and decreased blood levels of calcium (tumour lysis syndrome) confusion, disorientation disturbances of brain function (encephalopathy) such as difficulty in communicating (aphasia), tingling of skin (paraesthesia), seizure, difficulty thinking or processing thoughts, difficulty remembering, difficulty in controlling movement (ataxia) feeling sleepy (somnolence), numbness, dizziness nerve problems affecting the head and neck such as visual disturbances, drooping eyelid and/or sagging muscles on one side of the face, difficulty hearing or trouble swallowing (cranial nerve disorders) wheezing or difficulty in breathing (dyspnoea), breathlessness (respiratory failure) high blood pressure (hypertension) flushing coughing with phlegm increased bilirubin in the blood bone pain chest pain or other pain high levels of some enzymes including blood enzymes increase in your weight uncommon side effects (may affect up to 1 in 100 people): excessive activation of white blood cells associated with inflammation (hemophagocytic histiocytosis) swollen lymph nodes (lymphadenopathy) fever, swelling, chills, decreased or increased blood pressure and fluid in the lungs, which may be severe and can be fatal (cytokine storm) a condition which causes fluid to leak from the small blood vessels into your body (capillary leak syndrome) difficulty in speaking additionally, the side effects that happened more often in adolescents and children include: decreased levels of red blood cells (anaemia), decreased levels of platelets (thrombocytopenia), decreased levels of certain white blood cells (leukopenia) fever (pyrexia) reactions related to infusion may include face swelling, low blood pressure, high blood pressure (infusion-related reaction) increase in your weight high blood pressure (hypertension) reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'blincyto', 'Type': 'PRODUCT_NAME', 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0.706728458404541}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 5134, 'EndOffset': 5147}]}"},"Section_5":{"kind":"string","value":"{'Title': '5. how to store blincyto', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label and carton after exp. the expiry date refers to the last day of that month. unopened vials: - store and transport refrigerated (2 - 8). - do not freeze. - store in the original carton in order to protect from light. reconstituted solution (blincyto solution): - when refrigerated, the reconstituted solution must be used within 24 hours. alternatively the vials can be stored at room temperature (up to 27) for up to 4 hours. diluted solution (prepared infusion bag): if your infusion bag is changed at home: - infusion bags containing blincyto solution for infusion will arrive in special packaging containing cooling packs. do not open the package. store the package at room temperature (up to 27). do not refrigerate or freeze the package. - the package will be opened by your nurse and the infusion bags will be stored in a refrigerator until infusion. - when refrigerated, the infusion bags must be used within 10 days of preparation. - once at room temperature (up to 27) the solution will be infused within 96 hours. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'blincyto', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'reconstituted solution (blincyto solution', 'Type': 'TREATMENT', 'BeginOffset': 351, 'EndOffset': 392}, {'Text': 'the reconstituted solution', 'Type': 'TREATMENT', 'BeginOffset': 416, 'EndOffset': 442}, {'Id': 4, 'BeginOffset': 456, 'EndOffset': 471, 'Score': 0.9109519720077515, 'Text': 'within 24 hours', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_MEDICATION_NAME', 'Traits': [], 'Attributes': [{'Type': 'GENERIC_NAME', 'Score': 0.31020620465278625, 'RelationshipScore': 0.6317497491836548, 'RelationshipType': 'OVERLAP', 'Id': 0, 'BeginOffset': 375, 'EndOffset': 392, 'Text': 'blincyto solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 463, 'EndOffset': 465}, {'Text': '27', 'Type': 'NUMBER', 'BeginOffset': 538, 'EndOffset': 540}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 552, 'EndOffset': 553}, {'Text': 'diluted solution (prepared infusion bag', 'Type': 'TREATMENT', 'BeginOffset': 561, 'EndOffset': 600}, {'Text': 'your infusion bag', 'Type': 'TREATMENT', 'BeginOffset': 606, 'EndOffset': 623}, {'Text': 'infusion bags', 'Type': 'TREATMENT', 'BeginOffset': 646, 'EndOffset': 659}, {'Text': 'blincyto solution', 'Type': 'TREATMENT', 'BeginOffset': 671, 'EndOffset': 688}, {'Text': 'infusion', 'Type': 'TREATMENT', 'BeginOffset': 693, 'EndOffset': 701}, {'Text': 'cooling packs', 'Type': 'TREATMENT', 'BeginOffset': 746, 'EndOffset': 759}, {'Text': '27', 'Type': 'NUMBER', 'BeginOffset': 831, 'EndOffset': 833}, {'Text': 'the package', 'Type': 'TREATMENT', 'BeginOffset': 880, 'EndOffset': 891}, {'Text': 'the infusion bags', 'Type': 'TREATMENT', 'BeginOffset': 925, 'EndOffset': 942}, {'Text': 'infusion', 'Type': 'TREATMENT', 'BeginOffset': 982, 'EndOffset': 990}, {'Text': 'the infusion bags', 'Type': 'TREATMENT', 'BeginOffset': 1013, 'EndOffset': 1030}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 1051, 'EndOffset': 1053}, {'Text': '27', 'Type': 'NUMBER', 'BeginOffset': 1109, 'EndOffset': 1111}, {'Text': '96', 'Type': 'NUMBER', 'BeginOffset': 1149, 'EndOffset': 1151}]}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': 'what blincyto contains - the active substance is blinatumomab. each vial of powder contains 38.5 micrograms of blinatumomab. reconstitution with water for injections results in a final blinatumomab concentration of 12.5 micrograms/ml. - the other ingredients in the powder are citric acid monohydrate (e330), trehalose dihydrate, lysine hydrochloride, polysorbate 80, and sodium hydroxide. - the solution (stabiliser) contains citric acid monohydrate (e330), lysine hydrochloride, polysorbate 80, sodium hydroxide and water for injections. what blincyto looks like and contents of the pack blincyto is a powder for concentrate and solution for solution for infusion. each pack of blincyto contains: 1 glass vial containing a white to off-white powder. 1 glass vial containing a colourless-to-slightly yellow, clear solution.', 'Entity_Recognition': [{'Text': 'blincyto', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 49, 'EndOffset': 61, 'Score': 0.9882578253746033, 'Text': 'blinatumomab', 'Category': 'MEDICATION', 'Type': 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NAME OF THE MEDICINAL PRODUCT \n \nImatinib Actavis 50 mg hard capsules \nImatinib Actavis 100 mg hard capsules \nImatinib Actavis 400 mg hard capsules \n \n \n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \nImatinib Actavis 50 mg hard capsules \nEach hard capsule contains 50 mg imatinib (as mesilate). \n \nImatinib Actavis 100 mg hard capsules \nEach hard capsule contains 100 mg imatinib (as mesilate). \n \nImatinib Actavis 400 mg hard capsules \nEach hard capsule contains 400 mg imatinib (as mesilate). \n \nFor the full list of excipients, see section 6.1. \n \n \n3. PHARMACEUTICAL FORM \n \nHard capsule (capsule). \n \nImatinib Actavis 50 mg hard capsules \nHard capsule of size 3 with light yellow cap and light yellow body imprinted with “50 mg” in black \nink. \n \nImatinib Actavis 100 mg hard capsules \nHard capsule of size 1 with light orange cap and light orange body imprinted with “100 mg” in black \nink. \n \nImatinib Actavis 400 mg hard capsules \nHard capsule of size 00 with orange opaque colour cap and body imprinted with “400 mg” in black \nink. \n \n \n4. CLINICAL PARTICULARS \n \n4.1 Therapeutic indications \n \nImatinib Actavis is indicated for the treatment of \n- paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) \n\nchronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as \nthe first line of treatment. \n\n- paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or \nin accelerated phase or blast crisis. \n\n- adult patients with Ph+ CML in blast crisis. \n- adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute \n\nlymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy. \n- adult patients with relapsed or refractory Ph+ ALL as monotherapy. \n- adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with \n\nplatelet-derived growth factor receptor (PDGFR) gene re-arrangements. \n- adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic \n\nleukaemia (CEL) with FIP1L1-PDGFRα rearrangement. \n \n\n2 \n\n\n\nThe effect of imatinib on the outcome of bone marrow transplantation has not been determined. \n \nImatinib Actavis is indicated for \n- the treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and \n\nadult patients with recurrent and/or metastatic DFSP who are not eligible for surgery. \n \nIn adult and paediatric patients, the effectiveness of imatinib is based on overall haematological and \ncytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic \nresponse rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on \nobjective response rates in adult patients with unresectable and/or metastatic DFSP. The experience \nwith imatinib in patients with MDS/MPD associated with PDGFR gene re-arrangements is very \nlimited (see section 5.1). There are no controlled trials demonstrating a clinical benefit or increased \nsurvival for these diseases. \n \n4.2 Posology and method of administration \n \nTherapy should be initiated by a physician experienced in the treatment of patients with \nhaematological malignancies and malignant sarcomas, as appropriate. \n \nPosology \n \nPosology for CML in adult patients \nThe recommended dose of imatinib is 600 mg/day for adult patients in blast crisis. Blast crisis is \ndefined as blasts ≥ 30% in blood or bone marrow or extramedullary disease other than \nhepatosplenomegaly. \n \nTreatment duration: In clinical trials, treatment with imatinib was continued until disease progression. \nThe effect of stopping treatment after the achievement of a complete cytogenetic response has not \nbeen investigated. \n \nDose increases from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients with \nblast crisis may be considered in the absence of severe adverse drug reaction and severe non-\nleukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease \nprogression (at any time); failure to achieve a satisfactory haematological response after at least \n3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss \nof a previously achieved haematological and/or cytogenetic response. Patients should be monitored \nclosely following dose escalation given the potential for an increased incidence of adverse reactions at \nhigher dosages. \n \nPosology for CML in paediatric patients \nDosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily \nis recommended for children with chronic phase CML and advanced phase CML (not to exceed the \ntotal dose of 800 mg). Treatment can be given as a once daily dose or alternatively the daily dose may \nbe split into two administrations – one in the morning and one in the evening. The dose \nrecommendation is currently based on a small number of paediatric patients (see sections 5.1 and 5.2). \nThere is no experience with the treatment of children below 2 years of age. \n \nDose increases from 340 mg/m2 daily to 570 mg/m2 daily (not to exceed the total dose of 800 mg) may \nbe considered in children in the absence of severe adverse drug reaction and severe non-leukaemia-\nrelated neutropenia or thrombocytopenia in the following circumstances: disease progression (at any \ntime); failure to achieve a satisfactory haematological response after at least 3 months of treatment; \nfailure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved \nhaematological and/or cytogenetic response. Patients should be monitored closely following dose \nescalation given the potential for an increased incidence of adverse reactions at higher dosages. \n \nPosology for Ph+ ALL in adult patients \n\n3 \n\n\n\nThe recommended dose of imatinib is 600 mg/day for adult patients with Ph+ ALL. Haematological \nexperts in the management of this disease should supervise the therapy throughout all phases of care. \n \nTreatment schedule: On the basis of the existing data, imatinib has been shown to be effective and safe \nwhen administered at 600 mg/day in combination with chemotherapy in the induction phase, the \nconsolidation and maintenance phases of chemotherapy (see section 5.1) for adult patients with newly \ndiagnosed Ph+ ALL. The duration of imatinib therapy can vary with the treatment programme \nselected, but generally longer exposures to imatinib have yielded better results. \n \nFor adult patients with relapsed or refractory Ph+ALL imatinib monotherapy at 600 mg/day is safe, \neffective and can be given until disease progression occurs. \n \nPosology for Ph+ ALL in paediatric patients \nDosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily \nis recommended for children with Ph+ ALL (not to exceed the total dose of 600 mg). \n \nPosology for MDS/MPD \nThe recommended dose of imatinib is 400 mg/day for adult patients with MDS/MPD. \n \nTreatment duration: In the only clinical trial performed up to now, treatment with imatinib was \ncontinued until disease progression (see section 5.1). At the time of analysis, the treatment \nduration was a median of 47 months (24 days - 60 months). \n \nPosology for HES/CEL \nThe recommended dose of imatinib is 100 mg/day for adult patients with HES/CEL. \n \nDose increase from 100 mg to 400 mg may be considered in the absence of adverse drug reactions \nif assessments demonstrate an insufficient response to therapy. \n \nTreatment should be continued as long as the patient continues to benefit. \n \nPosology for DFSP \nThe recommended dose of imatinib is 800 mg/day for adult patients with DFSP. \n \nDose adjustment for adverse reactions \nNon-haematological adverse reactions \nIf a severe non-haematological adverse reaction develops with imatinib use, treatment must be \nwithheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending \non the initial severity of the event. \n \nIf elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases \n> 5 x IULN occur, imatinib should be withheld until bilirubin levels have returned to < 1.5 x IULN \nand transaminase levels to < 2.5 x IULN. Treatment with imatinib may then be continued at a reduced \ndaily dose. In adults the dose should be reduced from 400 to 300 mg or from 600 to 400 mg, or from \n800 mg to 600 mg, and in children from 340 to 260 mg/m2/day. \n \nHaematological adverse reactions \nDose reduction or treatment interruption for severe neutropenia and thrombocytopenia are \nrecommended as indicated in the table below. \n \nDose adjustments for neutropenia and thrombocytopenia: \n \nHES/CEL (starting dose \n100 mg) \n\nANC < 1.0 x 109/L \nand/or \nplatelets < 50 x 109/L \n\n1. Stop imatinib until ANC ≥ 1.5 x 109/L \nand platelets ≥ 75 x 109/L. \n\n2. Resume treatment with imatinib at \nprevious dose (i.e. before severe \nadverse reaction). \n\n4 \n\n\n\nMDS/MPD (starting dose \n400 mg) \nHES/CEL (at dose \n400 mg) \n\nANC < 1.0 x 109/L \nand/or \nplatelets < 50 x 109/L \n\n1. Stop imatinib until ANC ≥ 1.5 x 109/L \nand platelets ≥ 75 x 109/L. \n\n2. Resume treatment with imatinib at \nprevious dose (i.e. before severe \nadverse reaction). \n\n3. In the event of recurrence of ANC \n< 1.0 x 109/L and/or platelets \n< 50 x 109/L, repeat step 1 and resume \nimatinib at reduced dose of 300 mg. \n\nPaediatric chronic phase \nCML (at dose \n340 mg/m2) \n\nANC < 1.0 x 109/L \nand/or \nplatelets < 50 x 109/L \n\n1. Stop imatinib until ANC ≥ 1.5 x 109/L \nand platelets ≥ 75 x 109/L. \n\n2. Resume treatment with imatinib at \nprevious dose (i.e. before severe \nadverse reaction). \n\n3. In the event of recurrence of ANC \n< 1.0 x 109/L and/or platelets \n< 50 x 109/L, repeat step 1 and resume \nimatinib at reduced dose of \n260 mg/m2. \n\nCML in blast crisis and \nPh+ ALL (starting dose \n600 mg) \n\naANC < 0.5 x 109/L \nand/or \nplatelets < 10 x 109/L \n\n1. Check whether cytopenia is related to \nleukaemia (marrow aspirate or \nbiopsy). \n\n2. If cytopenia is unrelated to leukaemia, \nreduce dose of imatinib to 400 mg. \n\n3. If cytopenia persists for 2 weeks, \nreduce further to 300 mg. \n\n4. If cytopenia persists for 4 weeks and \nis still unrelated to leukaemia, stop \nimatinib until ANC ≥ 1 x 109/L and \nplatelets ≥ 20 x 109/L, then resume \ntreatment at 300 mg. \n\nPaediatric accelerated \nphase CML and blast \ncrisis (starting dose \n340 mg/m2) \n\naANC < 0.5 x 109/L \nand/or \nplatelets < 10 x 109/L \n\n1. Check whether cytopenia is related to \nleukaemia (marrow aspirate or \nbiopsy). \n\n2. If cytopenia is unrelated to leukaemia, \nreduce dose of imatinib to 260 mg/m2. \n\n3. If cytopenia persists for 2 weeks, \nreduce further to 200 mg/m2. \n\n4. If cytopenia persists for 4 weeks and \nis still unrelated to leukaemia, stop \nimatinib until ANC ≥ 1 x 109/L and \nplatelets ≥ 20 x 109/L, then resume \ntreatment at 200 mg/m2. \n\nDFSP (at dose 800 mg) ANC < 1.0 x 109/L \nand/or \nplatelets < 50 x 109/L \n\n1. Stop imatinib until ANC ≥ 1.5 x 109/L \nand platelets ≥ 75 x 109/L. \n\n2. Resume treatment with imatinib at \n600 mg. \n\n3. In the event of recurrence of ANC \n< 1.0 x 109/L and/or platelets \n< 50 x 109/L, repeat step 1 and resume \nimatinib at reduced dose of 400 mg. \n\nANC = absolute neutrophil count \na occurring after at least 1 month of treatment \n \nSpecial populations \n \n\n5 \n\n\n\nPaediatric use: There is no experience in children with CML below 2 years of age and with Ph+ALL \nbelow 1 year of age (see section 5.1).There is very limited experience in children with MDS/MPD, \nDFSP, and HES/CEL. \n \nThe safety and efficacy of imatinib in children with MDS/MPD, DFSP and HES/CEL aged less than \n18 years of age have not been established in clinical trials. Currently available published data are \nsummarised in section 5.1 but no recommendation on a posology can be made. \n \nHepatic insufficiency: Imatinib is mainly metabolised through the liver. Patients with mild, moderate \nor severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The \ndose can be reduced if not tolerated (see sections 4.4, 4.8 and 5.2). \n \nLiver dysfunction classification: \n \nLiver dysfunction Liver function tests \nMild Total bilirubin: = 1.5 ULN \n\nAST: >ULN (can be normal or <ULN if total bilirubin is >ULN) \nModerate Total bilirubin: >1.5-3.0 ULN \n\nAST: any \nSevere Total bilirubin: >3-10 ULN \n\nAST: any \nULN = upper limit of normal for the institution \nAST = aspartate aminotransferase \n \nRenal insufficiency: Patients with renal dysfunction or on dialysis should be given the minimum \nrecommended dose of 400 mg daily as starting dose. However, in these patients caution is \nrecommended. The dose can be reduced if not tolerated. If tolerated, the dose can be increased for lack \nof efficacy (see sections 4.4 and 5.2). \n \nElderly patients: Imatinib pharmacokinetics have not been specifically studied in older people. No \nsignificant age-related pharmacokinetic differences have been observed in adult patients in clinical \ntrials which included over 20% of patients age 65 and older. No specific dose recommendation is \nnecessary in older people. \n \nMethod of administration \n \nThe prescribed dose should be administered orally with a meal and a large glass of water to minimise \nthe risk of gastrointestinal irritations. Doses of 400 mg or 600 mg should be administered once daily, \nwhereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in \nthe evening. \n \nFor patients (children) unable to swallow the capsules, their content may be diluted in a glass of either \nstill water or apple juice. Since studies in animals have shown reproductive toxicity, and the potential \nrisk for the human foetus is unknown, women of child-bearing potential who open capsules should be \nadvised to handle the contents with caution and avoid skin-eye contact or inhalation (see section 4.6). \nHands should be washed immediately after handling open capsules. \n \n4.3 Contraindications \n \nHypersensitivity to the active substance or to any of the excipients listed in section 6.1. \n \n4.4 Special warnings and precautions for use \n \nWhen imatinib is co-administered with other medicinal products, there is a potential for drug \ninteractions. Caution should be used when taking imatinib with protease inhibitors, azole antifungals, \ncertain macrolides (see section 4.5), CYP3A4 substrates with a narrow therapeutic window (e.g. \ncyclosporine, pimozide tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, \n\n6 \n\n\n\nterfenadine, bortezomib, docetaxel, quinidine) or warfarin and other coumarin derivatives (see \nsection 4.5). \n \nConcomitant use of imatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, \nphenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. \nJohn’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of \ntherapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should be \navoided (see section 4.5). \n \nHypothyroidism \nClinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing \nlevothyroxine replacement during treatment with imatinib (see section 4.5). Thyroid stimulating \nhormone (TSH) levels should be closely monitored in such patients. \n \nHepatotoxicity \nMetabolism of imatinib is mainly hepatic, and only 13% of excretion is through the kidneys. In \npatients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver \nenzymes should be carefully monitored (see sections 4.2, 4.8 and 5.2). It should be noted that GIST \npatients may have hepatic metastases which could lead to hepatic impairment. \n \nCases of liver injury, including hepatic failure and hepatic necrosis, have been observed with imatinib. \nWhen imatinib is combined with high dose chemotherapy regimens, an increase in serious hepatic \nreactions has been detected. Hepatic function should be carefully monitored in circumstances where \nimatinib is combined with chemotherapy regimens also known to be associated with hepatic \ndysfunction (see sections 4.5 and 4.8). \n \nFluid retention \nOccurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, \nsuperficial oedema) have been reported in approximately 2.5% of newly diagnosed CML patients \ntaking imatinib. Therefore, it is highly recommended that patients be weighed regularly. An \nunexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive \ncare and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence \nof these events in elderly patients and those with a prior history of cardiac disease. Therefore, caution \nshould be exercised in patients with cardiac dysfunction. \n \nPatients with cardiac disease \nPatients with cardiac disease, risk factors for cardiac failure or history of renal failure should be \nmonitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure \nshould be evaluated and treated. \n \nIn patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the \nmyocardium, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated \nwith HES cell degranulation upon the initiation of imatinib therapy. The condition was reported to be \nreversible with the administration of systemic steroids, circulatory support measures and temporarily \nwithholding imatinib. As cardiac adverse events have been reported uncommonly with imatinib, a \ncareful assessment of the benefit/risk of imatinib therapy should be considered in the HES/CEL \npopulation before treatment initiation. \n \nMyelodysplastic/myeloproliferative diseases with PDGFR gene re-arrangements could be associated \nwith high eosinophil levels. Evaluation by a cardiology specialist, performance of an echocardiogram \nand determination of serum troponin should therefore be considered in patients with HES/CEL, and in \npatients with MDS/MPD associated with high eosinophil levels before imatinib is administered. If \neither is abnormal, follow-up with a cardiology specialist and the prophylactic use of systemic steroids \n(1-2 mg/kg) for one to two weeks concomitantly with imatinib should be considered at the initiation of \ntherapy. \n \nGastrointestinal haemorrhage \n\n7 \n\n\n\nIn the study in patients with unresectable and/or metastatic GIST, both gastrointestinal and \nintra-tumoural haemorrhages were reported (see section 4.8). Based on the available data, no \npredisposing factors (e.g. tumour size, tumour location, coagulation disorders) have been identified \nthat place patients with GIST at a higher risk of either type of haemorrhage. Since increased \nvascularity and propensity for bleeding is a part of the nature and clinical course of GIST, standard \npractices and procedures for the monitoring and management of haemorrhage in all patients should be \napplied. \nIn addition, gastric antral vascular ectasia (GAVE), a rare cause of gastrointestinal haemorrhage, has \nbeen reported in post-marketing experience in patients with CML, ALL and other diseases (see \nsection 4.8). When needed, discontinuation of imatinib treatment may be considered. \n \nTumour lysis syndrome \nDue to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significant \ndehydration and treatment of high uric acid levels are recommended prior to initiation of imatinib (see \nsection 4.8). \n \nHepatitis B reactivation \nReactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these \npatients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or \nfulminant hepatitis leading to liver transplantation or a fatal outcome. \nPatients should be tested for HBV infection before initiating treatment with Imatinib Actavis. Experts \nin liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in \npatients with positive hepatitis B serology (including those with active disease) and for patients who \ntest positive for HBV infection during treatment. Carriers of HBV who require treatment with Imatinib \nActavis should be closely monitored for signs and symptoms of active HBV infection throughout \ntherapy and for several months following termination of therapy (see section 4.8). \n \nPhototoxicity \nExposure to direct sunlight should be avoided or minimised due to the risk of phototoxicity associated \nwith imatinib treatment. Patients should be instructed to use measures such as protective clothing and \nsunscreen with high sun protection factor (SPF). \n \nThrombotic microangiopathy \nBCR-ABL tyrosine kinase inhibitors (TKIs) have been associated with thrombotic microangiopathy \n(TMA), including individual case reports for Imatinib Actavis (see section 4.8). If laboratory or \nclinical findings associated with TMA occur in a patient receiving Imatinib Actavis, treatment should \nbe discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti-\nADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevated \nin conjunction with low ADAMTS13 activity, treatment with Imatinib Actavis should not be resumed. \n \nLaboratory tests \nComplete blood counts must be performed regularly during therapy with imatinib. Treatment of CML \npatients with imatinib has been associated with neutropenia or thrombocytopenia. However, the \noccurrence of these cytopenias is likely to be related to the stage of the disease being treated and they \nwere more frequent in patients with accelerated phase CML or blast crisis as compared to patients with \nchronic phase CML. Treatment with imatinib may be interrupted or the dose may be reduced, as \nrecommended in section 4.2. \n \nLiver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in \npatients receiving imatinib. \n \nIn patients with impaired renal function, imatinib plasma exposure seems to be higher than that in \npatients with normal renal function, probably due to an elevated plasma level of alpha-acid \nglycoprotein (AGP), an imatinib-binding protein, in these patients. Patients with renal impairment \nshould be given the minimum starting dose. Patients with severe renal impairment should be treated \nwith caution. The dose can be reduced if not tolerated (see sections 4.2 and 5.2). \n \n\n8 \n\n\n\nLong-term treatment with imatinib may be associated with a clinically significant decline in renal \nfunction. Renal function should, therefore, be evaluated prior to the start of imatinib therapy and \nclosely monitored during therapy, with particular attention to those patients exhibiting risk factors for \nrenal dysfunction. If renal dysfunction is observed, appropriate management and treatment should be \nprescribed in accordance with standard treatment guidelines. \n \nPaediatric population \nThere have been case reports of growth retardation occurring in children and pre-adolescents receiving \nimatinib. In an observational study in the CML paediatric population, a statistically significant \ndecrease (but of uncertain clinical relevance) in median height standard deviation scores after 12 and \n24 months of treatment was reported in two small subsets irrespective of pubertal status or gender. \nClose monitoring of growth in children under imatinib treatment is recommended (see section 4.8). \n \nExcipients(s) \n \nSodium \nThis medicinal product contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say \nessentially ‘sodium-free’. \n \n4.5 Interaction with other medicinal products and other forms of interaction \n \nActive substances that may increase imatinib plasma concentrations: \nSubstances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. protease inhibitors \nsuch as indinavir, lopinavir/ritonavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; azole \nantifungals including ketoconazole, itraconazole, posaconazole, voriconazole; certain macrolides such \nas erythromycin, clarithromycin and telithromycin) could decrease metabolism and increase imatinib \nconcentrations. There was a significant increase in exposure to imatinib (the mean Cmax and AUC of \nimatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a \nsingle dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering \nimatinib with inhibitors of the CYP3A4 family. \n \nActive substances that may decrease imatinib plasma concentrations: \nSubstances that are inducers of CYP3A4 activity e.g. dexamethasone, phenytoin, carbamazepine, \nrifampicin, phenobarbital, fosphenytoin, primidone or Hypericum perforatum, also known as \nSt. John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of \ntherapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed by a single \n400 mg dose of imatinib resulted in decrease in Cmax and AUC(0-∞) by at least 54% and 74%, of the \nrespective values without rifampicin treatment. Similar results were observed in patients with \nmalignant gliomas treated with imatinib while taking enzyme-inducing anti-epileptic medicinal \nproducts (EIAEDs) such as carbamazepine, oxcarbazepine and phenytoin. The plasma AUC for \nimatinib decreased by 73% compared to patients not on EIAEDs. Concomitant use of rifampicin or \nother strong CYP3A4 inducers and imatinib should be avoided. \n \nActive substances that may have their plasma concentration altered by imatinib \nImatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, \nrespectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended \nwhen administering imatinib with CYP3A4 substrates with a narrow therapeutic window (e.g. \ncyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, \nterfenadine, bortezomib, docetaxel and quinidine). Imatinib may increase plasma concentration of \nother CYP3A4 metabolised drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel \nblockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.). \n \nBecause of known increased risks of bleeding in conjunction with the use of imatinib (e.g. \nhaemorrhage), patients who require anticoagulation should receive low-molecular-weight or standard \nheparin instead of coumarin derivatives such as warfarin. \n \n\n9 \n\n\n\nIn vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar \nto those that affect CYP3A4 activity. Imatinib at 400 mg twice daily had an inhibitory effect on \nCYP2D6-mediated metoprolol metabolism, with metoprolol Cmax and AUC being increased by \napproximately 23% (90%CI [1.16-1.30]). Dose adjustments do not seem to be necessary when \nimatinib is co-administrated with CYP2D6 substrates, however caution is advised for CYP2D6 \nsubstrates with a narrow therapeutic window such as metoprolol. In patients treated with metoprolol \nclinical monitoring should be considered. \n \nIn vitro, imatinib inhibits paracetamol O-glucuronidation with Ki value of 58.5 micromol/L. This \ninhibition has not been observed in vivo after the administration of imatinib 400 mg and \nparacetamol 1000 mg. Higher doses of imatinib and paracetamol have not been studied. \n \nCaution should therefore be exercised when using high doses of imatinib and paracetamol \nconcomitantly. \n \nIn thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be \ndecreased when imatinib is co-administered (see section 4.4). Caution is therefore recommended. \nHowever, the mechanism of the observed interaction is presently unknown. \n \nIn Ph+ ALL patients, there is clinical experience of co-administering imatinib with chemotherapy (see \nsection 5.1), but drug-drug interactions between imatinib and chemotherapy regimens are not well \ncharacterised. Imatinib adverse events, i.e. hepatotoxicity, myelosuppression or others, may increase \nand it has been reported that concomitant use with L-asparaginase could be associated with increased \nhepatotoxicity (see section 4.8). Therefore, the use of imatinib in combination requires special \nprecaution. \n \n4.6 Fertility, pregnancy and lactation \n \nWomen of childbearing potential \nWomen of childbearing potential must be advised to use effective contraception during treatment. \n \nPregnancy \nThere are limited data on the use of imatinib in pregnant women. There have been post-marketing \nreports of spontaneous abortions and infant congenital anomalies from women who have taken \nimatinib. Studies in animals have however shown reproductive toxicity (see section 5.3) and the \npotential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly \nnecessary. If it is used during pregnancy, the patient must be informed of the potential risk to the \nfoetus. \n \nBreast-feeding \nThere is limited information on imatinib distribution on human milk. Studies in two breast-feeding \nwomen revealed that both imatinib and its active metabolite can be distributed into human milk. The \nmilk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the \nmetabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined \nconcentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total \nexposure would be expected to be low (~10% of a therapeutic dose). However, since the effects of \nlow-dose exposure of the infant to imatinib are unknown, women taking imatinib should not \nbreast-feed. \n \nFertility \nIn non-clinical studies, the fertility of male and female rats was not affected (see section 5.3). Studies \non patients receiving imatinib and its effect on fertility and gametogenesis have not been performed. \nPatients concerned about their fertility on imatinib treatment should consult with their physician. \n \n4.7 Effects on ability to drive and use machines \n \n\n10 \n\n\n\nPatients should be advised that they may experience undesirable effects such as dizziness,blurred \nvision or somnolence during treatment with imatinib. Therefore, caution should be recommended \nwhen driving a car or operating machinery. \n \n4.8 Undesirable effects \n \nSummary of safety profile \nPatients with advanced stages of malignancies may have numerous confounding medical conditions \nthat make causality of adverse reactions difficult to assess due to the variety of symptoms related to \nthe underlying disease, its progression, and the co-administration of numerous medicinal products. \n \nIn clinical trials in CML, drug discontinuation for drug-related adverse reactions was observed in 2.4% \nof newly diagnosed patients, 4% of patients in late chronic phase after failure of interferon therapy, \n4% of patients in accelerated phase after failure of interferon therapy and 5% of blast crisis patients \nafter failure of interferon therapy. In GIST the study drug was discontinued for drug-related adverse \nreactions in 4% of patients. \n \nThe adverse reactions were similar in all indications, with two exceptions. There was more \nmyelosuppression seen in CML patients than in GIST, which is probably due to the underlying \ndisease. In the study in patients with unresectable and/or metastatic GIST, 7 (5%) patients experienced \nCTC grade 3/4 GI bleeds (3 patients), intra-tumoural bleeds (3 patients) or both (1 patient). GI tumour \nsites may have been the source of the GI bleeds (see section 4.4). GI and tumoural bleeding may be \nserious and sometimes fatal. The most commonly reported (≥ 10%) drug-related adverse reactions in \nboth settings were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps \nand rash. Superficial oedemas were a common finding in all studies and were described primarily as \nperiorbital or lower limb oedemas. However, these oedemas were rarely severe and may be managed \nwith diuretics, other supportive measures, or by reducing the dose of imatinib. \n \n\nWhen imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient liver \ntoxicity in the form of transaminase elevation and hyperbilirubinaemia were observed. Considering the \nlimited safety database, the adverse events thus far reported in children are consistent with the known \nsafety profile in adult patients with Ph+ ALL. The safety database for children with Ph+ALL is very \nlimited though no new safety concerns have been identified. \n \nMiscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and rapid weight \ngain with or without superficial oedema may be collectively described as “fluid retention”. These \nreactions can usually be managed by withholding imatinib temporarily and with diuretics and other \nappropriate supportive care measures. However, some of these reactions may be serious or life-\nthreatening and several patients with blast crisis died with a complex clinical history of pleural \neffusion, congestive heart failure and renal failure. There were no special safety findings in paediatric \nclinical trials. \n \nAdverse reactions \nAdverse reactions reported as more than an isolated case are listed below, by system organ class and \nby frequency. Frequency categories are defined using the following convention: very common \n(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), \nvery rare (<1/10,000), not known (cannot be estimated from the available data). \n \nWithin each frequency grouping, undesirable effects are presented in order of frequency, the most \nfrequent first. \n \nAdverse reactions and their frequencies are reported in Table 1. \n \nTable 1 Tabulated summary of adverse reactions \n \nInfections and infestations \nUncommon Herpes zoster, herpes simplex, nasopharyngitis, pneumonia1, sinusitis, \n\n11 \n\n\n\ncellulitis, upper respiratory tract infection, influenza, urinary tract infection, \ngastroenteritis, sepsis \n\nRare Fungal infection \nNot known Hepatitis B reactivation* \nNeoplasm benign, malignant and unspecified (including cysts and polyps) \nRare Tumour lysis syndrome \nNot known Tumour haemorrhage/tumour necrosis* \nImmune system disorders \nNot known Anaphylactic shock* \nBlood and lymphatic system disorders \nVery common Neutropenia, thrombocytopenia, anaemia \nCommon Pancytopenia, febrile neutropenia \nUncommon Thrombocythaemia, lymphopenia, bone marrow depression, eosinophilia, \n\nlymphadenopathy \nRare Haemolytic anaemia, thrombotic microangiopathy \nMetabolism and nutrition disorders \nCommon Anorexia \nUncommon Hypokalaemia, increased appetite, hypophosphataemia, decreased appetite, \n\ndehydration, gout, hyperuricaemia, hypercalcaemia, hyperglycaemia, \nhyponatraemia \n\nRare Hyperkalaemia, hypomagnesaemia \nPsychiatric disorders \nCommon Insomnia \nUncommon Depression, libido decreased, anxiety \nRare Confusional state \nNervous system disorders \nVery common Headache2 \nCommon Dizziness, paraesthesia, taste disturbance, hypoaesthesia \nUncommon Migraine, somnolence, syncope, peripheral neuropathy, memory impairment, \n\nsciatica, restless leg syndrome, tremor, cerebral haemorrhage \nRare Increased intracranial pressure, convulsions, optic neuritis \nNot known Cerebral oedema* \nEye disorders \nCommon Eyelid oedema, lacrimation increased, conjunctival haemorrhage, \n\nconjunctivitis, dry eye, blurred vision \nUncommon Eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal \n\nhaemorrhage, blepharitis, macular oedema \nRare Cataract, glaucoma, papilloedema \nNot known Vitreous haemorrhage* \nEar and labyrinth disorders \nUncommon Vertigo, tinnitus, hearing loss \nCardiac disorders \nUncommon Palpitations, tachycardia, cardiac failure congestive3, pulmonary oedema \nRare Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina \n\npectoris, pericardial effusion \nNot known Pericarditis*, cardiac tamponade* \nVascular disorders4 \nCommon Flushing, haemorrhage \nUncommon Hypertension, haematoma, subdural haematoma, peripheral coldness, \n\nhypotension, Raynaud’s phenomenon \nNot known Thrombosis/embolism* \nRespiratory, thoracic and mediastinal disorders \nCommon Dyspnoea, epistaxis, cough \nUncommon Pleural effusion5, pharyngolaryngeal pain, pharyngitis \nRare Pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary \n\n12 \n\n\n\nhaemorrhage \nNot known Acute respiratory failure11*, interstitial lung disease* \nGastrointestinal disorders \nVery common Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain6 \nCommon Flatulence, abdominal distension, gastro-oesophageal reflux, constipation, dry \n\nmouth, gastritis \nUncommon Stomatitis, mouth ulceration, gastrointestinal haemorrhage7, eructation, \n\nmelaena, oesophagitis, ascites, gastric ulcer, haematemesis, cheilitis, \ndysphagia, pancreatitis \n\nRare Colitis, ileus, inflammatory bowel disease \nNot known Ileus/intestinal obstruction*, gastrointestinal perforation*, diverticulitis*, \n\ngastric antral vascular ectasia (GAVE)* \nHepatobiliary disorders \nCommon Increased hepatic enzymes \nUncommon Hyperbilirubinaemia, hepatitis, jaundice \nRare Hepatic failure8, hepatic necrosis \nSkin and subcutaneous tissue disorders \nVery common Periorbital oedema, dermatitis/eczema/rash \nCommon Pruritus, face oedema, dry skin, erythema, alopecia, night sweats, \n\nphotosensitivity reaction \nUncommon Rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased \n\ntendency to bruise, hypotrichosis, skin hypopigmentation, dermatitis \nexfoliative, onychoclasis, folliculitis, petechiae, psoriasis, purpura, skin \nhyperpigmentation, bullous eruptions \n\nRare Acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail \ndiscolouration, angioneurotic oedema, rash vesicular, erythema multiforme, \nleucocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalised \nexanthematous pustulosis (AGEP) \n\nNot known Palmoplantar erythrodysesthesia syndrome*, lichenoid keratosis*, lichen \nplanus*, toxic epidermal necrolysis*, drug rash with eosinophilia and \nsystemic symptoms (DRESS)*, pseudoporphyria* \n\nMusculoskeletal and connective tissue disorders \nVery common Muscle spasm and cramps, musculoskeletal pain including myalgia9, \n\narthralgia, bone pain10 \nCommon Joint swelling \nUncommon Joint and muscle stiffness \nRare Muscular weakness, arthritis, rhabdomyolysis/myopathy \nNot known Avascular necrosis/hip necrosis*, growth retardation in children* \nRenal and urinary disorders \nUncommon Renal pain, haematuria, renal failure acute, urinary frequency increased \nNot known Renal failure chronic \nReproductive system and breast disorders \nUncommon Gynaecomastia, erectile dysfunction, menorrhagia, menstruation irregular, \n\nsexual dysfunction, nipple pain, breast enlargement, scrotal oedema \nRare Haemorrhagic corpus luteum/haemorrhagic ovarian cyst \nGeneral disorders and administration site conditions \nVery common Fluid retention and oedema, fatigue \nCommon Weakness, pyrexia, anasarca, chills, rigors \nUncommon Chest pain, malaise \nInvestigations \nVery common Weight increased \nCommon Weight decreased \nUncommon Blood creatinine increased, blood creatine phosphokinase increased, blood \n\nlactate dehydrogenase increased, blood alkaline phosphatase increased \nRare Blood amylase increased \n\n13 \n\n\n\n \n* These types of reactions have been reported mainly from post-marketing experience with \n\nimatinib. This includes spontaneous case reports as well as serious adverse events from ongoing \nstudies, the expanded access programmes, clinical pharmacology studies and exploratory \nstudies in unapproved indications. Because these reactions are reported from a population of \nuncertain size, it is not always possible to reliably estimate their frequency or establish a causal \nrelationship to imatinib exposure. \n\n1 Pneumonia was reported most commonly in patients with transformed CML and in patients with \nGIST. \n\n2 Headache was the most common in GIST patients. \n3 On a patient-year basis, cardiac events including congestive heart failure were more commonly \n\nobserved in patients with transformed CML than in patients with chronic CML. \n4 Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was \n\nmost common in patients with GIST and with transformed CML (CML-AP and CML-BC). \n5 Pleural effusion was reported more commonly in patients with GIST and in patients with \n\ntransformed CML (CML-AP and CML-BC) than in patients with chronic CML. \n6+7 Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST \n\npatients. \n8 Some fatal cases of hepatic failure and of hepatic necrosis have been reported. \n9 Musculoskeletal pain during treatment with imatinib or after discontinuation has been observed \n\nin post-marketing. \n10 Musculoskeletal pain and related events were more commonly observed in patients with CML \n\nthan in GIST patients. \n11 Fatal cases have been reported in patients with advanced disease, severe infections, severe \n\nneutropenia and other serious concomitant conditions. \n \nLaboratory test abnormalities \nHaematology \nIn CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in \nall studies, with the suggestion of a higher frequency at high doses ≥ 750 mg (phase I study). \nHowever, the occurrence of cytopenias was also clearly dependent on the stage of the disease, the \nfrequency of grade 3 or 4 neutropenias (ANC < 1.0 x 109/L) and thrombocytopenias (platelet \ncount < 50 x 109/L) being between 4 and 6 times higher in blast crisis and accelerated phase (59–64% \nand 44–63% for neutropenia and thrombocytopenia, respectively) as compared to newly diagnosed \npatients in chronic phase CML (16.7% neutropenia and 8.9% thrombocytopenia). In newly diagnosed \nchronic phase CML grade 4 neutropenia (ANC < 0.5 x 109/L) and thrombocytopenia (platelet count \n< 10 x 109/L) were observed in 3.6% and < 1% of patients, respectively. The median duration of the \nneutropenic and thrombocytopenic episodes usually ranged from 2 to 3 weeks, and from 3 to 4 weeks, \nrespectively. These events can usually be managed with either a reduction of the dose or an \ninterruption of treatment with imatinib, but can in rare cases lead to permanent discontinuation of \ntreatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or \n4 cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within the \nfirst several months of therapy. \n \nIn the study in patients with unresectable and/or metastatic GIST, grade 3 and 4 anaemia was reported \nin 5.4% and 0.7% of patients, respectively, and may have been related to gastrointestinal or intra-\ntumoural bleeding in at least some of these patients. Grade 3 and 4 neutropenia was seen in 7.5% and \n2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient \ndeveloped grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts \noccurred mainly during the first six weeks of therapy, with values remaining relatively stable \nthereafter. \n \nBiochemistry \nSevere elevation of transaminases (<5%) or bilirubin (<1%) was seen in CML patients and was \nusually managed with dose reduction or interruption (the median duration of these episodes was \napproximately one week). Treatment was discontinued permanently because of liver laboratory \nabnormalities in less than 1% of CML patients. In GIST patients (study B2222), 6.8% of grade 3 or 4 \n\n14 \n\n\n\nALT (alanine aminotransferase) elevations and 4.8% of grade 3 or 4 AST (aspartate aminotransferase) \nelevations were observed. Bilirubin elevation was below 3%. \n \nThere have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of them \noutcome was fatal, including one patient on high dose paracetamol. \n \nDescription of selected adverse reactions \nHepatitis B reactivation \nHepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in \nacute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see \nsection 4.4). \n \nReporting of suspected adverse reactions \nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V. \n \n4.9 Overdose \n \nExperience with doses higher than the recommended therapeutic dose is limited. Isolated cases of \nimatinib overdose have been reported spontaneously and in the literature. In the event of overdose the \npatient should be observed and appropriate symptomatic treatment given. Generally the reported \noutcome in these cases was “improved” or “recovered”. Events that have been reported at different \ndose ranges are as follows: \n \nAdult population \n1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, \nerythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal \npain, headache, decreased appetite. \n1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine \nphosphokinase, increased bilirubin, gastrointestinal pain. \n6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, \nvomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased \ntransaminases. \n8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported. \n \nPaediatric population \nOne 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia \nand another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood \ncell count and diarrhoea. \n \nIn the event of overdose, the patient should be observed and appropriate supportive treatment given. \n \n \n5. PHARMACOLOGICAL PROPERTIES \n \n5.1 Pharmacodynamic properties \n \nPharmacotherapeutic group: antineoplastic agents, protein kinase inhibitor, ATC code: L01XE01 \n \nMechanism of action \nImatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the \nBcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor \n(SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the \ncolony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and \n\n15 \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\nbeta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation \nof these receptor kinases. \n \nPharmacodynamic effects \nImatinib is a protein-tyrosine kinase inhibitor which potently inhibits the Bcr-Abl tyrosine kinase at \nthe in vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and induces \napoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia \nchromosome positive CML and acute lymphoblastic leukaemia (ALL) patients. \n \nIn vivo the compound shows anti-tumour activity as a single agent in animal models using Bcr-Abl \npositive tumour cells. \n \nImatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF), \nPDGF-R, and inhibits PDGF-mediated cellular events. Constitutive activation of the PDGF receptor or \nthe Abl protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive \nproduction of PDGF have been implicated in the pathogenesis of MDS/MPD, HES/CEL and DFSP. \nImatinib inhibits signalling and proliferation of cells driven by dysregulated PDGFR and Abl kinase \nactivity. \n \nClinical studies in chronic myeloid leukaemia \nThe effectiveness of imatinib is based on overall haematological and cytogenetic response rates and \nprogression-free survival. There are no controlled trials demonstrating a clinical benefit, such as \nimprovement in disease-related symptoms or increased survival. \n \nA large, international, open-label, non-controlled phase II study was conducted in patients with \nPhiladelphia chromosome positive (Ph+) CML in the blast crisis phase of the disease. In addition, \nchildren and adolescents have been treated in two phase I studies (in patients with CML or Ph+ acute \nleukaemia) and one phase II study. \n \nIn the clinical study 38% of patients were ≥ 60 years of age and 12% of patients were ≥ 70 years of \nage. \n \nMyeloid blast crisis: 260 patients with myeloid blast crisis were enrolled. 95 (37%) had received prior \nchemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas \n165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg, the protocol \nwas subsequently amended to allow higher dosing and the remaining 223 patients were started at \n600 mg. \n \nThe primary efficacy variable was the rate of haematological response, reported as either complete \nhaematological response, no evidence of leukaemia (i.e. clearance of blasts from the marrow and the \nblood, but without a full peripheral blood recovery as for complete responses), or return to chronic \nphase CML. In this study, 31% of patients achieved a haematological response (36% in previously \nuntreated patients and 22% in previously treated patients) (Table 2). The rate of response was also \nhigher in the patients treated at 600 mg (33%) as compared to the patients treated at 400 mg (16%, \np=0.0220). The current estimate of the median survival of the previously untreated and treated patients \nwas 7.7 and 4.7 months, respectively. \n \nLymphoid blast crisis: a limited number of patients were enrolled in phase I studies (n=10). The rate of \nhaematological response was 70% with a duration of 2–3 months. \n \n\n16 \n\n\n\nTable 2 Response in adult CML study \n \n\n Study 0102 \n38-month data \n\nMyeloid blast crisis \n(n=260) \n\n % of patients (CI95%) \nHaematological response1 \n Complete haematological response (CHR) \n \n No evidence of leukaemia (NEL) \n \n Return to chronic phase (RTC) \n\n31% (25.2–36.8) \n8% \n\n \n5% \n\n \n18% \n\nMajor cytogenetic response2 \n Complete \n (Confirmed3) [95% CI] \n Partial \n\n15% (11.2–20.4) \n7% \n\n(2%) [0.6–4.4] \n8% \n\n1 Haematological response criteria (all responses to be confirmed after ≥ 4 weeks): \nCHR: In study 0102 [ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, no blood blasts, BM blasts < 5% and \n\nno extramedullary disease] \nNEL Same criteria as for CHR but ANC ≥ 1 x 109/L and platelets ≥ 20 x 109/L \nRTC < 15% blasts BM and PB, < 30% blasts+promyelocytes in BM and PB, < 20% basophils in PB, \n\nno extramedullary disease other than spleen and liver. \nBM = bone marrow, PB = peripheral blood \n2 Cytogenetic response criteria: \nA major response combines both complete and partial responses: complete (0% Ph+ metaphases), \npartial (1–35%) \n3 Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation \nperformed at least one month after the initial bone marrow study. \n \nPaediatric patients: A total of 26 paediatric patients of age < 18 years with either chronic phase CML \n(n=11) or CML in blast crisis or Ph+ acute leukaemias (n=15) were enrolled in a dose-escalation phase \nI trial. This was a population of heavily pretreated patients, as 46% had received prior BMT and 73% a \nprior multi-agent chemotherapy. Patients were treated at doses of imatinib of 260 mg/m2/day (n=5), \n340 mg/m2/day (n=9), 440 mg/m2/day (n=7) and 570 mg/m2/day (n=5). Out of 9 patients with chronic \nphase CML and cytogenetic data available, 4 (44%) and 3 (33%) achieved a complete and partial \ncytogenetic response, respectively, for a rate of MCyR of 77%. \n \nA total of 51 paediatric patients with newly diagnosed and untreated CML in chronic phase have been \nenrolled in an open-label, multicentre, single-arm phase II trial. Patients were treated with imatinib \n340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. Imatinib treatment \ninduces a rapid response in newly diagnosed paediatric CML patients with a CHR of 78% after \n8 weeks of therapy. The high rate of CHR is accompanied by the development of a complete \ncytogenetic response (CCyR) of 65% which is comparable to the results observed in adults. \nAdditionally, partial cytogenetic response (PCyR) was observed in 16% for a MCyR of 81%. The \nmajority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a \nmedian time to response based on the Kaplan-Meier estimate of 5.6 months. \n \nThe European Medicines Agency has waived the obligation to submit the results of studies with \nimatinib in all subsets of the paediatric population in Philadelphia chromosome (bcr-abl translocation)-\npositive chronic myeloid leukaemia (see section 4.2 for information on paediatric use). \n \nClinical studies in Ph+ ALL \nNewly diagnosed Ph+ ALL: In a controlled study (ADE10) of imatinib versus chemotherapy induction \nin 55 newly diagnosed patients aged 55 years and over, imatinib used as single agent induced a \nsignificantly higher rate of complete haematological response than chemotherapy (96.3% vs. 50%; \n\n17 \n\n\n\np=0.0001). When salvage therapy with imatinib was administered in patients who did not respond or \nwho responded poorly to chemotherapy, it resulted in 9 patients (81.8%) out of 11 achieving a \ncomplete haematological response. This clinical effect was associated with a higher reduction in bcr- \nabl transcripts in the imatinib-treated patients than in the chemotherapy arm after 2 weeks of therapy \n(p=0.02). All patients received imatinib and consolidation chemotherapy (see Table 3) after induction \nand the levels of bcr-abl transcripts were identical in the two arms at 8 weeks. As expected on the \nbasis of the study design, no difference was observed in remission duration, disease-free survival or \noverall survival, although patients with complete molecular response and remaining in minimal \nresidual disease had a better outcome in terms of both remission duration (p=0.01) and disease-free \nsurvival (p=0.02). \n \nThe results observed in a population of 211 newly diagnosed Ph+ ALL patients in four uncontrolled \nclinical studies (AAU02, ADE04, AJP01 and AUS01) are consistent with the results described above. \nImatinib in combination with chemotherapy induction (see Table 3) resulted in a complete \nhaematological response rate of 93% (147 out of 158 evaluable patients) and in a major cytogenetic \nresponse rate of 90% (19 out of 21 evaluable patients). The complete molecular response rate was \n48% (49 out of 102 evaluable patients). Disease-free survival (DFS) and overall survival (OS) \nconstantly exceeded 1 year and were superior to historical control (DFS p<0.001; OS p<0.0001) in \ntwo studies (AJP01 and AUS01). \n \nTable 3 Chemotherapy regimen used in combination with imatinib \n \nStudy ADE10 \n\nPrephase DEX 10 mg/m2 oral, days 1-5; CP 200 mg/m2 i.v., days 3, 4, 5; MTX \n12 mg intrathecal, day 1 \n\nRemission induction DEX 10 mg/m2 oral, days 6-7, 13-16; VCR 1 mg i.v., days 7, 14; IDA \n8 mg/m2 i.v. (0.5 h), days 7, 8, 14, 15; CP 500 mg/m2 i.v.(1 h) day 1; Ara- \nC 60 mg/m2 i.v., days 22-25, 29-32 \n\nConsolidation \ntherapy I, III, V \n\nMTX 500 mg/m2 i.v. (24 h), days 1, 15; 6-MP 25 mg/m2 oral, days 1-20 \n\nConsolidation \ntherapy II, IV \n\nAra-C 75 mg/m2 i.v. (1 h), days 1-5; VM26 60 mg/m2 i.v. (1 h), days 1-5 \n\nStudy AAU02 \n\nInduction therapy \n(de novo Ph+ ALL) \n\nDaunorubicin 30 mg/m2 i.v., days 1-3, 15-16; VCR 2 mg total dose i.v., \ndays 1, 8, 15, 22; CP 750 mg/m2 i.v., days 1, 8; prednisone \n60 mg/m2 oral, days 1-7, 15-21; IDA 9 mg/m2 oral, days 1-28; MTX \n15 mg intrathecal, days 1, 8, 15, 22; Ara-C 40 mg intrathecal, days 1, 8, \n15, 22; methylprednisolone 40 mg intrathecal, days 1, 8, 15, 22 \n\nConsolidation (de \nnovo Ph+ ALL) \n\nAra-C 1,000 mg/m2 /12 h i.v.(3 h), days 1-4; mitoxantrone \n10 mg/m2 i.v. days 3-5; MTX 15 mg intrathecal, day 1; \nmethylprednisolone 40 mg intrathecal, day 1 \n\nStudy ADE04 \n\nPrephase DEX 10 mg/m2 oral, days 1-5; CP 200 mg/m2 i.v., days 3-5; MTX 15 mg \nintrathecal, day 1 \n\nInduction therapy I DEX 10 mg/m2 oral, days 1-5; VCR 2 mg i.v., days 6, 13, 20; \ndaunorubicin 45 mg/m2 i.v., days 6-7, 13-14 \n\nInduction therapy II CP 1 g/m2 i.v. (1 h), days 26, 46; Ara-C 75 mg/m2 i.v. (1 h), days 28-31, \n35-38, 42-45; 6-MP 60 mg/m2 oral, days 26-46 \n\n18 \n\n\n\nConsolidation \ntherapy \n\nDEX 10 mg/m2 oral, days 1-5; vindesine 3 mg/m2 i.v., day 1; MTX \n1.5 g/m2 i.v. (24 h), day 1; etoposide 250 mg/m2 i.v. (1 h) days 4-5; Ara- C \n2x 2 g/m2 i.v. (3 h, q 12 h), day 5 \n\nStudy AJP01 \n\nInduction therapy CP 1.2 g/m2 i.v. (3 h), day 1; daunorubicin 60 mg/m2 i.v. (1 h), days 1-3; \nvincristine 1.3 mg/m2 i.v., days 1, 8, 15, 21; prednisolone 60 mg/m2/day \noral \n\nConsolidation \ntherapy \n\nAlternating chemotherapy course: high dose chemotherapy with MTX \n1 g/m2 i.v. (24 h), day 1, and Ara-C 2 g/m2 i.v. (q 12 h), days 2-3, for \n4 cycles \n\nMaintenance VCR 1.3 g/m2 i.v., day 1; prednisolone 60 mg/m2 oral, days 1-5 \n\nStudy AUS01 \n\nInduction- \nconsolidation therapy \n\nHyper-CVAD regimen: CP 300 mg/m2 i.v. (3 h, q 12 h), days 1-3; \nvincristine 2 mg i.v., days 4, 11; doxorubicine 50 mg/m2 i.v. (24 h), day 4; \nDEX 40 mg/day on days 1-4 and 11-14, alternated with MTX 1 g/m2 i.v. \n(24 h), day 1, Ara-C 1 g/m2 i.v. (2 h, q 12 h), days 2-3 (total of 8 courses) \n\nMaintenance VCR 2 mg i.v. monthly for 13 months; prednisolone 200 mg oral, 5 days \nper month for 13 months \n\nAll treatment regimens include administration of steroids for CNS prophylaxis. \n\nAra-C: cytosine arabinoside; CP: cyclophosphamide; DEX: dexamethasone; MTX: methotrexate; \n6-MP: 6-mercaptopurine; VM26: Teniposide; VCR: vincristine; IDA: idarubicine; i.v.: intravenous \n\n \nPaediatric patients: In study I2301, a total of 93 paediatric, adolescent and young adult patients (from \n1 to 22 years old) with Ph+ ALL were enrolled in an open-label, multicentre, sequential cohort, \nnon-randomised phase III trial, and were treated with imatinib (340 mg/m2/day) in combination with \nintensive chemotherapy after induction therapy. Imatinib was administered intermittently in cohorts \n1-5, with increasing duration and earlier start of imatinib from cohort to cohort; cohort 1 receiving the \nlowest intensitiy and cohort 5 receiving the highest intensity of imatinib (longest duration in days with \ncontinuous daily imatinib dosing during the first chemotherapy treatment courses). Continuous daily \nexposure to imatinib early in the course of treatment in combination with chemotherapy in \ncohort 5-patients (n=50) improved the 4-year event-free survival (EFS) compared to historical controls \n(n=120), who received standard chemotherapy without imatinib (69.6% vs. 31.6%, respectively). The \nestimated 4-year OS in cohort 5-patients was 83.6% compared to 44.8% in the historical controls. 20 \nout of the 50 (40%) patients in cohort 5 received haematopoietic stem cell transplant. \n \nTable 4 Chemotherapy regimen used in combination with imatinib in study I2301 \n \nConsolidation block 1 \n(3 weeks) \n\nVP-16 (100 mg/m2/day, IV): days 1-5 \nIfosfamide (1.8 g/m2/day, IV): days 1-5 \nMESNA (360 mg/m2/dose q3h, x 8 doses/day, IV): days 1-5 \nG-CSF (5 μg/kg, SC): days 6-15 or until ANC > 1500 post nadir \nIT Methotrexate (age-adjusted): day 1 ONLY \nTriple IT therapy (age-adjusted): day 8, 15 \n\nConsolidation block 2 \n(3 weeks) \n\nMethotrexate (5 g/m2 over 24 hours, IV): day 1 \nLeucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: \nDays 2 and 3 \nTriple IT therapy (age-adjusted): day 1 \nARA-C (3 g/m2/dose q 12 h x 4, IV): days 2 and 3 \nG-CSF (5 μg/kg, SC): days 4-13 or until ANC > 1500 post nadir \n\n19 \n\n\n\nReinduction block 1 \n(3 weeks) \n\nVCR (1.5 mg/m2/day, IV): days 1, 8, and 15 \nDAUN (45 mg/m2/day bolus, IV): days 1 and 2 \nCPM (250 mg/m2/dose q12h x 4 doses, IV): days 3 and 4 \nPEG-ASP (2500 IUnits/m2, IM): day 4 \nG-CSF (5 μg/kg, SC): days 5-14 or until ANC > 1500 post nadir \nTriple IT therapy (age-adjusted): days 1 and 15 \nDEX (6 mg/m2/day, PO): days 1-7 and 15-21 \n\nIntensification block 1 \n(9 weeks) \n\nMethotrexate (5 g/m2 over 24 hours, IV): days 1 and 15 \nLeucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: \nDays 2, 3, 16, and 17 \nTriple IT therapy (age-adjusted): days 1 and 22 \nVP-16 (100 mg/m2/day, IV): days 22-26 \nCPM (300 mg/m2/day, IV): days 22-26 \nMESNA (150 mg/m2/day, IV): days 22-26 \nG-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir \nARA-C (3 g/m2, q12h, IV): days 43, 44 \nL-ASP (6000 IUnits/m2, IM): day 44 \n\nReinduction block 2 \n(3 weeks) \n\nVCR (1.5 mg/m2/day, IV): days 1, 8 and 15 \nDAUN (45 mg/m2/day bolus, IV): days 1 and 2 \nCPM (250 mg/m2/dose q12h x 4 doses, iv): Days 3 and 4 \nPEG-ASP (2500 IUnits/m2, IM): day 4 \nG-CSF (5 μg/kg, SC): days 5-14 or until ANC > 1500 post nadir \nTriple IT therapy (age-adjusted): days 1 and 15 \nDEX (6 mg/m2/day, PO): days 1-7 and 15-21 \n\nIntensification block 2 \n(9 weeks) \n\nMethotrexate (5 g/m2 over 24 hours, IV): days 1 and 15 \nLeucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: \ndays 2, 3, 16, and 17 \nTriple IT therapy (age-adjusted): days 1 and 22 \nVP-16 (100 mg/m2/day, IV): days 22-26 \nCPM (300 mg/m2/day, IV): days 22-26 \nMESNA (150 mg/m2/day, IV): days 22-26 \nG-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir \nARA-C (3 g/m2, q12h, IV): days 43, 44 \nL-ASP (6000 IUnits/m2, IM): day 44 \n\nMaintenance \n(8-week cycles) \nCycles 1–4 \n\nMTX (5 g/m2 over 24 hours, IV): day 1 \nLeucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: \ndays 2 and 3 \nTriple IT therapy (age-adjusted): days 1, 29 \nVCR (1.5 mg/m2, IV): days 1, 29 \nDEX (6 mg/m2/day PO): days 1-5; 29-33 \n6-MP (75 mg/m2/day, PO): days 8-28 \nMethotrexate (20 mg/m2/week, PO): days 8, 15, 22 \nVP-16 (100 mg/m2, IV): days 29-33 \nCPM (300 mg/m2, IV): days 29-33 \nMESNA IV days 29-33 \nG-CSF (5 μg/kg, SC): days 34-43 \n\nMaintenance \n(8-week cycles) \nCycle 5 \n\nCranial irradiation (Block 5 only) \n12 Gy in 8 fractions for all patients that are CNS1 and CNS2 at diagnosis \n18 Gy in 10 fractions for patients that are CNS3 at diagnosis \nVCR (1.5 mg/m2/day, IV): days 1, 29 \nDEX (6 mg/m2/day, PO): days 1-5; 29-33 \n6-MP (75 mg/m2/day, PO): days 11-56 (Withhold 6-MP during the \n6-10 days of cranial irradiation beginning on day 1 of Cycle 5. Start 6-MP \nthe 1st day after cranial irradiation completion.) \nMethotrexate (20 mg/m2/week, PO): days 8, 15, 22, 29, 36, 43, 50 \n\n20 \n\n\n\nMaintenance \n(8-week cycles) \nCycles 6-12 \n\nVCR (1.5 mg/m2/day, IV): days 1, 29 \nDEX (6 mg/m2/day, PO): days 1-5; 29-33 \n6-MP (75 mg/m2/day, PO): days 1-56 \nMethotrexate (20 mg/m2/week, PO): days 1, 8, 15, 22, 29, 36, 43, 50 \n\nG-CSF = granulocyte colony stimulating factor, VP-16 = etoposide, MTX = methotrexate, IV = \nintravenous, SC = subcutaneous, IT = intrathecal, PO = oral, IM = intramuscular, ARA-C = \ncytarabine, CPM = cyclophosphamide, VCR = vincristine, DEX = dexamethasone, DAUN = \ndaunorubicin, 6-MP = 6-mercaptopurine, E.Coli L-ASP = L-asparaginase, PEG-ASP = PEG \nasparaginase, MESNA= 2-mercaptoethane sulfonate sodium, iii= or until MTX level is < 0.1 µM, q6h \n= every 6 hours, Gy= Gray \n \nStudy AIT07 was a multicentre, open-label, randomised, phase II/III study that included 128 patients \n(1 to < 18 years) treated with imatinib in combination with chemotherapy. Safety data from this study \nseem to be in line with the safety profile of imatinib in Ph+ ALL patients. \n \nRelapsed/refractory Ph+ ALL: When imatinib was used as single agent in patients with \nrelapsed/refractory Ph+ ALL, it resulted, in the 53 out of 411 patients evaluable for response, in a \nhaematological response rate of 30% (9% complete) and a major cytogenetic response rate of 23%. \n(Of note, out of the 411 patients, 353 were treated in an expanded access program without primary \nresponse data collected.) The median time to progression in the overall population of 411 patients with \nrelapsed/refractory Ph+ ALL ranged from 2.6 to 3.1 months, and median overall survival in the \n401 evaluable patients ranged from 4.9 to 9 months. The data was similar when re-analysed to include \nonly those patients age 55 or older. \n \nClinical studies in MDS/MPD \nExperience with imatinib in this indication is very limited and is based on haematological and \ncytogenetic response rates. There are no controlled trials demonstrating a clinical benefit or increased \nsurvival. One open label, multicentre, phase II clinical trial (study B2225) was conducted testing \nimatinib in diverse populations of patients suffering from life-threatening diseases associated with \nAbl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD who were \ntreated with imatinib 400 mg daily. Three patients presented a complete haematological response \n(CHR) and one patient experienced a partial haematological response (PHR). At the time of the \noriginal analysis, three of the four patients with detected PDGFR gene rearrangements developed \nhaematological response (2 CHR and 1 PHR). The age of these patients ranged from 20 to 72 years. \n \nAn observational registry (study L2401) was conducted to collect long-term safety and efficacy data in \npatients suffering from myeloproliferative neoplasms with PDGFR- β rearrangement and who were \ntreated with imatinib. The 23 patients enrolled in this registry received imatinib at a median daily dose \nof 264 mg (range: 100 to 400 mg) for a median duration of 7.2 years (range 0.1 to 12.7 years). Due to \nthe observational nature of this registry, haematologic, cytogenetic and molecular assessment data \nwere available for 22, 9 and 17 of the 23 enrolled patients, respectively. When assuming \nconservatively that patients with missing data were non-responders, CHR was observed in 20/23 \n(87%) patients, CCyR in 9/23 (39.1%) patients, and MR in 11/23 (47.8%) patients, respectively. When \nthe response rate is calculated from patients with at least one valid assessment, the response rate for \nCHR, CCyR and MR was 20/22 (90.9%), 9/9 (100%) and 11/17 (64.7%), respectively. \n \nIn addition a further 24 patients with MDS/MPD were reported in 13 publications. 21 patients were \ntreated with imatinib 400 mg daily, while the other 3 patients received lower doses. In eleven patients \nPDGFR gene rearrangements was detected, 9 of them achieved a CHR and 1 PHR. The age of these \npatients ranged from 2 to 79 years. In a recent publication updated information from 6 of these \n11 patients revealed that all these patients remained in cytogenetic remission (range 32-38 months). \nThe same publication reported long term follow-up data from 12 MDS/MPD patients with PDGFR \ngene rearrangements (5 patients from study B2225). These patients received imatinib for a median of \n47 months (range 24 days – 60 months). In 6 of these patients follow-up now exceeds 4 years. Eleven \npatients achieved rapid CHR; ten had complete resolution of cytogenetic abnormalities and a decrease \nor disappearance of fusion transcripts as measured by RT-PCR. Haematological and cytogenetic \nresponses have been sustained for a median of 49 months (range 19-60) and 47 months (range 16-59), \n\n21 \n\n\n\nrespectively. The overall survival is 65 months since diagnosis (range 25-234). Imatinib administration \nto patients without the genetic translocation generally results in no improvement. \n \nThere are no controlled trials in paediatric patients with MDS/MPD. Five (5) patients with MDS/MPD \nassociated with PDGFR gene re-arrangements were reported in 4 publications. The age of these \npatients ranged from 3 months to 4 years and imatinib was given at dose 50 mg daily or doses ranging \nfrom 92.5 to 340 mg/m2 daily. All patients achieved complete haematological response, cytogenetic \nresponse and/or clinical response. \n \nClinical studies in HES/CEL \nOne open-label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib in \ndiverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or \nPDGFR protein tyrosine kinases. In this study, 14 patients with HES/CEL were treated with 100 mg to \n1,000 mg of imatinib daily. A further 162 patients with HES/CEL, reported in 35 published case \nreports and case series received imatinib at doses from 75 mg to 800 mg daily. Cytogenetic \nabnormalities were evaluated in 117 of the total population of 176 patients. In 61 of these 117 patients \nFIP1L1-PDGFRα fusion kinase was identified. An additional four HES patients were found to be \nFIP1L1-PDGFRα-positive in other 3 published reports. All 65 FIP1L1-PDGFRα fusion kinase \npositive patients achieved a CHR sustained for months (range from 1+ to 44+ months censored at the \ntime of the reporting). As reported in a recent publication 21 of these 65 patients also achieved \ncomplete molecular remission with a median follow-up of 28 months (range 13-67 months). The age \nof these patients ranged from 25 to 72 years. Additionally, improvements in symptomatology and \nother organ dysfunction abnormalities were reported by the investigators in the case reports. \nImprovements were reported in cardiac, nervous, skin/subcutaneous tissue, \nrespiratory/thoracic/mediastinal, musculoskeletal/connective tissue/vascular, and gastrointestinal \norgan systems. \n \nThere are no controlled trials in paediatric patients with HES/CEL. Three (3) patients with HES and \nCEL associated with PDGFR gene re-arrangements were reported in 3 publications. The age of these \npatients ranged from 2 to 16 years and imatinib was given at dose 300 mg/m2 daily or doses ranging \nfrom 200 to 400 mg daily. All patients achieved complete haematological response, complete \ncytogenetic response and/or complete molecular response. \n \nClinical studies in DFSP \nOne phase II, open label, multicentre clinical trial (study B2225) was conducted including 12 patients \nwith DFSP treated with imatinib 800 mg daily. The age of the DFSP patients ranged from 23 to \n75 years; DFSP was metastatic, locally recurrent following initial resective surgery and not considered \namenable to further resective surgery at the time of study entry. The primary evidence of efficacy was \nbased on objective response rates. Out of the 12 patients enrolled, 9 responded, one completely and \n8 partially. Three of the partial responders were subsequently rendered disease free by surgery. The \nmedian duration of therapy in study B2225 was 6.2 months, with a maximum duration of 24.3 months. \nA further 6 DFSP patients treated with imatinib were reported in 5 published case reports, their ages \nranging from 18 months to 49 years. The adult patients reported in the published literature were \ntreated with either 400 mg (4 cases) or 800 mg (1 case) imatinib daily. 5 patients responded, \n3 completely and 2 partially. The median duration of therapy in the published literature ranged \nbetween 4 weeks and more than 20 months. The translocation t(17:22)[(q22:q13)], or its gene product, \nwas present in nearly all responders to imatinib treatment. \n \nThere are no controlled trials in paediatric patients with DFSP. Five (5) patients with DFSP and \nPDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged from \nnewborn to 14 years and imatinib was given at dose 50 mg daily or doses ranging from 400 to \n520 mg/m2 daily. All patients achieved partial and/or complete response. \n \n5.2 Pharmacokinetic properties \n \nPharmacokinetics of imatinib \n\n22 \n\n\n\nThe pharmacokinetics of imatinib have been evaluated over a dosage range of 25 to 1,000 mg. Plasma \npharmacokinetic profiles were analysed on day 1 and on either day 7 or day 28, by which time plasma \nconcentrations had reached steady state. \n \nAbsorption \nMean absolute bioavailability for imatinib is 98%. There was high between-patient variability in \nplasma imatinib AUC levels after an oral dose. When given with a high-fat meal, the rate of \nabsorption of imatinib was minimally reduced (11% decrease in Cmax and prolongation of tmax by \n1.5 h), with a small reduction in AUC (7.4%) compared to fasting conditions. The effect of prior \ngastrointestinal surgery on drug absorption has not been investigated. \n \nDistribution \nAt clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% \non the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding \nto lipoprotein. \n \nBiotransformation \nThe main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows \nsimilar in vitro potency to the parent. The plasma AUC for this metabolite was found to be only 16% \nof the AUC for imatinib. The plasma protein binding of the N-demethylated metabolite is similar to \nthat of the parent compound. \n \nImatinib and the N-demethyl metabolite together accounted for about 65% of the circulating \nradioactivity (AUC(0-48h)). The remaining circulating radioactivity consisted of a number of minor \nmetabolites. \n \nThe in vitro results showed that CYP3A4 was the major human P450 enzyme catalysing the \nbiotransformation of imatinib. Of a panel of potential comedications (acetaminophen, aciclovir, \nallopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, \npenicillin V) only erythromycin (IC50 50 µM) and fluconazole (IC50 118 µM) showed inhibition of \nimatinib metabolism which could have clinical relevance. \n \nImatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6 \nand CYP3A4/5. Ki values in human liver microsomes were 27, 7.5 and 7.9 μmol/L, respectively. \nMaximal plasma concentrations of imatinib in patients are 2–4 μmol/L, consequently an inhibition of \nCYP2D6 and/or CYP3A4/5-mediated metabolism of co-administered drugs is possible. Imatinib did \nnot interfere with the biotransformation of 5-fluorouracil, but it inhibited paclitaxel metabolism as a \nresult of competitive inhibition of CYP2C8 (Ki - 34.7 µM). This Ki value is far higher than the \nexpected plasma levels of imatinib in patients, consequently no interaction is expected upon co-\nadministration of either 5-fluorouracil or paclitaxel and imatinib. \n \nElimination \nBased on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% \nof the dose was recovered within 7 days in faeces (68% of dose) and urine (13% of dose). Unchanged \nimatinib accounted for 25% of the dose (5% urine, 20% faeces), the remainder being metabolites. \n \nPlasma pharmacokinetics \nFollowing oral administration in healthy volunteers, the t½ was approximately 18 h, suggesting that \nonce-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose \nproportional in the range of 25–1,000 mg imatinib after oral administration. There was no change in \nthe kinetics of imatinib on repeated dosing, and accumulation was 1.5–2.5-fold at steady state when \ndosed once daily. \n \nPopulation pharmacokinetics \nBased on population pharmacokinetic analysis in CML patients, there was a small effect of age on the \nvolume of distribution (12% increase in patients > 65 years old). This change is not thought to be \nclinically significant. The effect of bodyweight on the clearance of imatinib is such that for a patient \n\n23 \n\n\n\nweighing 50 kg the mean clearance is expected to be 8.5 L/h, while for a patient weighing 100 kg the \nclearance will rise to 11.8 L/h. These changes are not considered sufficient to warrant dose adjustment \nbased on kg bodyweight. There is no effect of gender on the kinetics of imatinib. \n \nPharmacokinetics in paediatric population \nAs in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients in \nboth phase I and phase II studies. Dosing in children at 260 and 340 mg/m2/day achieved the same \nexposure, respectively, as doses of 400 mg and 600 mg in adult patients. The comparison of AUC(0-24) \non day 8 and day 1 at the 340 mg/m2/day dose level revealed a 1.7-fold drug accumulation after \nrepeated once-daily dosing. \n \nBased on pooled population pharmacokinetic analysis in paediatric patients with haematological \ndisorders (CML, Ph+ALL, or other haematological disorders treated with imatinib), clearance of \nimatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other \ndemographics such as age, body weight and body mass index did not have clinically significant effects \non the exposure of imatinib. The analysis confirmed that exposure of imatinib in paediatric patients \nreceiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (not \nexceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or \n600 mg once daily. \n \nOrgan function impairment \nImatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mild \nand moderate impairment of renal function appear to have a higher plasma exposure than patients with \nnormal renal function. The increase is approximately 1.5- to 2-fold, corresponding to a 1.5-fold \nelevation of plasma AGP, to which imatinib binds strongly. The free drug clearance of imatinib is \nprobably similar between patients with renal impairment and those with normal renal function, since \nrenal excretion represents only a minor elimination pathway for imatinib (see sections 4.2 and 4.4). \n \nAlthough the results of pharmacokinetic analysis showed that there is considerable inter-subject \nvariation, the mean exposure to imatinib did not increase in patients with varying degrees of liver \ndysfunction as compared to patients with normal liver function (see sections 4.2, 4.4 and 4.8). \n \n5.3 Preclinical safety data \n \nThe preclinical safety profile of imatinib was assessed in rats, dogs, monkeys and rabbits. \n \nMultiple dose toxicity studies revealed mild to moderate haematological changes in rats, dogs and \nmonkeys, accompanied by bone marrow changes in rats and dogs. \n \nThe liver was a target organ in rats and dogs. Mild to moderate increases in transaminases and slight \ndecreases in cholesterol, triglycerides, total protein and albumin levels were observed in both species. \nNo histopathological changes were seen in rat liver. Severe liver toxicity was observed in dogs treated \nfor 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct \nhyperplasia. \n \nRenal toxicity was observed in monkeys treated for 2 weeks, with focal mineralisation and dilation of \nthe renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were \nobserved in several of these animals. In rats, hyperplasia of the transitional epithelium in the renal \npapilla and in the urinary bladder was observed at doses ≥ 6 mg/kg in the 13-week study, without \nchanges in serum or urinary parameters. An increased rate of opportunistic infections was observed \nwith chronic imatinib treatment. \n \nIn a 39-week monkey study, no NOAEL (no observed adverse effect level) was established at the \nlowest dose of 15 mg/kg, approximately one-third the maximum human dose of 800 mg based on \nbody surface. Treatment resulted in worsening of normally suppressed malarial infections in these \nanimals. \n \n\n24 \n\n\n\nImatinib was not considered genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in \nvitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus test. Positive \ngenotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster \novary) for clastogenicity (chromosome aberration) in the presence of metabolic activation. Two \nintermediates of the manufacturing process, which are also present in the final product, are positive for \nmutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma \nassay. \n \nIn a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights \nand percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinical \ndose of 800 mg/day, based on body surface area. This was not seen at doses ≤ 20 mg/kg. A slight to \nmoderate reduction in spermatogenesis was also observed in the dog at oral doses ≥ 30 mg/kg. When \nfemale rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on \nmating or on number of pregnant females. At a dose of 60 mg/kg, female rats had significant post-\nimplantation foetal loss and a reduced number of live foetuses. This was not seen at doses ≤ 20 mg/kg. \n \nIn an oral pre- and postnatal development study in rats, red vaginal discharge was noted in the \n45 mg/kg/day group on either day 14 or day 15 of gestation. At the same dose, the number of stillborn \npups as well as those dying between postpartum days 0 and 4 was increased. In the F1 offspring, at the \nsame dose level, mean body weights were reduced from birth until terminal sacrifice and the number \nof litters achieving criterion for preputial separation was slightly decreased. F1 fertility was not \naffected, while an increased number of resorptions and a decreased number of viable foetuses was \nnoted at 45 mg/kg/day. The no observed effect level (NOEL) for both the maternal animals and the F1 \ngeneration was 15 mg/kg/day (one quarter of the maximum human dose of 800 mg). \n \nImatinib was teratogenic in rats when administered during organogenesis at doses ≥ 100 mg/kg, \napproximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. \nTeratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal \nbones. These effects were not seen at doses ≤ 30 mg/kg. \n \nNo new target organs were identified in the rat juvenile development toxicology study (day 10 to 70 \npostpartum) with respect to the known target organs in adult rats. In the juvenile toxicology study, \neffects upon growth, delay in vaginal opening and preputial separation were observed at \napproximately 0.3 to 2 times the average paediatric exposure at the highest recommended dose of \n340 mg/m2. In addition, mortality was observed in juvenile animals (around weaning phase) at \napproximately 2 times the average paediatric exposure at the highest recommended dose of \n340 mg/m2. \n \nIn the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resulted \nin a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at \n≥ 30 mg/kg/day. Histopathological examination of decedents revealed cardiomyopathy (both sexes), \nchronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death \nor reasons for sacrifice. Target organs for neoplastic changes were the kidneys, urinary bladder, \nurethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-\nglandular stomach. \n \nPapilloma/carcinoma of the preputial/clitoral gland were noted from 30 mg/kg/day onwards, \nrepresenting approximately 0.5 or 0.3 times the human daily exposure (based on AUC) at 400 mg/day \nor 800 mg/day, respectively, and 0.4 times the daily exposure in children (based on AUC) at \n340 mg/m2/day. The no observed effect level (NOEL) was 15 mg/kg/day. The renal \nadenoma/carcinoma, the urinary bladder and urethra papilloma, the small intestine adenocarcinomas, \nthe parathyroid glands adenomas, the benign and malignant medullary tumours of the adrenal glands \nand the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day, representing \napproximately 1.7 or 1 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, \nrespectively, and 1.2 times the daily exposure in children (based on AUC) at 340 mg/m2/day. The no \nobserved effect level (NOEL) was 30 mg/kg/day. \n \n\n25 \n\n\n\nThe mechanism and relevance of these findings in the rat carcinogenicity study for humans are not yet \nclarified. \n \nNon-neoplastic lesions not identified in earlier preclinical studies were the cardiovascular system, \npancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and \ndilatation, leading to signs of cardiac insufficiency in some animals. \n \nThe active substance imatinib demonstrates an environmental risk for sediment organisms. \n \n \n6. PHARMACEUTICAL PARTICULARS \n \n6.1 List of excipients \n \nImatinib Actavis 50 mg hard capsules \nCapsule content \nCellulose microcrystalline \nCopovidone \nCrospovidone \nSodium stearyl fumarate \nSilica, hydrophobic colloidal \nSilica, colloidal anhydrous \n \nCapsule shell \nHypromellose \nTitanium dioxide (E171) \nIron oxide yellow (E172) \n \nPrinting ink \nShellac \nBlack iron oxide (E172) \nPropylene glycol \nAmmonia solution \nPotassium hydroxide \n \nImatinib Actavis 100 mg hard capsules \nCapsule content \nCellulose microcrystalline \nCopovidone \nCrospovidone \nSodium stearyl fumarate \nSilica, hydrophobic colloidal \nSilica, colloidal anhydrous \n \nCapsule shell \nHypromellose \nTitanium dioxide (E171) \nIron oxide yellow (E172) \nIron oxide red (E172) \n \nPrinting ink \nShellac \nBlack iron oxide (E172) \nPropylene glycol \nAmmonia solution \nPotassium hydroxide \n \n\n26 \n\n\n\nImatinib Actavis 400 mg hard capsules \nCapsule content \nCellulose microcrystalline \nCopovidone \nCrospovidone \nSodium stearyl fumarate \nSilica, hydrophobic colloidal \nSilica, colloidal anhydrous \n \nCapsule shell \nHypromellose \nTitanium dioxide (E171) \nIron oxide yellow (E172) \nIron oxide red (E172) \nIron oxide black (E172) \n \nPrinting ink \nShellac Glaze-45% \nBlack iron oxide (E172) \nPropylene glycol \nAmmonium Hydroxide 28% \n \n \n6.2 Incompatibilities \n \nNot applicable. \n \n6.3 Shelf life \n \n2 years \n \n6.4 Special precautions for storage \n \nDo not store above 25°C. \nStore in the original package in order to protect from moisture. \n \n6.5 Nature and contents of container \n \nImatinib Actavis 50 mg hard capsules \nAl/PVC/Aclar blister. One blister contains 10 capsules. \nPack containing either 30 or 90 capsules. \n \nImatinib Actavis 100 mg hard capsules \nAl/PVC/Aclar blister. One blister contains either 8 or 10 capsules. \nPack containing either 24, 48, 60, 96, 120 or 180 capsules \n \nImatinib Actavis 400 mg hard capsules \nAl/PVC-PVDC blister. One blister contains 10 capsules. \nPack containing either 10, 30, 60, or 90 capsules. \n \nNot all pack sizes may be marketed. \n \n6.6 Special precautions for disposal and other handling \n \nHandling of opened capsules by women of child-bearing potential \nSince studies in animals have shown reproductive toxicity, and the potential risk for the human foetus \nis unknown, women of child-bearing potential who open capsules should be advised to handle the \n\n27 \n\n\n\ncontents with caution and avoid skin-eye contact or inhalation (see section 4.6). Hands should be \nwashed immediately after handling open capsules. \n \nAny unused medicinal product or waste material should be disposed of in accordance with local \nrequirements. \n \n \n7. MARKETING AUTHORISATION HOLDER \n \nActavis Group PTC ehf. \nReykjavíkurvegur 76-78 \nIS-220 Hafnarfjörður \nIceland \n \n \n8. MARKETING AUTHORISATION NUMBER(S) \n \nImatinib Actavis 50 mg hard capsules \nEU/1/13/825/001 \nEU/1/13/825/002 \n \nImatinib Actavis 100 mg hard capsules \nEU/1/13/825/003 \nEU/1/13/825/004 \nEU/1/13/825/005 \nEU/1/13/825/006 \nEU/1/13/825/007 \nEU/1/13/825/019 \n \nImatinib Actavis 400 mg hard capsules \nEU/1/13/825/020 \nEU/1/13/825/021 \nEU/1/13/825/022 \nEU/1/13/825/023 \n \n \n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n \nDate of first authorisation: 17 April 2013 \n \n \n10. DATE OF REVISION OF THE TEXT \n \nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency http://www.ema.europa.eu \n \n \n\n28 \n\nhttp://www.ema.europa.eu/\n\n\n1. NAME OF THE MEDICINAL PRODUCT \n \nImatinib Actavis 100 mg film-coated tablets \nImatinib Actavis 400 mg film-coated tablets \n \n \n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \nImatinib Actavis 100 mg film-coated tablets \nEach film-coated tablet contains 100 mg imatinib (as mesilate). \n \nExcipients with known effect: \nEach film-coated tablet contains 0.19 mg lecithin (soya) (E322) \n \nImatinib Actavis 400 mg film-coated tablets \nEach film-coated tablet contains 400 mg imatinib (as mesilate). \n \nExcipients with known effect: \nEach film-coated tablet contains 0.75 mg lecithin (soya) (E322) \n \nFor the full list of excipients, see section 6.1. \n \n \n3. PHARMACEUTICAL FORM \n \nFilm-coated tablet (tablet). \n \nImatinib Actavis 100 mg film-coated tablets \nRound, 9.2 mm in diameter, biconvex dark yellow to brownish film-coated tablet, embossed with \ncompany logo on one side and “36” with score line on the other side. \nThe tablet can be divided into equal doses. \n \nImatinib Actavis 400 mg film-coated tablets \nOval-shape, 18.6x6.6 mm, biconvex dark yellow to brownish film-coated tablet, embossed with \ncompany logo on one side and “37” with score line on the other side. \nThe score line is not intended for breaking the tablet. \n \n \n4. CLINICAL PARTICULARS \n \n4.1 Therapeutic indications \n \nImatinib Actavis is indicated for the treatment of \n- paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) \n\nchronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as \nthe first line of treatment. \n\n- paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or \nin accelerated phase or blast crisis. \n\n- adult patients with Ph+ CML in blast crisis. \n- adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute \n\nlymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy. \n- adult patients with relapsed or refractory Ph+ ALL as monotherapy. \n- adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with \n\nplatelet-derived growth factor receptor (PDGFR) gene re-arrangements. \n- adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic \n\nleukaemia (CEL) with FIP1L1-PDGFRα rearrangement. \n \n\n29 \n\n\n\nThe effect of imatinib on the outcome of bone marrow transplantation has not been determined. \n \nImatinib Actavis is indicated for \n- the treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and \n\nadult patients with recurrent and/or metastatic DFSP who are not eligible for surgery. \n \nIn adult and paediatric patients, the effectiveness of imatinib is based on overall haematological and \ncytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic \nresponse rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on \nobjective response rates in adult patients with unresectable and/or metastatic DFSP. The experience \nwith imatinib in patients with MDS/MPD associated with PDGFR gene re-arrangements is very \nlimited (see section 5.1). There are no controlled trials demonstrating a clinical benefit or increased \nsurvival for these diseases. \n \n4.2 Posology and method of administration \n \nTherapy should be initiated by a physician experienced in the treatment of patients with \nhaematological malignancies and malignant sarcomas, as appropriate. \n \nPosology \n \nPosology for CML in adult patients \nThe recommended dose of imatinib is 600 mg/day for adult patients in blast crisis. Blast crisis is \ndefined as blasts ≥ 30% in blood or bone marrow or extramedullary disease other than \nhepatosplenomegaly. \n \nTreatment duration: In clinical trials, treatment with imatinib was continued until disease progression. \nThe effect of stopping treatment after the achievement of a complete cytogenetic response has not \nbeen investigated. \n \nDose increases from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients with \nblast crisis may be considered in the absence of severe adverse drug reaction and severe non-\nleukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease \nprogression (at any time); failure to achieve a satisfactory haematological response after at least \n3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss \nof a previously achieved haematological and/or cytogenetic response. Patients should be monitored \nclosely following dose escalation given the potential for an increased incidence of adverse reactions at \nhigher dosages. \n \nPosology for CML in paediatric patients \nDosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily \nis recommended for children with chronic phase CML and advanced phase CML (not to exceed the \ntotal dose of 800 mg). Treatment can be given as a once daily dose or alternatively the daily dose may \nbe split into two administrations – one in the morning and one in the evening. The dose \nrecommendation is currently based on a small number of paediatric patients (see sections 5.1 and 5.2). \nThere is no experience with the treatment of children below 2 years of age. \n \nDose increases from 340 mg/m2 daily to 570 mg/m2 daily (not to exceed the total dose of 800 mg) may \nbe considered in children in the absence of severe adverse drug reaction and severe non-leukaemia-\nrelated neutropenia or thrombocytopenia in the following circumstances: disease progression (at any \ntime); failure to achieve a satisfactory haematological response after at least 3 months of treatment; \nfailure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved \nhaematological and/or cytogenetic response. Patients should be monitored closely following dose \nescalation given the potential for an increased incidence of adverse reactions at higher dosages. \n \nPosology for Ph+ ALL in adult patients \n\n30 \n\n\n\nThe recommended dose of imatinib is 600 mg/day for adult patients with Ph+ ALL. Haematological \nexperts in the management of this disease should supervise the therapy throughout all phases of care. \n \nTreatment schedule: On the basis of the existing data, imatinib has been shown to be effective and safe \nwhen administered at 600 mg/day in combination with chemotherapy in the induction phase, the \nconsolidation and maintenance phases of chemotherapy (see section 5.1) for adult patients with newly \ndiagnosed Ph+ ALL. The duration of imatinib therapy can vary with the treatment programme \nselected, but generally longer exposures to imatinib have yielded better results. \n \nFor adult patients with relapsed or refractory Ph+ALL imatinib monotherapy at 600 mg/day is safe, \neffective and can be given until disease progression occurs. \n \nPosology for Ph+ ALL in paediatric patients \nDosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily \nis recommended for children with Ph+ ALL (not to exceed the total dose of 600 mg). \n \nPosology for MDS/MPD \nThe recommended dose of imatinib is 400 mg/day for adult patients with MDS/MPD. \n \nTreatment duration: In the only clinical trial performed up to now, treatment with imatinib was \ncontinued until disease progression (see section 5.1). At the time of analysis, the treatment \nduration was a median of 47 months (24 days - 60 months). \n \nPosology for HES/CEL \nThe recommended dose of imatinib is 100 mg/day for adult patients with HES/CEL. \n \nDose increase from 100 mg to 400 mg may be considered in the absence of adverse drug reactions \nif assessments demonstrate an insufficient response to therapy. \n \nTreatment should be continued as long as the patient continues to benefit. \n \nPosology for DFSP \nThe recommended dose of imatinib is 800 mg/day for adult patients with DFSP. \n \nDose adjustment for adverse reactions \nNon-haematological adverse reactions \nIf a severe non-haematological adverse reaction develops with imatinib use, treatment must be \nwithheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending \non the initial severity of the event. \n \nIf elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases \n> 5 x IULN occur, imatinib should be withheld until bilirubin levels have returned to < 1.5 x IULN \nand transaminase levels to < 2.5 x IULN. Treatment with imatinib may then be continued at a reduced \ndaily dose. In adults the dose should be reduced from 400 to 300 mg or from 600 to 400 mg, or from \n800 mg to 600 mg, and in children from 340 to 260 mg/m2/day. \n \nHaematological adverse reactions \nDose reduction or treatment interruption for severe neutropenia and thrombocytopenia are \nrecommended as indicated in the table below. \n \nDose adjustments for neutropenia and thrombocytopenia: \n \nHES/CEL (starting dose \n100 mg) \n\nANC < 1.0 x 109/L \nand/or \nplatelets < 50 x 109/L \n\n1. Stop imatinib until ANC ≥ 1.5 x 109/L \nand platelets ≥ 75 x 109/L. \n\n2. Resume treatment with imatinib at \nprevious dose (i.e. before severe \nadverse reaction). \n\n31 \n\n\n\nMDS/MPD (starting dose \n400 mg) \nHES/CEL (at dose \n400 mg) \n\nANC < 1.0 x 109/L \nand/or \nplatelets < 50 x 109/L \n\n1. Stop imatinib until ANC ≥ 1.5 x 109/L \nand platelets ≥ 75 x 109/L. \n\n2. Resume treatment with imatinib at \nprevious dose (i.e. before severe \nadverse reaction). \n\n3. In the event of recurrence of ANC \n< 1.0 x 109/L and/or platelets \n< 50 x 109/L, repeat step 1 and resume \nimatinib at reduced dose of 300 mg. \n\nPaediatric chronic phase \nCML (at dose \n340 mg/m2) \n\nANC < 1.0 x 109/L \nand/or \nplatelets < 50 x 109/L \n\n1. Stop imatinib until ANC ≥ 1.5 x 109/L \nand platelets ≥ 75 x 109/L. \n\n2. Resume treatment with imatinib at \nprevious dose (i.e. before severe \nadverse reaction). \n\n3. In the event of recurrence of ANC \n< 1.0 x 109/L and/or platelets \n< 50 x 109/L, repeat step 1 and resume \nimatinib at reduced dose of \n260 mg/m2. \n\nCML in blast crisis and \nPh+ ALL (starting dose \n600 mg) \n\naANC < 0.5 x 109/L \nand/or \nplatelets < 10 x 109/L \n\n1. Check whether cytopenia is related to \nleukaemia (marrow aspirate or \nbiopsy). \n\n2. If cytopenia is unrelated to leukaemia, \nreduce dose of imatinib to 400 mg. \n\n3. If cytopenia persists for 2 weeks, \nreduce further to 300 mg. \n\n4. If cytopenia persists for 4 weeks and \nis still unrelated to leukaemia, stop \nimatinib until ANC ≥ 1 x 109/L and \nplatelets ≥ 20 x 109/L, then resume \ntreatment at 300 mg. \n\nPaediatric accelerated \nphase CML and blast \ncrisis (starting dose \n340 mg/m2) \n\naANC < 0.5 x 109/L \nand/or \nplatelets < 10 x 109/L \n\n1. Check whether cytopenia is related to \nleukaemia (marrow aspirate or \nbiopsy). \n\n2. If cytopenia is unrelated to leukaemia, \nreduce dose of imatinib to 260 mg/m2. \n\n3. If cytopenia persists for 2 weeks, \nreduce further to 200 mg/m2. \n\n4. If cytopenia persists for 4 weeks and \nis still unrelated to leukaemia, stop \nimatinib until ANC ≥ 1 x 109/L and \nplatelets ≥ 20 x 109/L, then resume \ntreatment at 200 mg/m2. \n\nDFSP (at dose 800 mg) ANC < 1.0 x 109/L \nand/or \nplatelets < 50 x 109/L \n\n1. Stop imatinib until ANC ≥ 1.5 x 109/L \nand platelets ≥ 75 x 109/L. \n\n2. Resume treatment with imatinib at \n600 mg. \n\n3. In the event of recurrence of ANC \n< 1.0 x 109/L and/or platelets \n< 50 x 109/L, repeat step 1 and resume \nimatinib at reduced dose of 400 mg. \n\nANC = absolute neutrophil count \na occurring after at least 1 month of treatment \n \nSpecial populations \n \n\n32 \n\n\n\nPaediatric use: There is no experience in children with CML below 2 years of age and with Ph+ALL \nbelow 1 year of age (see section 5.1). There is very limited experience in children with MDS/MPD, \nDFSP, and HES/CEL. \n \nThe safety and efficacy of imatinib in children with MDS/MPD, DFSP and HES/CEL aged less than \n18 years of age have not been established in clinical trials. Currently available published data are \nsummarised in section 5.1 but no recommendation on a posology can be made. \n \nHepatic insufficiency: Imatinib is mainly metabolised through the liver. Patients with mild, moderate \nor severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The \ndose can be reduced if not tolerated (see sections 4.4, 4.8 and 5.2). \n \nLiver dysfunction classification: \n \nLiver dysfunction Liver function tests \nMild Total bilirubin: = 1.5 ULN \n\nAST: >ULN (can be normal or <ULN if total bilirubin \nis >ULN) \n\nModerate Total bilirubin: >1.5-3.0 ULN \nAST: any \n\nSevere Total bilirubin: >3-10 ULN \nAST: any \n\nULN = upper limit of normal for the institution \nAST = aspartate aminotransferase \n \nRenal insufficiency: Patients with renal dysfunction or on dialysis should be given the minimum \nrecommended dose of 400 mg daily as starting dose. However, in these patients caution is \nrecommended. The dose can be reduced if not tolerated. If tolerated, the dose can be increased for lack \nof efficacy (see sections 4.4 and 5.2). \n \nElderly patients: Imatinib pharmacokinetics have not been specifically studied in older people. No \nsignificant age-related pharmacokinetic differences have been observed in adult patients in clinical \ntrials which included over 20% of patients age 65 and older. No specific dose recommendation is \nnecessary in older people. \n \nMethod of administration \n \nFor doses of 400 mg and above (see dosage recommendation above) a 400 mg tablet (not divisible) is \navailable. \nFor doses other than 400 mg and 800 mg (see dosage recommendation above) a 100 mg divisible \ntablet is available. \n \nThe prescribed dose should be administered orally with a meal and a large glass of water to minimise \nthe risk of gastrointestinal irritations. Doses of 400 mg or 600 mg should be administered once daily, \nwhereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in \nthe evening. \n \nFor patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of still \nwater or apple juice. The required number of tablets should be placed in the appropriate volume of \nbeverage (approximately 50 ml for a 100 mg tablet, and 200 ml for a 400 mg tablet) and stirred with a \nspoon. The suspension should be administered immediately after complete disintegration of the \ntablet(s). \n \n4.3 Contraindications \n \nHypersensitivity to the active substance or to any of the excipients listed in section 6.1. \n \n\n33 \n\n\n\nHypersensitivity to soya or peanut. \n \n4.4 Special warnings and precautions for use \n \nWhen imatinib is co-administered with other medicinal products, there is a potential for drug \ninteractions. Caution should be used when taking imatinib with protease inhibitors, azole antifungals, \ncertain macrolides (see section 4.5), CYP3A4 substrates with a narrow therapeutic window (e.g. \ncyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, \nterfenadine, bortezomib, docetaxel, quinidine) or warfarin and other coumarin derivatives (see \nsection 4.5). \n \nConcomitant use of imatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, \nphenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. \nJohn’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of \ntherapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should be \navoided (see section 4.5). \n \nHypothyroidism \nClinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing \nlevothyroxine replacement during treatment with imatinib (see section 4.5). Thyroid stimulating \nhormone (TSH) levels should be closely monitored in such patients. \n \nHepatotoxicity \nMetabolism of imatinib is mainly hepatic, and only 13% of excretion is through the kidneys. In \npatients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver \nenzymes should be carefully monitored (see sections 4.2, 4.8 and 5.2). It should be noted that GIST \npatients may have hepatic metastases which could lead to hepatic impairment. \n \nCases of liver injury, including hepatic failure and hepatic necrosis, have been observed with imatinib. \nWhen imatinib is combined with high dose chemotherapy regimens, an increase in serious hepatic \nreactions has been detected. Hepatic function should be carefully monitored in circumstances where \nimatinib is combined with chemotherapy regimens also known to be associated with hepatic \ndysfunction (see sections 4.5 and 4.8). \n \nFluid retention \nOccurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, \nsuperficial oedema) have been reported in approximately 2.5% of newly diagnosed CML patients \ntaking imatinib. Therefore, it is highly recommended that patients be weighed regularly. An \nunexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive \ncare and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence \nof these events in elderly patients and those with a prior history of cardiac disease. Therefore, caution \nshould be exercised in patients with cardiac dysfunction. \n \nPatients with cardiac disease \nPatients with cardiac disease, risk factors for cardiac failure or history of renal failure should be \nmonitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure \nshould be evaluated and treated. \n \nIn patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the \nmyocardium, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated \nwith HES cell degranulation upon the initiation of imatinib therapy. The condition was reported to be \nreversible with the administration of systemic steroids, circulatory support measures and temporarily \nwithholding imatinib. As cardiac adverse events have been reported uncommonly with imatinib, a \ncareful assessment of the benefit/risk of imatinib therapy should be considered in the HES/CEL \npopulation before treatment initiation. \n \n\n34 \n\n\n\nMyelodysplastic/myeloproliferative diseases with PDGFR gene re-arrangements could be associated \nwith high eosinophil levels. Evaluation by a cardiology specialist, performance of an echocardiogram \nand determination of serum troponin should therefore be considered in patients with HES/CEL, and in \npatients with MDS/MPD associated with high eosinophil levels before imatinib is administered. If \neither is abnormal, follow-up with a cardiology specialist and the prophylactic use of systemic steroids \n(1-2 mg/kg) for one to two weeks concomitantly with imatinib should be considered at the initiation of \ntherapy. \n \nGastrointestinal haemorrhage \nIn the study in patients with unresectable and/or metastatic GIST, both gastrointestinal and \nintra-tumoural haemorrhages were reported (see section 4.8). Based on the available data, no \npredisposing factors (e.g. tumour size, tumour location, coagulation disorders) have been identified \nthat place patients with GIST at a higher risk of either type of haemorrhage. Since increased \nvascularity and propensity for bleeding is a part of the nature and clinical course of GIST, standard \npractices and procedures for the monitoring and management of haemorrhage in all patients should be \napplied. \nIn addition, gastric antral vascular ectasia (GAVE), a rare cause of gastrointestinal haemorrhage, has \nbeen reported in post-marketing experience in patients with CML, ALL and other diseases (see \nsection 4.8). When needed, discontinuation of imatinib treatment may be considered. \n \nTumour lysis syndrome \nDue to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significant \ndehydration and treatment of high uric acid levels are recommended prior to initiation of imatinib (see \nsection 4.8). \n \nHepatitis B reactivation \nReactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these \npatients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or \nfulminant hepatitis leading to liver transplantation or a fatal outcome. \nPatients should be tested for HBV infection before initiating treatment with Imatinib Actavis. Experts \nin liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in \npatients with positive hepatitis B serology (including those with active disease) and for patients who \ntest positive for HBV infection during treatment. Carriers of HBV who require treatment with Imatinib \nActavis should be closely monitored for signs and symptoms of active HBV infection throughout \ntherapy and for several months following termination of therapy (see section 4.8). \n \nPhototoxicity \nExposure to direct sunlight should be avoided or minimised due to the risk of phototoxicity associated \nwith imatinib treatment. Patients should be instructed to use measures such as protective clothing and \nsunscreen with high sun protection factor (SPF). \n \nThrombotic microangiopathy \nBCR-ABL tyrosine kinase inhibitors (TKIs) have been associated with thrombotic microangiopathy \n(TMA), including individual case reports for Imatinib Actavis (see section 4.8). If laboratory or \nclinical findings associated with TMA occur in a patient receiving Imatinib Actavis, treatment should \nbe discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti-\nADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevated \nin conjunction with low ADAMTS13 activity, treatment with Imatinib Actavis should not be resumed. \n \nLaboratory tests \nComplete blood counts must be performed regularly during therapy with imatinib. Treatment of CML \npatients with imatinib has been associated with neutropenia or thrombocytopenia. However, the \noccurrence of these cytopenias is likely to be related to the stage of the disease being treated and they \nwere more frequent in patients with accelerated phase CML or blast crisis as compared to patients with \nchronic phase CML. Treatment with imatinib may be interrupted or the dose may be reduced, as \nrecommended in section 4.2. \n \n\n35 \n\n\n\nLiver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in \npatients receiving imatinib. \n \nIn patients with impaired renal function, imatinib plasma exposure seems to be higher than that in \npatients with normal renal function, probably due to an elevated plasma level of alpha-acid \nglycoprotein (AGP), an imatinib-binding protein, in these patients. Patients with renal impairment \nshould be given the minimum starting dose. Patients with severe renal impairment should be treated \nwith caution. The dose can be reduced if not tolerated (see sections 4.2 and 5.2). \n \nLong-term treatment with imatinib may be associated with a clinically significant decline in renal \nfunction. Renal function should, therefore, be evaluated prior to the start of imatinib therapy and \nclosely monitored during therapy, with particular attention to those patients exhibiting risk factors for \nrenal dysfunction. If renal dysfunction is observed, appropriate management and treatment should be \nprescribed in accordance with standard treatment guidelines. \n \nPaediatric population \nThere have been case reports of growth retardation occurring in children and pre-adolescents receiving \nimatinib. In an observational study in the CML paediatric population, a statistically significant \ndecrease (but of uncertain clinical relevance) in median height standard deviation scores after 12 and \n24 months of treatment was reported in two small subsets irrespective of pubertal status or gender. \nClose monitoring of growth in children under imatinib treatment is recommended (see section 4.8). \n \nExcipients \n \nLecithin (soya) \nThis medicinal product contains lecithin (soya). Patients, who are allergic to peanut or soya, may not \nuse this medicinal product. \n \nSodium \nThis medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say \nessentially ‘sodium-free’. \n \n4.5 Interaction with other medicinal products and other forms of interaction \n \nActive substances that may increase imatinib plasma concentrations: \nSubstances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. protease inhibitors \nsuch as indinavir, lopinavir/ritonavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; azole \nantifungals including ketoconazole, itraconazole, posaconazole, voriconazole; certain macrolides such \nas erythromycin, clarithromycin and telithromycin) could decrease metabolism and increase imatinib \nconcentrations. There was a significant increase in exposure to imatinib (the mean Cmax and AUC of \nimatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a \nsingle dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering \nimatinib with inhibitors of the CYP3A4 family. \n \nActive substances that may decrease imatinib plasma concentrations: \nSubstances that are inducers of CYP3A4 activity e.g. dexamethasone, phenytoin, carbamazepine, \nrifampicin, phenobarbital, fosphenytoin, primidone or Hypericum perforatum, also known as \nSt. John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of \ntherapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed by a single \n400 mg dose of imatinib resulted in decrease in Cmax and AUC(0-∞) by at least 54% and 74%, of the \nrespective values without rifampicin treatment. Similar results were observed in patients with \nmalignant gliomas treated with imatinib while taking enzyme-inducing anti-epileptic medicinal \nproducts (EIAEDs) such as carbamazepine, oxcarbazepine and phenytoin. The plasma AUC for \nimatinib decreased by 73% compared to patients not on EIAEDs. Concomitant use of rifampicin or \nother strong CYP3A4 inducers and imatinib should be avoided. \n \nActive substances that may have their plasma concentration altered by imatinib: \n\n36 \n\n\n\nImatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, \nrespectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended \nwhen administering imatinib with CYP3A4 substrates with a narrow therapeutic window (e.g. \ncyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, \nterfenadine, bortezomib, docetaxel and quinidine). Imatinib may increase plasma concentration of \nother CYP3A4 metabolised drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel \nblockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.). \n \nBecause of known increased risks of bleeding in conjunction with the use of imatinib (e.g. \nhaemorrhage), patients who require anticoagulation should receive low-molecular-weight or standard \nheparin instead of coumarin derivatives such as warfarin. \n \nIn vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar \nto those that affect CYP3A4 activity. Imatinib at 400 mg twice daily had an inhibitory effect on \nCYP2D6-mediated metoprolol metabolism, with metoprolol Cmax and AUC being increased by \napproximately 23% (90%CI [1.16-1.30]). Dose adjustments do not seem to be necessary when \nimatinib is co-administrated with CYP2D6 substrates, however caution is advised for CYP2D6 \nsubstrates with a narrow therapeutic window such as metoprolol. In patients treated with metoprolol \nclinical monitoring should be considered. \n \nIn vitro, imatinib inhibits paracetamol O-glucuronidation with Ki value of 58.5 micromol/L. This \ninhibition has not been observed in vivo after the administration of imatinib 400 mg and \nparacetamol 1000 mg. Higher doses of imatinib and paracetamol have not been studied. \n \nCaution should therefore be exercised when using high doses of imatinib and paracetamol \nconcomitantly. \n \nIn thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be \ndecreased when imatinib is co-administered (see section 4.4). Caution is therefore recommended. \nHowever, the mechanism of the observed interaction is presently unknown. \n \nIn Ph+ ALL patients, there is clinical experience of co-administering imatinib with chemotherapy (see \nsection 5.1), but drug-drug interactions between imatinib and chemotherapy regimens are not well \ncharacterised. Imatinib adverse events, i.e. hepatotoxicity, myelosuppression or others, may increase \nand it has been reported that concomitant use with L-asparaginase could be associated with increased \nhepatotoxicity (see section 4.8). Therefore, the use of imatinib in combination requires special \nprecaution. \n \n4.6 Fertility, pregnancy and lactation \n \nWomen of childbearing potential \nWomen of childbearing potential must be advised to use effective contraception during treatment. \n \nPregnancy \nThere are limited data on the use of imatinib in pregnant women. There have been post-marketing \nreports of spontaneous abortions and infant congenital anomalies from women who have taken \nimatinib. Studies in animals have however shown reproductive toxicity (see section 5.3) and the \npotential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly \nnecessary. If it is used during pregnancy, the patient must be informed of the potential risk to the \nfoetus. \n \nBreast-feeding \nThere is limited information on imatinib distribution on human milk. Studies in two breast-feeding \nwomen revealed that both imatinib and its active metabolite can be distributed into human milk. The \nmilk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the \nmetabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined \nconcentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total \n\n37 \n\n\n\nexposure would be expected to be low (~10% of a therapeutic dose). However, since the effects of \nlow-dose exposure of the infant to imatinib are unknown, women taking imatinib should not \nbreast-feed. \n \nFertility \nIn non-clinical studies, the fertility of male and female rats was not affected (see section 5.3). Studies \non patients receiving imatinib and its effect on fertility and gametogenesis have not been performed. \nPatients concerned about their fertility on imatinib treatment should consult with their physician. \n \n4.7 Effects on ability to drive and use machines \n \nPatients should be advised that they may experience undesirable effects such as dizziness,blurred \nvision or somnolence during treatment with imatinib. Therefore, caution should be recommended \nwhen driving a car or operating machinery. \n \n4.8 Undesirable effects \n \nSummary of safety profile \nPatients with advanced stages of malignancies may have numerous confounding medical conditions \nthat make causality of adverse reactions difficult to assess due to the variety of symptoms related to \nthe underlying disease, its progression, and the co-administration of numerous medicinal products. \n \nIn clinical trials in CML, drug discontinuation for drug-related adverse reactions was observed in 2.4% \nof newly diagnosed patients, 4% of patients in late chronic phase after failure of interferon therapy, \n4% of patients in accelerated phase after failure of interferon therapy and 5% of blast crisis patients \nafter failure of interferon therapy. In GIST the study drug was discontinued for drug-related adverse \nreactions in 4% of patients. \n \nThe adverse reactions were similar in all indications, with two exceptions. There was more \nmyelosuppression seen in CML patients than in GIST, which is probably due to the underlying \ndisease. In the study in patients with unresectable and/or metastatic GIST, 7 (5%) patients experienced \nCTC grade 3/4 GI bleeds (3 patients), intra-tumoural bleeds (3 patients) or both (1 patient). GI tumour \nsites may have been the source of the GI bleeds (see section 4.4). GI and tumoural bleeding may be \nserious and sometimes fatal. The most commonly reported (≥ 10%) drug-related adverse reactions in \nboth settings were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps \nand rash. Superficial oedemas were a common finding in all studies and were described primarily as \nperiorbital or lower limb oedemas. However, these oedemas were rarely severe and may be managed \nwith diuretics, other supportive measures, or by reducing the dose of imatinib. \n \n\nWhen imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient liver \ntoxicity in the form of transaminase elevation and hyperbilirubinaemia were observed. Considering the \nlimited safety database, the adverse events thus far reported in children are consistent with the known \nsafety profile in adult patients with Ph+ ALL. The safety database for children with Ph+ALL is very \nlimited though no new safety concerns have been identified. \n \nMiscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and rapid weight \ngain with or without superficial oedema may be collectively described as “fluid retention”. These \nreactions can usually be managed by withholding imatinib temporarily and with diuretics and other \nappropriate supportive care measures. However, some of these reactions may be serious or life-\nthreatening and several patients with blast crisis died with a complex clinical history of pleural \neffusion, congestive heart failure and renal failure. There were no special safety findings in paediatric \nclinical trials. \n \nAdverse reactions \nAdverse reactions reported as more than an isolated case are listed below, by system organ class and \nby frequency. Frequency categories are defined using the following convention: very common \n\n38 \n\n\n\n(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), \nvery rare (<1/10,000), not known (cannot be estimated from the available data). \n \nWithin each frequency grouping, undesirable effects are presented in order of frequency, the most \nfrequent first. \n \nAdverse reactions and their frequencies are reported in Table 1. \n \nTable 1 Tabulated summary of adverse reactions \n \nInfections and infestations \nUncommon Herpes zoster, herpes simplex, nasopharyngitis, pneumonia1, sinusitis, \n\ncellulitis, upper respiratory tract infection, influenza, urinary tract infection, \ngastroenteritis, sepsis \n\nRare Fungal infection \nNot known Hepatitis B reactivation* \nNeoplasm benign, malignant and unspecified (including cysts and polyps) \nRare Tumour lysis syndrome \nNot known Tumour haemorrhage/tumour necrosis* \nImmune system disorders \nNot known Anaphylactic shock* \nBlood and lymphatic system disorders \nVery common Neutropenia, thrombocytopenia, anaemia \nCommon Pancytopenia, febrile neutropenia \nUncommon Thrombocythaemia, lymphopenia, bone marrow depression, eosinophilia, \n\nlymphadenopathy \nRare Haemolytic anaemia, thrombotic microangiopathy \nMetabolism and nutrition disorders \nCommon Anorexia \nUncommon Hypokalaemia, increased appetite, hypophosphataemia, decreased appetite, \n\ndehydration, gout, hyperuricaemia, hypercalcaemia, hyperglycaemia, \nhyponatraemia \n\nRare Hyperkalaemia, hypomagnesaemia \nPsychiatric disorders \nCommon Insomnia \nUncommon Depression, libido decreased, anxiety \nRare Confusional state \nNervous system disorders \nVery common Headache2 \nCommon Dizziness, paraesthesia, taste disturbance, hypoaesthesia \nUncommon Migraine, somnolence, syncope, peripheral neuropathy, memory impairment, \n\nsciatica, restless leg syndrome, tremor, cerebral haemorrhage \nRare Increased intracranial pressure, convulsions, optic neuritis \nNot known Cerebral oedema* \nEye disorders \nCommon Eyelid oedema, lacrimation increased, conjunctival haemorrhage, \n\nconjunctivitis, dry eye, blurred vision \nUncommon Eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal \n\nhaemorrhage, blepharitis, macular oedema \nRare Cataract, glaucoma, papilloedema \nNot known Vitreous haemorrhage* \nEar and labyrinth disorders \nUncommon Vertigo, tinnitus, hearing loss \nCardiac disorders \nUncommon Palpitations, tachycardia, cardiac failure congestive3, pulmonary oedema \nRare Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina \n\n39 \n\n\n\npectoris, pericardial effusion \nNot known Pericarditis*, cardiac tamponade* \nVascular disorders4 \nCommon Flushing, haemorrhage \nUncommon Hypertension, haematoma, subdural haematoma, peripheral coldness, \n\nhypotension, Raynaud’s phenomenon \nNot known Thrombosis/embolism* \nRespiratory, thoracic and mediastinal disorders \nCommon Dyspnoea, epistaxis, cough \nUncommon Pleural effusion5, pharyngolaryngeal pain, pharyngitis \nRare Pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary \n\nhaemorrhage \nNot known Acute respiratory failure11*, interstitial lung disease* \nGastrointestinal disorders \nVery common Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain6 \nCommon Flatulence, abdominal distension, gastro-oesophageal reflux, constipation, dry \n\nmouth, gastritis \nUncommon Stomatitis, mouth ulceration, gastrointestinal haemorrhage7, eructation, \n\nmelaena, oesophagitis, ascites, gastric ulcer, haematemesis, cheilitis, \ndysphagia, pancreatitis \n\nRare Colitis, ileus, inflammatory bowel disease \nNot known Ileus/intestinal obstruction*, gastrointestinal perforation*, diverticulitis*, \n\ngastric antral vascular ectasia (GAVE)* \nHepatobiliary disorders \nCommon Increased hepatic enzymes \nUncommon Hyperbilirubinaemia, hepatitis, jaundice \nRare Hepatic failure8, hepatic necrosis \nSkin and subcutaneous tissue disorders \nVery common Periorbital oedema, dermatitis/eczema/rash \nCommon Pruritus, face oedema, dry skin, erythema, alopecia, night sweats, \n\nphotosensitivity reaction \nUncommon Rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased \n\ntendency to bruise, hypotrichosis, skin hypopigmentation, dermatitis \nexfoliative, onychoclasis, folliculitis, petechiae, psoriasis, purpura, skin \nhyperpigmentation, bullous eruptions \n\nRare Acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail \ndiscolouration, angioneurotic oedema, rash vesicular, erythema multiforme, \nleucocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalised \nexanthematous pustulosis (AGEP) \n\nNot known Palmoplantar erythrodysesthesia syndrome*, lichenoid keratosis*, lichen \nplanus*, toxic epidermal necrolysis*, drug rash with eosinophilia and \nsystemic symptoms (DRESS)*, pseudoporphyria* \n\nMusculoskeletal and connective tissue disorders \nVery common Muscle spasm and cramps, musculoskeletal pain including myalgia9, \n\narthralgia, bone pain10 \nCommon Joint swelling \nUncommon Joint and muscle stiffness \nRare Muscular weakness, arthritis, rhabdomyolysis/myopathy \nNot known Avascular necrosis/hip necrosis*, growth retardation in children* \nRenal and urinary disorders \nUncommon Renal pain, haematuria, renal failure acute, urinary frequency increased \nNot known Renal failure chronic \nReproductive system and breast disorders \nUncommon Gynaecomastia, erectile dysfunction, menorrhagia, menstruation irregular, \n\nsexual dysfunction, nipple pain, breast enlargement, scrotal oedema \nRare Haemorrhagic corpus luteum/haemorrhagic ovarian cyst \n\n40 \n\n\n\nGeneral disorders and administration site conditions \nVery common Fluid retention and oedema, fatigue \nCommon Weakness, pyrexia, anasarca, chills, rigors \nUncommon Chest pain, malaise \nInvestigations \nVery common Weight increased \nCommon Weight decreased \nUncommon Blood creatinine increased, blood creatine phosphokinase increased, blood \n\nlactate dehydrogenase increased, blood alkaline phosphatase increased \nRare Blood amylase increased \n\n \n* These types of reactions have been reported mainly from post-marketing experience with \n\nimatinib. This includes spontaneous case reports as well as serious adverse events from ongoing \nstudies, the expanded access programmes, clinical pharmacology studies and exploratory \nstudies in unapproved indications. Because these reactions are reported from a population of \nuncertain size, it is not always possible to reliably estimate their frequency or establish a causal \nrelationship to imatinib exposure. \n\n1 Pneumonia was reported most commonly in patients with transformed CML and in patients with \nGIST. \n\n2 Headache was the most common in GIST patients. \n3 On a patient-year basis, cardiac events including congestive heart failure were more commonly \n\nobserved in patients with transformed CML than in patients with chronic CML. \n4 Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was \n\nmost common in patients with GIST and with transformed CML (CML-AP and CML-BC). \n5 Pleural effusion was reported more commonly in patients with GIST and in patients with \n\ntransformed CML (CML-AP and CML-BC) than in patients with chronic CML. \n6+7 Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST \n\npatients. \n8 Some fatal cases of hepatic failure and of hepatic necrosis have been reported. \n9 Musculoskeletal pain during treatment with imatinib or after discontinuation has been observed \n\nin post-marketing. \n10 Musculoskeletal pain and related events were more commonly observed in patients with CML \n\nthan in GIST patients. \n11 Fatal cases have been reported in patients with advanced disease, severe infections, severe \n\nneutropenia and other serious concomitant conditions. \n \nLaboratory test abnormalities \nHaematology \nIn CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in \nall studies, with the suggestion of a higher frequency at high doses ≥ 750 mg (phase I study). \nHowever, the occurrence of cytopenias was also clearly dependent on the stage of the disease, the \nfrequency of grade 3 or 4 neutropenias (ANC < 1.0 x 109/L) and thrombocytopenias (platelet \ncount < 50 x 109/L) being between 4 and 6 times higher in blast crisis and accelerated phase (59–64% \nand 44–63% for neutropenia and thrombocytopenia, respectively) as compared to newly diagnosed \npatients in chronic phase CML (16.7% neutropenia and 8.9% thrombocytopenia). In newly diagnosed \nchronic phase CML grade 4 neutropenia (ANC < 0.5 x 109/L) and thrombocytopenia (platelet count \n< 10 x 109/L) were observed in 3.6% and < 1% of patients, respectively. The median duration of the \nneutropenic and thrombocytopenic episodes usually ranged from 2 to 3 weeks, and from 3 to 4 weeks, \nrespectively. These events can usually be managed with either a reduction of the dose or an \ninterruption of treatment with imatinib, but can in rare cases lead to permanent discontinuation of \ntreatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or \n4 cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within the \nfirst several months of therapy. \n \nIn the study in patients with unresectable and/or metastatic GIST, grade 3 and 4 anaemia was reported \nin 5.4% and 0.7% of patients, respectively, and may have been related to gastrointestinal or intra-\ntumoural bleeding in at least some of these patients. Grade 3 and 4 neutropenia was seen in 7.5% and \n\n41 \n\n\n\n2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient \ndeveloped grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts \noccurred mainly during the first six weeks of therapy, with values remaining relatively stable \nthereafter. \n \nBiochemistry \nSevere elevation of transaminases (<5%) or bilirubin (<1%) was seen in CML patients and was \nusually managed with dose reduction or interruption (the median duration of these episodes was \napproximately one week). Treatment was discontinued permanently because of liver laboratory \nabnormalities in less than 1% of CML patients. In GIST patients (study B2222), 6.8% of grade 3 or 4 \nALT (alanine aminotransferase) elevations and 4.8% of grade 3 or 4 AST (aspartate aminotransferase) \nelevations were observed. Bilirubin elevation was below 3%. \n \nThere have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of them \noutcome was fatal, including one patient on high dose paracetamol. \n \nDescription of selected adverse reactions \nHepatitis B reactivation \nHepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in \nacute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see \nsection 4.4). \n \nReporting of suspected adverse reactions \nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V. \n \n4.9 Overdose \n \nExperience with doses higher than the recommended therapeutic dose is limited. Isolated cases of \nimatinib overdose have been reported spontaneously and in the literature. In the event of overdose the \npatient should be observed and appropriate symptomatic treatment given. Generally the reported \noutcome in these cases was “improved” or “recovered”. Events that have been reported at different \ndose ranges are as follows: \n \nAdult population \n1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, \nerythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal \npain, headache, decreased appetite. \n1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine \nphosphokinase, increased bilirubin, gastrointestinal pain. \n6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, \nvomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased \ntransaminases. \n8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported. \n \nPaediatric population \nOne 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia \nand another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood \ncell count and diarrhoea. \n \nIn the event of overdose, the patient should be observed and appropriate supportive treatment given. \n \n \n5. PHARMACOLOGICAL PROPERTIES \n \n\n42 \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n5.1 Pharmacodynamic properties \n \nPharmacotherapeutic group: antineoplastic agents, protein kinase inhibitor, ATC code: L01XE01 \n \nMechanism of action \nImatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the \nBcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor \n(SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the \ncolony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and \nbeta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation \nof these receptor kinases. \n \nPharmacodynamic effects \nImatinib is a protein-tyrosine kinase inhibitor which potently inhibits the Bcr-Abl tyrosine kinase at \nthe in vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and induces \napoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia \nchromosome positive CML and acute lymphoblastic leukaemia (ALL) patients. \n \nIn vivo the compound shows anti-tumour activity as a single agent in animal models using Bcr-Abl \npositive tumour cells. \n \nImatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF), \nPDGF-R, and inhibits PDGF-mediated cellular events. Constitutive activation of the PDGF receptor or \nthe Abl protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive \nproduction of PDGF have been implicated in the pathogenesis of MDS/MPD, HES/CEL and DFSP. \nImatinib inhibits signalling and proliferation of cells driven by dysregulated PDGFR and Abl kinase \nactivity. \n \nClinical studies in chronic myeloid leukaemia \nThe effectiveness of imatinib is based on overall haematological and cytogenetic response rates and \nprogression-free survival. There are no controlled trials demonstrating a clinical benefit, such as \nimprovement in disease-related symptoms or increased survival. \n \nA large, international, open-label, non-controlled phase II study was conducted in patients with \nPhiladelphia chromosome positive (Ph+) CML -in the blast crisis phase of the disease. In addition, \nchildren and adolescents have been treated in two phase I studies (in patients with CML or Ph+ acute \nleukaemia) and one phase II study. \n \nIn the clinical study 38% of patients were ≥ 60 years of age and 12% of patients were ≥ 70 years of \nage. \n \nMyeloid blast crisis: 260 patients with myeloid blast crisis were enrolled. 95 (37%) had received prior \nchemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas \n165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg, the protocol \nwas subsequently amended to allow higher dosing and the remaining 223 patients were started at \n600 mg. \n \nThe primary efficacy variable was the rate of haematological response, reported as either complete \nhaematological response, no evidence of leukaemia (i.e. clearance of blasts from the marrow and the \nblood, but without a full peripheral blood recovery as for complete responses), or return to chronic \nphase CML. In this study, 31% of patients achieved a haematological response (36% in previously \nuntreated patients and 22% in previously treated patients) (Table 2). The rate of response was also \nhigher in the patients treated at 600 mg (33%) as compared to the patients treated at 400 mg (16%, \np=0.0220). The current estimate of the median survival of the previously untreated and treated patients \nwas 7.7 and 4.7 months, respectively. \n \n\n43 \n\n\n\nLymphoid blast crisis: a limited number of patients were enrolled in phase I studies (n=10). The rate of \nhaematological response was 70% with a duration of 2–3 months. \n \nTable 2 Response in adult CML study \n \n\n Study 0102 \n38-month data \nMyeloid blast \n\ncrisis \n(n=260) \n\n % of patients (CI95%) \nHaematological response1 \n Complete haematological response (CHR) \n \n No evidence of leukaemia (NEL) \n \n Return to chronic phase (RTC) \n\n31% (25.2–36.8) \n8% \n\n \n5% \n\n \n18% \n\nMajor cytogenetic response2 \n Complete \n (Confirmed3) [95% CI] \n Partial \n\n15% (11.2–20.4) \n7% \n\n(2%) [0.6–4.4] \n8% \n\n1 Haematological response criteria (all responses to be confirmed after ≥ 4 weeks): \nCHR: In study 0102 [ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, no blood blasts, BM blasts < 5% and \n\nno extramedullary disease] \nNEL Same criteria as for CHR but ANC ≥ 1 x 109/L and platelets ≥ 20 x 109/L \nRTC < 15% blasts BM and PB, < 30% blasts+promyelocytes in BM and PB, < 20% basophils in PB, \n\nno extramedullary disease other than spleen and liver. \nBM = bone marrow, PB = peripheral blood \n2 Cytogenetic response criteria: \nA major response combines both complete and partial responses: complete (0% Ph+ metaphases), \npartial (1–35%) \n3 Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation \nperformed at least one month after the initial bone marrow study. \n \nPaediatric patients: A total of 26 paediatric patients of age < 18 years with either chronic phase CML \n(n=11) or CML in blast crisis or Ph+ acute leukaemias (n=15) were enrolled in a dose-escalation phase \nI trial. This was a population of heavily pretreated patients, as 46% had received prior BMT and 73% a \nprior multi-agent chemotherapy. Patients were treated at doses of imatinib of 260 mg/m2/day (n=5), \n340 mg/m2/day (n=9), 440 mg/m2/day (n=7) and 570 mg/m2/day (n=5). Out of 9 patients with chronic \nphase CML and cytogenetic data available, 4 (44%) and 3 (33%) achieved a complete and partial \ncytogenetic response, respectively, for a rate of MCyR of 77%. \n \nA total of 51 paediatric patients with newly diagnosed and untreated CML in chronic phase have been \nenrolled in an open-label, multicentre, single-arm phase II trial. Patients were treated with imatinib \n340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. Imatinib treatment \ninduces a rapid response in newly diagnosed paediatric CML patients with a CHR of 78% after \n8 weeks of therapy. The high rate of CHR is accompanied by the development of a complete \ncytogenetic response (CCyR) of 65% which is comparable to the results observed in adults. \nAdditionally, partial cytogenetic response (PCyR) was observed in 16% for a MCyR of 81%. The \nmajority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a \nmedian time to response based on the Kaplan-Meier estimate of 5.6 months. \n \nThe European Medicines Agency has waived the obligation to submit the results of studies with \nimatinib in all subsets of the paediatric population in Philadelphia chromosome (bcr-abl translocation)-\npositive chronic myeloid leukaemia (see section 4.2 for information on paediatric use). \n \nClinical studies in Ph+ ALL \n\n44 \n\n\n\nNewly diagnosed Ph+ ALL: In a controlled study (ADE10) of imatinib versus chemotherapy induction \nin 55 newly diagnosed patients aged 55 years and over, imatinib used as single agent induced a \nsignificantly higher rate of complete haematological response than chemotherapy (96.3% vs. 50%; \np=0.0001). When salvage therapy with imatinib was administered in patients who did not respond or \nwho responded poorly to chemotherapy, it resulted in 9 patients (81.8%) out of 11 achieving a \ncomplete haematological response. This clinical effect was associated with a higher reduction in bcr- \nabl transcripts in the imatinib-treated patients than in the chemotherapy arm after 2 weeks of therapy \n(p=0.02). All patients received imatinib and consolidation chemotherapy (see Table 3) after induction \nand the levels of bcr-abl transcripts were identical in the two arms at 8 weeks. As expected on the \nbasis of the study design, no difference was observed in remission duration, disease-free survival or \noverall survival, although patients with complete molecular response and remaining in minimal \nresidual disease had a better outcome in terms of both remission duration (p=0.01) and disease-free \nsurvival (p=0.02). \n \nThe results observed in a population of 211 newly diagnosed Ph+ ALL patients in four uncontrolled \nclinical studies (AAU02, ADE04, AJP01 and AUS01) are consistent with the results described above. \nImatinib in combination with chemotherapy induction (see Table 3) resulted in a complete \nhaematological response rate of 93% (147 out of 158 evaluable patients) and in a major cytogenetic \nresponse rate of 90% (19 out of 21 evaluable patients). The complete molecular response rate was \n48% (49 out of 102 evaluable patients). Disease-free survival (DFS) and overall survival (OS) \nconstantly exceeded 1 year and were superior to historical control (DFS p<0.001; OS p<0.0001) in \ntwo studies (AJP01 and AUS01). \n \nTable 3 Chemotherapy regimen used in combination with imatinib \n \nStudy ADE10 \n\nPrephase DEX 10 mg/m2 oral, days 1-5; CP 200 mg/m2 i.v., days 3, 4, 5; MTX \n12 mg intrathecal, day 1 \n\nRemission induction DEX 10 mg/m2 oral, days 6-7, 13-16; VCR 1 mg i.v., days 7, 14; IDA \n8 mg/m2 i.v. (0.5 h), days 7, 8, 14, 15; CP 500 mg/m2 i.v.(1 h) day 1; Ara- \nC 60 mg/m2 i.v., days 22-25, 29-32 \n\nConsolidation \ntherapy I, III, V \n\nMTX 500 mg/m2 i.v. (24 h), days 1, 15; 6-MP 25 mg/m2 oral, days 1-20 \n\nConsolidation \ntherapy II, IV \n\nAra-C 75 mg/m2 i.v. (1 h), days 1-5; VM26 60 mg/m2 i.v. (1 h), days 1-5 \n\nStudy AAU02 \n\nInduction therapy \n(de novo Ph+ ALL) \n\nDaunorubicin 30 mg/m2 i.v., days 1-3, 15-16; VCR 2 mg total dose i.v., \ndays 1, 8, 15, 22; CP 750 mg/m2 i.v., days 1, 8; prednisone \n60 mg/m2 oral, days 1-7, 15-21; IDA 9 mg/m2 oral, days 1-28; MTX \n15 mg intrathecal, days 1, 8, 15, 22; Ara-C 40 mg intrathecal, days 1, 8, \n15, 22; methylprednisolone 40 mg intrathecal, days 1, 8, 15, 22 \n\nConsolidation (de \nnovo Ph+ ALL) \n\nAra-C 1,000 mg/m2 /12 h i.v.(3 h), days 1-4; mitoxantrone \n10 mg/m2 i.v. days 3-5; MTX 15 mg intrathecal, day 1; \nmethylprednisolone 40 mg intrathecal, day 1 \n\nStudy ADE04 \n\nPrephase DEX 10 mg/m2 oral, days 1-5; CP 200 mg/m2 i.v., days 3-5; MTX 15 mg \nintrathecal, day 1 \n\nInduction therapy I DEX 10 mg/m2 oral, days 1-5; VCR 2 mg i.v., days 6, 13, 20; \ndaunorubicin 45 mg/m2 i.v., days 6-7, 13-14 \n\nInduction therapy II CP 1 g/m2 i.v. (1 h), days 26, 46; Ara-C 75 mg/m2 i.v. (1 h), days 28-31, \n35-38, 42-45; 6-MP 60 mg/m2 oral, days 26-46 \n\n45 \n\n\n\nConsolidation \ntherapy \n\nDEX 10 mg/m2 oral, days 1-5; vindesine 3 mg/m2 i.v., day 1; MTX \n1.5 g/m2 i.v. (24 h), day 1; etoposide 250 mg/m2 i.v. (1 h) days 4-5; Ara- C \n2x 2 g/m2 i.v. (3 h, q 12 h), day 5 \n\nStudy AJP01 \n\nInduction therapy CP 1.2 g/m2 i.v. (3 h), day 1; daunorubicin 60 mg/m2 i.v. (1 h), days 1-3; \nvincristine 1.3 mg/m2 i.v., days 1, 8, 15, 21; prednisolone 60 mg/m2/day \noral \n\nConsolidation \ntherapy \n\nAlternating chemotherapy course: high dose chemotherapy with MTX \n1 g/m2 i.v. (24 h), day 1, and Ara-C 2 g/m2 i.v. (q 12 h), days 2-3, for \n4 cycles \n\nMaintenance VCR 1.3 g/m2 i.v., day 1; prednisolone 60 mg/m2 oral, days 1-5 \n\nStudy AUS01 \n\nInduction- \nconsolidation therapy \n\nHyper-CVAD regimen: CP 300 mg/m2 i.v. (3 h, q 12 h), days 1-3; \nvincristine 2 mg i.v., days 4, 11; doxorubicine 50 mg/m2 i.v. (24 h), day 4; \nDEX 40 mg/day on days 1-4 and 11-14, alternated with MTX 1 g/m2 i.v. \n(24 h), day 1, Ara-C 1 g/m2 i.v. (2 h, q 12 h), days 2-3 (total of 8 courses) \n\nMaintenance VCR 2 mg i.v. monthly for 13 months; prednisolone 200 mg oral, 5 days \nper month for 13 months \n\nAll treatment regimens include administration of steroids for CNS prophylaxis. \n\nAra-C: cytosine arabinoside; CP: cyclophosphamide; DEX: dexamethasone; MTX: methotrexate; \n6-MP: 6-mercaptopurine; VM26: Teniposide; VCR: vincristine; IDA: idarubicine; i.v.: intravenous \n \nPaediatric patients: In study I2301, a total of 93 paediatric, adolescent and young adult patients (from \n1 to 22 years old) with Ph+ ALL were enrolled in an open-label, multicentre, sequential cohort, \nnon-randomised phase III trial, and were treated with imatinib (340 mg/m2/day) in combination with \nintensive chemotherapy after induction therapy. Imatinib was administered intermittently in cohorts \n1-5, with increasing duration and earlier start of imatinib from cohort to cohort; cohort 1 receiving the \nlowest intensitiy and cohort 5 receiving the highest intensity of imatinib (longest duration in days with \ncontinuous daily imatinib dosing during the first chemotherapy treatment courses). Continuous daily \nexposure to imatinib early in the course of treatment in combination with chemotherapy in \ncohort 5-patients (n=50) improved the 4-year event-free survival (EFS) compared to historical controls \n(n=120), who received standard chemotherapy without imatinib (69.6% vs. 31.6%, respectively). The \nestimated 4-year OS in cohort 5-patients was 83.6% compared to 44.8% in the historical controls. 20 \nout of the 50 (40%) patients in cohort 5 received haematopoietic stem cell transplant. \n \nTable 4 Chemotherapy regimen used in combination with imatinib in study I2301 \n \nConsolidation block 1 \n(3 weeks) \n\nVP-16 (100 mg/m2/day, IV): days 1-5 \nIfosfamide (1.8 g/m2/day, IV): days 1-5 \nMESNA (360 mg/m2/dose q3h, x 8 doses/day, IV): days 1-5 \nG-CSF (5 μg/kg, SC): days 6-15 or until ANC > 1500 post nadir \nIT Methotrexate (age-adjusted): day 1 ONLY \nTriple IT therapy (age-adjusted): day 8, 15 \n\nConsolidation block 2 \n(3 weeks) \n\nMethotrexate (5 g/m2 over 24 hours, IV): day 1 \nLeucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: \nDays 2 and 3 \nTriple IT therapy (age-adjusted): day 1 \nARA-C (3 g/m2/dose q 12 h x 4, IV): days 2 and 3 \nG-CSF (5 μg/kg, SC): days 4-13 or until ANC > 1500 post nadir \n\n46 \n\n\n\nReinduction block 1 \n(3 weeks) \n\nVCR (1.5 mg/m2/day, IV): days 1, 8, and 15 \nDAUN (45 mg/m2/day bolus, IV): days 1 and 2 \nCPM (250 mg/m2/dose q12h x 4 doses, IV): days 3 and 4 \nPEG-ASP (2500 IUnits/m2, IM): day 4 \nG-CSF (5 μg/kg, SC): days 5-14 or until ANC > 1500 post nadir \nTriple IT therapy (age-adjusted): days 1 and 15 \nDEX (6 mg/m2/day, PO): days 1-7 and 15-21 \n\nIntensification block 1 \n(9 weeks) \n\nMethotrexate (5 g/m2 over 24 hours, IV): days 1 and 15 \nLeucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: \nDays 2, 3, 16, and 17 \nTriple IT therapy (age-adjusted): days 1 and 22 \nVP-16 (100 mg/m2/day, IV): days 22-26 \nCPM (300 mg/m2/day, IV): days 22-26 \nMESNA (150 mg/m2/day, IV): days 22-26 \nG-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir \nARA-C (3 g/m2, q12h, IV): days 43, 44 \nL-ASP (6000 IUnits/m2, IM): day 44 \n\nReinduction block 2 \n(3 weeks) \n\nVCR (1.5 mg/m2/day, IV): days 1, 8 and 15 \nDAUN (45 mg/m2/day bolus, IV): days 1 and 2 \nCPM (250 mg/m2/dose q12h x 4 doses, iv): Days 3 and 4 \nPEG-ASP (2500 IUnits/m2, IM): day 4 \nG-CSF (5 μg/kg, SC): days 5-14 or until ANC > 1500 post nadir \nTriple IT therapy (age-adjusted): days 1 and 15 \nDEX (6 mg/m2/day, PO): days 1-7 and 15-21 \n\nIntensification block 2 \n(9 weeks) \n\nMethotrexate (5 g/m2 over 24 hours, IV): days 1 and 15 \nLeucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: \ndays 2, 3, 16, and 17 \nTriple IT therapy (age-adjusted): days 1 and 22 \nVP-16 (100 mg/m2/day, IV): days 22-26 \nCPM (300 mg/m2/day, IV): days 22-26 \nMESNA (150 mg/m2/day, IV): days 22-26 \nG-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir \nARA-C (3 g/m2, q12h, IV): days 43, 44 \nL-ASP (6000 IUnits/m2, IM): day 44 \n\nMaintenance \n(8-week cycles) \nCycles 1–4 \n\nMTX (5 g/m2 over 24 hours, IV): day 1 \nLeucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: \ndays 2 and 3 \nTriple IT therapy (age-adjusted): days 1, 29 \nVCR (1.5 mg/m2, IV): days 1, 29 \nDEX (6 mg/m2/day PO): days 1-5; 29-33 \n6-MP (75 mg/m2/day, PO): days 8-28 \nMethotrexate (20 mg/m2/week, PO): days 8, 15, 22 \nVP-16 (100 mg/m2, IV): days 29-33 \nCPM (300 mg/m2, IV): days 29-33 \nMESNA IV days 29-33 \nG-CSF (5 μg/kg, SC): days 34-43 \n\nMaintenance \n(8-week cycles) \nCycle 5 \n\nCranial irradiation (Block 5 only) \n12 Gy in 8 fractions for all patients that are CNS1 and CNS2 at diagnosis \n18 Gy in 10 fractions for patients that are CNS3 at diagnosis \nVCR (1.5 mg/m2/day, IV): days 1, 29 \nDEX (6 mg/m2/day, PO): days 1-5; 29-33 \n6-MP (75 mg/m2/day, PO): days 11-56 (Withhold 6-MP during the \n6-10 days of cranial irradiation beginning on day 1 of Cycle 5. Start 6-MP \nthe 1st day after cranial irradiation completion.) \nMethotrexate (20 mg/m2/week, PO): days 8, 15, 22, 29, 36, 43, 50 \n\n47 \n\n\n\nMaintenance \n(8-week cycles) \nCycles 6-12 \n\nVCR (1.5 mg/m2/day, IV): days 1, 29 \nDEX (6 mg/m2/day, PO): days 1-5; 29-33 \n6-MP (75 mg/m2/day, PO): days 1-56 \nMethotrexate (20 mg/m2/week, PO): days 1, 8, 15, 22, 29, 36, 43, 50 \n\nG-CSF = granulocyte colony stimulating factor, VP-16 = etoposide, MTX = methotrexate, IV = \nintravenous, SC = subcutaneous, IT = intrathecal, PO = oral, IM = intramuscular, ARA-C = \ncytarabine, CPM = cyclophosphamide, VCR = vincristine, DEX = dexamethasone, DAUN = \ndaunorubicin, 6-MP = 6-mercaptopurine, E.Coli L-ASP = L-asparaginase, PEG-ASP = PEG \nasparaginase, MESNA= 2-mercaptoethane sulfonate sodium, iii= or until MTX level is < 0.1 µM, q6h \n= every 6 hours, Gy= Gray \n \nStudy AIT07 was a multicentre, open-label, randomised, phase II/III study that included 128 patients \n(1 to < 18 years) treated with imatinib in combination with chemotherapy. Safety data from this study \nseem to be in line with the safety profile of imatinib in Ph+ ALL patients. \n \nRelapsed/refractory Ph+ ALL: When imatinib was used as single agent in patients with \nrelapsed/refractory Ph+ ALL, it resulted, in the 53 out of 411 patients evaluable for response, in a \nhaematological response rate of 30% (9% complete) and a major cytogenetic response rate of 23%. \n(Of note, out of the 411 patients, 353 were treated in an expanded access program without primary \nresponse data collected.) The median time to progression in the overall population of 411 patients with \nrelapsed/refractory Ph+ ALL ranged from 2.6 to 3.1 months, and median overall survival in the \n401 evaluable patients ranged from 4.9 to 9 months. The data was similar when re-analysed to include \nonly those patients age 55 or older. \n \nClinical studies in MDS/MPD \nExperience with imatinib in this indication is very limited and is based on haematological and \ncytogenetic response rates. There are no controlled trials demonstrating a clinical benefit or increased \nsurvival. One open label, multicentre, phase II clinical trial (study B2225) was conducted testing \nimatinib in diverse populations of patients suffering from life-threatening diseases associated with \nAbl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD who were \ntreated with imatinib 400 mg daily. Three patients presented a complete haematological response \n(CHR) and one patient experienced a partial haematological response (PHR). At the time of the \noriginal analysis, three of the four patients with detected PDGFR gene rearrangements developed \nhaematological response (2 CHR and 1 PHR). The age of these patients ranged from 20 to 72 years. \n \nAn observational registry (study L2401) was conducted to collect long-term safety and efficacy data in \npatients suffering from myeloproliferative neoplasms with PDGFR- β rearrangement and who were \ntreated with imatinib. The 23 patients enrolled in this registry received imatinib at a median daily dose \nof 264 mg (range: 100 to 400 mg) for a median duration of 7.2 years (range 0.1 to 12.7 years). Due to \nthe observational nature of this registry, haematologic, cytogenetic and molecular assessment data \nwere available for 22, 9 and 17 of the 23 enrolled patients, respectively. When assuming \nconservatively that patients with missing data were non-responders, CHR was observed in 20/23 \n(87%) patients, CCyR in 9/23 (39.1%) patients, and MR in 11/23 (47.8%) patients, respectively. When \nthe response rate is calculated from patients with at least one valid assessment, the response rate for \nCHR, CCyR and MR was 20/22 (90.9%), 9/9 (100%) and 11/17 (64.7%), respectively. \n \nIn addition a further 24 patients with MDS/MPD were reported in 13 publications. 21 patients were \ntreated with imatinib 400 mg daily, while the other 3 patients received lower doses. In eleven patients \nPDGFR gene rearrangements was detected, 9 of them achieved a CHR and 1 PHR. The age of these \npatients ranged from 2 to 79 years. In a recent publication updated information from 6 of these \n11 patients revealed that all these patients remained in cytogenetic remission (range 32-38 months). \nThe same publication reported long term follow-up data from 12 MDS/MPD patients with PDGFR \ngene rearrangements (5 patients from study B2225). These patients received imatinib for a median of \n47 months (range 24 days – 60 months). In 6 of these patients follow-up now exceeds 4 years. Eleven \npatients achieved rapid CHR; ten had complete resolution of cytogenetic abnormalities and a decrease \nor disappearance of fusion transcripts as measured by RT-PCR. Haematological and cytogenetic \nresponses have been sustained for a median of 49 months (range 19-60) and 47 months (range 16-59), \n\n48 \n\n\n\nrespectively. The overall survival is 65 months since diagnosis (range 25-234). Imatinib administration \nto patients without the genetic translocation generally results in no improvement. \n \nThere are no controlled trials in paediatric patients with MDS/MPD. Five (5) patients with MDS/MPD \nassociated with PDGFR gene re-arrangements were reported in 4 publications. The age of these \npatients ranged from 3 months to 4 years and imatinib was given at dose 50 mg daily or doses ranging \nfrom 92.5 to 340 mg/m2 daily. All patients achieved complete haematological response, cytogenetic \nresponse and/or clinical response. \n \nClinical studies in HES/CEL \nOne open-label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib in \ndiverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or \nPDGFR protein tyrosine kinases. In this study, 14 patients with HES/CEL were treated with 100 mg to \n1,000 mg of imatinib daily. A further 162 patients with HES/CEL, reported in 35 published case \nreports and case series received imatinib at doses from 75 mg to 800 mg daily. Cytogenetic \nabnormalities were evaluated in 117 of the total population of 176 patients. In 61 of these 117 patients \nFIP1L1-PDGFRα fusion kinase was identified. An additional four HES patients were found to be \nFIP1L1-PDGFRα-positive in other 3 published reports. All 65 FIP1L1-PDGFRα fusion kinase \npositive patients achieved a CHR sustained for months (range from 1+ to 44+ months censored at the \ntime of the reporting). As reported in a recent publication 21 of these 65 patients also achieved \ncomplete molecular remission with a median follow-up of 28 months (range 13-67 months). The age \nof these patients ranged from 25 to 72 years. Additionally, improvements in symptomatology and \nother organ dysfunction abnormalities were reported by the investigators in the case reports. \nImprovements were reported in cardiac, nervous, skin/subcutaneous tissue, \nrespiratory/thoracic/mediastinal, musculoskeletal/connective tissue/vascular, and gastrointestinal \norgan systems. \n \nThere are no controlled trials in paediatric patients with HES/CEL. Three (3) patients with HES and \nCEL associated with PDGFR gene re-arrangements were reported in 3 publications. The age of these \npatients ranged from 2 to 16 years and imatinib was given at dose 300 mg/m2 daily or doses ranging \nfrom 200 to 400 mg daily. All patients achieved complete haematological response, complete \ncytogenetic response and/or complete molecular response. \n \nClinical studies in DFSP \nOne phase II, open label, multicentre clinical trial (study B2225) was conducted including 12 patients \nwith DFSP treated with imatinib 800 mg daily. The age of the DFSP patients ranged from 23 to \n75 years; DFSP was metastatic, locally recurrent following initial resective surgery and not considered \namenable to further resective surgery at the time of study entry. The primary evidence of efficacy was \nbased on objective response rates. Out of the 12 patients enrolled, 9 responded, one completely and \n8 partially. Three of the partial responders were subsequently rendered disease free by surgery. The \nmedian duration of therapy in study B2225 was 6.2 months, with a maximum duration of 24.3 months. \nA further 6 DFSP patients treated with imatinib were reported in 5 published case reports, their ages \nranging from 18 months to 49 years. The adult patients reported in the published literature were \ntreated with either 400 mg (4 cases) or 800 mg (1 case) imatinib daily. 5 patients responded, \n3 completely and 2 partially. The median duration of therapy in the published literature ranged \nbetween 4 weeks and more than 20 months. The translocation t(17:22)[(q22:q13)], or its gene product, \nwas present in nearly all responders to imatinib treatment. \n \nThere are no controlled trials in paediatric patients with DFSP. Five (5) patients with DFSP and \nPDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged from \nnewborn to 14 years and imatinib was given at dose 50 mg daily or doses ranging from 400 to \n520 mg/m2 daily. All patients achieved partial and/or complete response. \n \n5.2 Pharmacokinetic properties \n \nPharmacokinetics of imatinib \n\n49 \n\n\n\nThe pharmacokinetics of imatinib have been evaluated over a dosage range of 25 to 1,000 mg. Plasma \npharmacokinetic profiles were analysed on day 1 and on either day 7 or day 28, by which time plasma \nconcentrations had reached steady state. \n \nAbsorption \nMean absolute bioavailability for imatinib is 98%. There was high between-patient variability in \nplasma imatinib AUC levels after an oral dose. When given with a high-fat meal, the rate of \nabsorption of imatinib was minimally reduced (11% decrease in Cmax and prolongation of tmax by \n1.5 h), with a small reduction in AUC (7.4%) compared to fasting conditions. The effect of prior \ngastrointestinal surgery on drug absorption has not been investigated. \n \nDistribution \nAt clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% \non the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding \nto lipoprotein. \n \nBiotransformation \nThe main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows \nsimilar in vitro potency to the parent. The plasma AUC for this metabolite was found to be only 16% \nof the AUC for imatinib. The plasma protein binding of the N-demethylated metabolite is similar to \nthat of the parent compound. \n \nImatinib and the N-demethyl metabolite together accounted for about 65% of the circulating \nradioactivity (AUC(0-48h)). The remaining circulating radioactivity consisted of a number of minor \nmetabolites. \n \nThe in vitro results showed that CYP3A4 was the major human P450 enzyme catalysing the \nbiotransformation of imatinib. Of a panel of potential comedications (acetaminophen, aciclovir, \nallopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, \npenicillin V) only erythromycin (IC50 50 µM) and fluconazole (IC50 118 µM) showed inhibition of \nimatinib metabolism which could have clinical relevance. \n \nImatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6 \nand CYP3A4/5. Ki values in human liver microsomes were 27, 7.5 and 7.9 μmol/L, respectively. \nMaximal plasma concentrations of imatinib in patients are 2–4 μmol/L, consequently an inhibition of \nCYP2D6 and/or CYP3A4/5-mediated metabolism of co-administered drugs is possible. Imatinib did \nnot interfere with the biotransformation of 5-fluorouracil, but it inhibited paclitaxel metabolism as a \nresult of competitive inhibition of CYP2C8 (Ki - 34.7 µM). This Ki value is far higher than the \nexpected plasma levels of imatinib in patients, consequently no interaction is expected upon co-\nadministration of either 5-fluorouracil or paclitaxel and imatinib. \n \nElimination \nBased on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% \nof the dose was recovered within 7 days in faeces (68% of dose) and urine (13% of dose). Unchanged \nimatinib accounted for 25% of the dose (5% urine, 20% faeces), the remainder being metabolites. \n \nPlasma pharmacokinetics \nFollowing oral administration in healthy volunteers, the t½ was approximately 18 h, suggesting that \nonce-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose \nproportional in the range of 25–1,000 mg imatinib after oral administration. There was no change in \nthe kinetics of imatinib on repeated dosing, and accumulation was 1.5–2.5-fold at steady state when \ndosed once daily. \n \nPopulation pharmacokinetics \nBased on population pharmacokinetic analysis in CML patients, there was a small effect of age on the \nvolume of distribution (12% increase in patients > 65 years old). This change is not thought to be \nclinically significant. The effect of bodyweight on the clearance of imatinib is such that for a patient \n\n50 \n\n\n\nweighing 50 kg the mean clearance is expected to be 8.5 L/h, while for a patient weighing 100 kg the \nclearance will rise to 11.8 L/h. These changes are not considered sufficient to warrant dose adjustment \nbased on kg bodyweight. There is no effect of gender on the kinetics of imatinib. \n \nPharmacokinetics in paediatric population \nAs in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients in \nboth phase I and phase II studies. Dosing in children at 260 and 340 mg/m2/day achieved the same \nexposure, respectively, as doses of 400 mg and 600 mg in adult patients. The comparison of AUC(0-24) \non day 8 and day 1 at the 340 mg/m2/day dose level revealed a 1.7-fold drug accumulation after \nrepeated once-daily dosing. \n \nBased on pooled population pharmacokinetic analysis in paediatric patients with haematological \ndisorders (CML, Ph+ALL, or other haematological disorders treated with imatinib), clearance of \nimatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other \ndemographics such as age, body weight and body mass index did not have clinically significant effects \non the exposure of imatinib. The analysis confirmed that exposure of imatinib in paediatric patients \nreceiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (not \nexceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or \n600 mg once daily. \n \nOrgan function impairment \nImatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mild \nand moderate impairment of renal function appear to have a higher plasma exposure than patients with \nnormal renal function. The increase is approximately 1.5- to 2-fold, corresponding to a 1.5-fold \nelevation of plasma AGP, to which imatinib binds strongly. The free drug clearance of imatinib is \nprobably similar between patients with renal impairment and those with normal renal function, since \nrenal excretion represents only a minor elimination pathway for imatinib (see sections 4.2 and 4.4). \n \nAlthough the results of pharmacokinetic analysis showed that there is considerable inter-subject \nvariation, the mean exposure to imatinib did not increase in patients with varying degrees of liver \ndysfunction as compared to patients with normal liver function (see sections 4.2, 4.4 and 4.8). \n \n5.3 Preclinical safety data \n \nThe preclinical safety profile of imatinib was assessed in rats, dogs, monkeys and rabbits. \n \nMultiple dose toxicity studies revealed mild to moderate haematological changes in rats, dogs and \nmonkeys, accompanied by bone marrow changes in rats and dogs. \n \nThe liver was a target organ in rats and dogs. Mild to moderate increases in transaminases and slight \ndecreases in cholesterol, triglycerides, total protein and albumin levels were observed in both species. \nNo histopathological changes were seen in rat liver. Severe liver toxicity was observed in dogs treated \nfor 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct \nhyperplasia. \n \nRenal toxicity was observed in monkeys treated for 2 weeks, with focal mineralisation and dilation of \nthe renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were \nobserved in several of these animals. In rats, hyperplasia of the transitional epithelium in the renal \npapilla and in the urinary bladder was observed at doses ≥ 6 mg/kg in the 13-week study, without \nchanges in serum or urinary parameters. An increased rate of opportunistic infections was observed \nwith chronic imatinib treatment. \n \nIn a 39-week monkey study, no NOAEL (no observed adverse effect level) was established at the \nlowest dose of 15 mg/kg, approximately one-third the maximum human dose of 800 mg based on \nbody surface. Treatment resulted in worsening of normally suppressed malarial infections in these \nanimals. \n \n\n51 \n\n\n\nImatinib was not considered genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in \nvitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus test. Positive \ngenotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster \novary) for clastogenicity (chromosome aberration) in the presence of metabolic activation. Two \nintermediates of the manufacturing process, which are also present in the final product, are positive for \nmutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma \nassay. \n \nIn a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights \nand percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinical \ndose of 800 mg/day, based on body surface area. This was not seen at doses ≤ 20 mg/kg. A slight to \nmoderate reduction in spermatogenesis was also observed in the dog at oral doses ≥ 30 mg/kg. When \nfemale rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on \nmating or on number of pregnant females. At a dose of 60 mg/kg, female rats had significant post-\nimplantation foetal loss and a reduced number of live foetuses. This was not seen at doses ≤ 20 mg/kg. \n \nIn an oral pre- and postnatal development study in rats, red vaginal discharge was noted in the \n45 mg/kg/day group on either day 14 or day 15 of gestation. At the same dose, the number of stillborn \npups as well as those dying between postpartum days 0 and 4 was increased. In the F1 offspring, at the \nsame dose level, mean body weights were reduced from birth until terminal sacrifice and the number \nof litters achieving criterion for preputial separation was slightly decreased. F1 fertility was not \naffected, while an increased number of resorptions and a decreased number of viable foetuses was \nnoted at 45 mg/kg/day. The no observed effect level (NOEL) for both the maternal animals and the F1 \ngeneration was 15 mg/kg/day (one quarter of the maximum human dose of 800 mg). \n \nImatinib was teratogenic in rats when administered during organogenesis at doses ≥ 100 mg/kg, \napproximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. \nTeratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal \nbones. These effects were not seen at doses ≤ 30 mg/kg. \n \nNo new target organs were identified in the rat juvenile development toxicology study (day 10 to 70 \npostpartum) with respect to the known target organs in adult rats. In the juvenile toxicology study, \neffects upon growth, delay in vaginal opening and preputial separation were observed at \napproximately 0.3 to 2 times the average paediatric exposure at the highest recommended dose of \n340 mg/m2. In addition, mortality was observed in juvenile animals (around weaning phase) at \napproximately 2 times the average paediatric exposure at the highest recommended dose of \n340 mg/m2. \n \nIn the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resulted \nin a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at \n≥ 30 mg/kg/day. Histopathological examination of decedents revealed cardiomyopathy (both sexes), \nchronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death \nor reasons for sacrifice. Target organs for neoplastic changes were the kidneys, urinary bladder, \nurethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-\nglandular stomach. \n \nPapilloma/carcinoma of the preputial/clitoral gland were noted from 30 mg/kg/day onwards, \nrepresenting approximately 0.5 or 0.3 times the human daily exposure (based on AUC) at 400 mg/day \nor 800 mg/day, respectively, and 0.4 times the daily exposure in children (based on AUC) at \n340 mg/m2/day. The no observed effect level (NOEL) was 15 mg/kg/day. The renal \nadenoma/carcinoma, the urinary bladder and urethra papilloma, the small intestine adenocarcinomas, \nthe parathyroid glands adenomas, the benign and malignant medullary tumours of the adrenal glands \nand the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day, representing \napproximately 1.7 or 1 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, \nrespectively, and 1.2 times the daily exposure in children (based on AUC) at 340 mg/m2/day. The no \nobserved effect level (NOEL) was 30 mg/kg/day. \n \n\n52 \n\n\n\nThe mechanism and relevance of these findings in the rat carcinogenicity study for humans are not yet \nclarified. \n \nNon-neoplastic lesions not identified in earlier preclinical studies were the cardiovascular system, \npancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and \ndilatation, leading to signs of cardiac insufficiency in some animals. \n \nThe active substance imatinib demonstrates an environmental risk for sediment organisms. \n \n \n6. PHARMACEUTICAL PARTICULARS \n \n6.1 List of excipients \n \nTablet core \nCellulose microcrystalline \nCopovidone \nCrospovidone \nSodium stearyl fumarate \nSilica, hydrophobic colloidal \nSilica, colloidal anhydrous \n \nTablet coat \nPolyvinyl alchol part. hydrolised \nTalc \nIron oxide yellow (E172) \nTitanium dioxide (E171) \nIron oxide red (E172) \nLecithin (soya) (E322) \nXanthan gum (E415) \n \n6.2 Incompatibilities \n \nNot applicable. \n \n6.3 Shelf life \n \nImatinib Actavis 100 mg film-coated tablets \n2 years \n \nImatinib Actavis 400 mg film-coated tablets \n21 month \n \n6.4 Special precautions for storage \n \nDo not store above 30°C. \nStore in the original package in order to protect from moisture. \n \n6.5 Nature and contents of container \n \nAl/PVC/Aclar blister. One blister contains 10 tablets. \n \nImatinib Actavis 100 mg film-coated tablets \nPack containing either 10, 20, 30, 60, 90, 120 or 180 film-coated tablets \n \nImatinib Actavis 400 mg film-coated tablets \nPack containing either 10, 30, 60 or 90 film-coated tablets \n\n53 \n\n\n\n \nNot all pack sizes may be marketed. \n \n6.6 Special precautions for disposal \n \nAny unused medicinal product or waste material should be disposed of in accordance with local \nrequirements. \n \n \n7. MARKETING AUTHORISATION HOLDER \n \nActavis Group PTC ehf. \nReykjavíkurvegur 76-78 \nIS-220 Hafnarfjörður \nIceland \n \n \n8. MARKETING AUTHORISATION NUMBER(S) \n \nImatinib Actavis 100 mg film-coated tablets \nEU/1/13/825/008 \nEU/1/13/825/009 \nEU/1/13/825/010 \nEU/1/13/825/011 \nEU/1/13/825/012 \nEU/1/13/825/013 \nEU/1/13/825/014 \n \nImatinib Actavis 400 mg film-coated tablets \nEU/1/13/825/015 \nEU/1/13/825/016 \nEU/1/13/825/017 \nEU/1/13/825/018 \n \n \n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n \nDate of first authorisation: 17 April 2013 \n \n \n10. DATE OF REVISION OF THE TEXT \n \nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency http://www.ema.europa.eu \n\n \n\n54 \n\nhttp://www.ema.europa.eu/\n\n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX II \n \n\nA. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE \n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND \n\nUSE \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE \n\nMARKETING AUTHORISATION \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE \n\nSAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT \n \n\n55 \n\n\n\nA. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE \n \nName and address of the manufacturer responsible for batch release \nS.C. Sindan-Pharma S.R.L. \n11th Ion Mihalache Ave, The 1st district, \nRO-011171 Bucharest \nRomania \n \n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n \nMedicinal product subject to restricted medical prescription (See Annex I: Summary of Product \nCharacteristics, section 4.2). \n \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n• Periodic safety update reports \n \nAt the time of granting the marketing authorisation, the submission of periodic safety update reports \nis not required for this medicinal product. However, the marketing authorisation holder shall submit \nperiodic safety update reports for this medicinal product if the product is included in the list of Union \nreference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and \npublished on the European medicines web-portal. \n \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n \n• Risk Management Plan (RMP) \nNot applicable. \n \n\n \n\n56 \n\n\n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX III \n \n\nLABELLING AND PACKAGE LEAFLET \n \n\n57 \n\n\n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nA. LABELLING \n \n\n58 \n\n\n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCARTON \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nImatinib Actavis 50 mg hard capsules \nimatinib \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nEach hard capsule contains 50 mg of imatinib (as mesilate). \n \n \n3. LIST OF EXCIPIENTS \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \n30 hard capsules \n90 hard capsules \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nOral use. \nRead the package leaflet before use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \nUse only as directed by a doctor. \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nDo not store above 25°C. \nStore in the original package in order to protect from moisture. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n59 \n\n\n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nActavis Group PTC ehf. \n220 Hafnarfjörður \nIceland \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/13/825/001 30 capsules \nEU/1/13/825/002 90 capsules \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nImatinib Actavis 50 mg \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n<2D barcode carrying the unique identifier included.> \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: {number} \nSN: {number} \nNN: {number} \n \n\n60 \n\n\n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCARTON \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nImatinib Actavis 100 mg hard capsules \nimatinib \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nEach hard capsule contains 100 mg of imatinib (as mesilate). \n \n \n3. LIST OF EXCIPIENTS \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \n24 hard capsules \n48 hard capsules \n60 hard capsules \n96 hard capsules \n120 hard capsules \n180 hard capsules \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nOral use. \nRead the package leaflet before use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \nUse only as directed by a doctor. \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nDo not store above 25°C. \nStore in the original package in order to protect from moisture. \n \n\n61 \n\n\n\n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nActavis Group PTC ehf. \n220 Hafnarfjörður \nIceland \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/13/825/003 24 capsules \nEU/1/13/825/004 48 capsules \nEU/1/13/825/019 60 capsules \nEU/1/13/825/005 96 capsules \nEU/1/13/825/006 120 capsules \nEU/1/13/825/007 180 capsules \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nImatinib Actavis 100 mg \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n<2D barcode carrying the unique identifier included.> \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: {number} \nSN: {number} \nNN: {number} \n\n62 \n\n\n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCARTON \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nImatinib Actavis 400 mg hard capsules \nimatinib \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nEach hard capsule contains 400 mg of imatinib (as mesilate). \n \n \n3. LIST OF EXCIPIENTS \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \n10 hard capsules \n30 hard capsules \n60 hard capsules \n90 hard capusles \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nOral use. \nRead the package leaflet before use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \nUse only as directed by a doctor. \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nDo not store above 25°C. \nStore in the original package in order to protect from moisture. \n \n \n\n63 \n\n\n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nActavis Group PTC ehf. \n220 Hafnarfjörður \nIceland \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/13/825/020 10 capsules \nEU/1/13/825/021 30 capsules \nEU/1/13/825/022 60 capsules \nEU/1/13/825/023 90 capsules \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nImatinib Actavis 400 mg \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n<2D barcode carrying the unique identifier included.> \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: {number} \nSN: {number} \nNN: {number} \n \n\n64 \n\n\n\nMINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS \n \nBLISTERS \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nImatinib Actavis 50 mg capsules \nimatinib \n \n \n2. NAME OF THE MARKETING AUTHORISATION HOLDER \n \n[Actavis logo] \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. OTHER \n \n \n \n\n65 \n\n\n\nMINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS \n \nBLISTERS \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nImatinib Actavis 100 mg capsules \nimatinib \n \n \n2. NAME OF THE MARKETING AUTHORISATION HOLDER \n \n[Actavis logo] \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. OTHER \n \n \n\n66 \n\n\n\nMINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS \n \nBLISTERS \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nImatinib Actavis 400 mg capsules \nimatinib \n \n \n2. NAME OF THE MARKETING AUTHORISATION HOLDER \n \n[Actavis logo] \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. OTHER \n \n\n67 \n\n\n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCARTON \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nImatinib Actavis 100 mg film-coated tablets \nimatinib \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nEach film-coated tablet contains 100 mg of imatinib (as mesilate). \n \n \n3. LIST OF EXCIPIENTS \n \nContains lecithin (soya) (E322). See leaflet for further information. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \n10 film-coated tablets \n20 film-coated tablets \n30 film-coated tablets \n60 film-coated tablets \n90 film-coated tablets \n120 film-coated tablets \n180 film-coated tablets \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nOral use. \nRead the package leaflet before use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \nUse only as directed by a doctor. \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \n\n68 \n\n\n\nDo not store above 30°C. \nStore in the original package in order to protect from moisture. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nActavis Group PTC ehf. \n220 Hafnarfjörður \nIceland \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/13/825/008 10 tablets \nEU/1/13/825/009 20 tablets \nEU/1/13/825/010 30 tablets \nEU/1/13/825/011 60 tablets \nEU/1/13/825/012 90 tablets \nEU/1/13/825/013 120 tablets \nEU/1/13/825/014 180 tablets \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nImatinib Actavis 100 mg \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n<2D barcode carrying the unique identifier included.> \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: {number} \nSN: {number} \nNN: {number} \n \n\n69 \n\n\n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCARTON \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nImatinib Actavis 400 mg film-coated tablets \nimatinib \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nEach film-coated tablet contains 400 mg of imatinib (as mesilate). \n \n \n3. LIST OF EXCIPIENTS \n \nContains lecithin (soya) (E322). See leaflet for further information. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \n10 film-coated tablets \n30 film-coated tablets \n60 film-coated tablets \n90 film-coated tablets \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nOral use. \nRead the package leaflet before use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \nUse only as directed by a doctor. \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nDo not store above 30°C. \nStore in the original package in order to protect from moisture. \n \n\n70 \n\n\n\n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nActavis Group PTC ehf. \n220 Hafnarfjörður \nIceland \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/13/825/015 10 tablets \nEU/1/13/825/016 30 tablets \nEU/1/13/825/017 60 tablets \nEU/1/13/825/018 90 tablets \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nImatinib Actavis 400 mg \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n<2D barcode carrying the unique identifier included.> \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: {number} \nSN: {number} \nNN: {number} \n \n \n\n71 \n\n\n\nMINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS \n \nBLISTERS \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nImatinib Actavis 100 mg tablets \nimatinib \n \n \n2. NAME OF THE MARKETING AUTHORISATION HOLDER \n \n[Actavis logo] \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. OTHER \n \n \n \n\n72 \n\n\n\nMINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS \n \nBLISTERS \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nImatinib Actavis 400 mg tablets \nimatinib \n \n \n2. NAME OF THE MARKETING AUTHORISATION HOLDER \n \n[Actavis logo] \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. OTHER \n \n \n\n \n\n73 \n\n\n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nB. PACKAGE LEAFLET \n \n\n74 \n\n\n\nPackage leaflet: Information for the user \n \n\nImatinib Actavis 50 mg hard capsules \nimatinib \n\n \n \nRead all of this leaflet carefully before you start taking this medicine because it contains \nimportant information for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor, pharmacist or nurse. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible \n\nside effects not listed in this leaflet. See section 4. \n \nWhat is in this leaflet \n \n1. What Imatinib Actavis is and what it is used for \n2. What you need to know before you take Imatinib Actavis \n3. How to take Imatinib Actavis \n4. Possible side effects \n5. How to store Imatinib Actavis \n6. Contents of the pack and other information \n \n \n1. What Imatinib Actavis is and what it is used for \n \nImatinib Actavis is a medicine containing an active substance called imatinib. This medicine works by \ninhibiting the growth of abnormal cells in the diseases listed below. These include some types of \ncancer. \n \nImatinib Actavis is a treatment for: \n \n- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white \n\ncells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia \nin which certain abnormal white cells (named myeloid cells) start growing out of control. \n\n \nIn adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast \ncrisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease \n(chronic, accelerated phase and blast crisis). \n \n- Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). \n\nLeukaemia is a cancer of white blood cells. These white cells usually help the body to fight \ninfection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal \nwhite cells (named lymphoblasts) start growing out of control. Imatinib Actavis inhibits the \ngrowth of these cells. \n\n \nImatinib Actavis is also a treatment for adults for: \n \n- Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are a group of blood \n\ndiseases in which some blood cells start growing out of control. Imatinib Actavis inhibits the \ngrowth of these cells in a certain subtype of these diseases. \n\n- Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These \nare blood diseases in which some blood cells (named eosinophils) start growing out of control. \nImatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. \n\n75 \n\n\n\n- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin \nin which some cells start growing out of control. Imatinib Actavis inhibits the growth of these \ncells. \n\n \nIn the rest of this leaflet, we will use the abbreviations when talking about these diseases. \n \nIf you have any questions about how Imatinib Actavis works or why this medicine has been prescribed \nfor you, ask your doctor. \n \n \n2. What you need to know before you take Imatinib Actavis \n \nImatinib Actavis will only be prescribed to you by a doctor with experience in medicines to treat blood \ncancers or solid tumours. \n \nFollow all your doctor’s instructions carefully, even if they differ from the general information \ncontained in this leaflet. \n \nDo not take Imatinib Actavis: \n- if you are allergic to imatinib or any of the other ingredients of this medicine (listed in \n\nsection 6). \n \nIf this applies to you, tell your doctor without taking Imatinib Actavis. \n \nIf you think you may be allergic but are not sure, ask your doctor for advice. \n \nWarnings and precautions \nTalk to your doctor before taking Imatinib Actavis: \n- if you have or have ever had a liver, kidney or heart problem. \n- if you are taking the medicine levothyroxine because your thyroid has been removed. \n- if you have ever had or might now have a hepatitis B infection. This is because Imatinib Actavis \n\ncould cause hepatitis B to become active again, which can be fatal in some cases. Patients will \nbe carefully checked by their doctor for signs of this infection before treatment is started. \n\n- if you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, \ncontact your doctor. This may be a sign of damage to blood vessels known as thrombotic \nmicroangiopathy (TMA). \n\nIf any of these apply to you, tell your doctor before taking Imatinib Actavis. \n \nYou may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun-\nexposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are \nalso applicable to children. \n \nDuring treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very \nquickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). \n \nWhile you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is \nworking. You will also have blood tests and be weighed regularly. \n \nChildren and adolescents \nImatinib Actavis is also a treatment for children with CML. There is no experience in children with \nCML below 2 years of age. There is limited experience in children with Ph-positive ALL and very \nlimited experience in children with MDS/MPD, DFSP and HES/CEL. \n \nSome children and adolescents taking Imatinib Actavis may have slower than normal growth. The \ndoctor will monitor the growth at regular visits. \n \nOther medicines and Imatinib Actavis \n\n76 \n\n\n\nTell your doctor or pharmacist if you are taking, have recently taken or might take any other \nmedicines, including medicines obtained without a prescription (such as paracetamol) and including \nherbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib \nActavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either \nleading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis may do \nthe same to some other medicines. \n \nTell your doctor if you are using medicines that prevent the formation of blood clots. \n \nPregnancy, breast-feeding and fertility \n- If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, \n\nask your doctor for advice before taking this medicine. \n- Imatinib Actavis is not recommended during pregnancy unless clearly necessary as it may harm \n\nyour baby. Your doctor will discuss with you the possible risks of taking Imatinib Actavis \nduring pregnancy. \n\n- Women who might become pregnant are advised to use effective contraception during \ntreatment. \n\n- Do not breast-feed during the treatment with Imatinib Actavis. \n- Patients who are concerned about their fertility while taking Imatinib Actavis are advised to \n\nconsult with their doctor. \n \nDriving and using machines \nYou may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not \ndrive or use any tools or machines until you are feeling well again. \n \nImatinib Actavis contains sodium \nThis medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially \n‘sodium-free’. \n \n \n3. How to take Imatinib Actavis \n \nYour doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib \nActavis can help you to fight this condition. \n \nHowever, always take this medicine exactly as your doctor or pharmacist has told you. It is important \nthat you do this as long as your doctor or pharmacist tells you to. Check with your doctor or \npharmacist if you are not sure. \n \nDo not stop taking Imatinib Actavis unless your doctor tells you to. If you are not able to take the \nmedicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor \nstraight away. \n \nHow much Imatinib Actavis to take \n \nUse in adults \nYour doctor will tell you exactly how many capsules of Imatinib Actavis to take. \n \n- If you are being treated for CML: \n\nThe usual starting dose is 600 mg to be taken as 12 capsules once a day. \n \nYour doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your \ndaily dose is 800 mg (16 capsules), you should take 8 capsules in the morning and 8 capsules in the \nevening. \n \n- If you are being treated for Ph-positive ALL: \n\nThe starting dose is 600 mg to be taken as 12 capsules once a day. \n\n77 \n\n\n\n \n- If you are being treated for MDS/MPD: \n\nThe starting dose is 400 mg, to be taken as 8 capsules once a day. \n \n- If you are being treated for HES/CEL: \n\nThe starting dose is 100 mg, to be taken as 2 capsules once a day. Your doctor may decide to \nincrease the dose to 400 mg, to be taken as 8 capsules once a day, depending on how you \nrespond to treatment. \n\n \n- If you are being treated for DFSP: \n\nThe dose is 800 mg per day (16 capsules), to be taken as 8 capsules in the morning and \n8 capsules in the evening. \n\n \nUse in children and adolescents \nThe doctor will tell you how many capsules of Imatinib Actavis to give to your child. The amount of \nImatinib Actavis given will depend on your child’s condition, body weight and height. \nThe total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The \ntreatment can either be given to your child as a once-daily dose or alternatively the daily dose can be \nsplit into two administrations (half in the morning and half in the evening). \n \nWhen and how to take Imatinib Actavis \n- Take Imatinib Actavis with a meal. This will help protect you from stomach problems when \n\ntaking Imatinib Actavis. \n- Swallow the capsules whole with a large glass of water. Do not open or crush the capsules \n\nunless you have difficulty in swallowing (e.g. in children). \n- If you are unable to swallow the capsules, you can open them up and pour the powder into a \n\nglass of still water or apple juice. \n- If you are a woman who is pregnant or might get pregnant and are trying to open the capsules, \n\nyou should handle the contents with caution in order to avoid skin-eye contact or inhalation. \nYou should wash your hands immediately after opening the capsules. \n\n \nHow long to take Imatinib Actavis \nKeep taking Imatinib Actavis every day for as long as your doctor tells you. \n \nIf you take more Imatinib Actavis than you should \nIf you have accidentally taken too many capsules, talk to your doctor straight away. You may require \nmedical attention. Take the medicine pack with you. \n \nIf you forget to take Imatinib Actavis \n- If you forget a dose, take it as soon as you remember. However if it is nearly time for the next \n\ndose, skip the missed dose. \n- Then continue with your normal schedule. \n- Do not take a double dose to make up a forgotten dose. \n \nIf you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. \n \n \n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. They are \nusually mild to moderate. \n \nSome side effects may be serious. Tell your doctor straight away if you get any of the following: \n \nVery common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): \n- Rapid weight gain. Imatinib Actavis may cause your body to retain water (severe fluid \n\nretention). \n\n78 \n\n\n\n- Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can \nreduce the number of white blood cells, so you might get infections more easily. \n\n- Unexpected bleeding or bruising (when you have not hurt yourself). \n \nUncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): \n- Chest pain, irregular heart rhythm (signs of heart problems). \n- Cough, having difficulty breathing or painful breathing (signs of lung problems). \n- Feeling light-headed, dizzy or fainting (signs of low blood pressure). \n- Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of \n\nliver problems). \n- Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or \n\npurple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). \n- Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of \n\ngastrointestinal disorders). \n- Severely decreased urine output, feeling thirsty (signs of kidney problems). \n- Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel \n\nproblems). \n- Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of \n\nconsciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). \n- Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red \n\nblood cells). \n- Eye pain or deterioration in vision, bleeding in the eyes. \n- Pain in your hips or difficulty walking. \n- Numb or cold toes and fingers (signs of Raynaud’s syndrome). \n- Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). \n- Difficulty hearing. \n- Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of \n\npotassium in your blood). \n- Bruising. \n- Stomach pain with feeling sick (nausea). \n- Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of \n\nmuscle problems). \n- Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling \n\ndizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). \n- Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint \n\ndiscomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and \ncalcium levels and low phosphorous levels in the blood). \n\n- Blood clots in small blood vessels (thrombotic microangiopathy). \n \nNot known (frequency cannot be estimated from the available data): \n- Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood \n\ncells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, \nseverely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic \nreaction). \n\n- Chronic renal failure. \n- Recurrence (reactivation) of Hepatitis B infection when you have had hepatitis B in the past (a \n\nliver infection). \n \nIf you get any of the above, tell your doctor straight away. \n \nOther side effects may include: \n \nVery common (may affect more than 1 in 10 people): \n- Headache or feeling tired. \n- Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. \n- Rash. \n\n79 \n\n\n\n- Muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have \nstopped taking imatinib. \n\n- Swelling such as round your ankles or puffy eyes. \n- Weight gain. \nIf any of these affect you severely, tell your doctor. \n \nCommon (may affect up to 1 in 10 people): \n- Anorexia, weight loss or a disturbed sense of taste. \n- Feeling dizzy or weak. \n- Difficulty in sleeping (insomnia). \n- Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or \n\nhaving blurred vision. \n- Nose bleeds. \n- Pain or swelling in your abdomen, flatulence, heartburn or constipation. \n- Itching. \n- Unusual hair loss or thinning. \n- Numbness of the hands or feet. \n- Mouth ulcers. \n- Joint pain with swelling. \n- Dry mouth, dry skin or dry eye. \n- Decreased or increased skin sensitivity. \n- Hot flushes, chills or night sweats. \nIf any of these affect you severely, tell your doctor. \n \nNot known (frequency cannot be estimated from the available data): \n- Reddening and/or swelling on the palms of the hands and soles of the feet which may be \n\naccompanied by tingling sensation and burning pain. \n- Painful and/or blistering skin lesions. \n- Slowing of growth in children and adolescents. \n- If any of these affect you severely, tell your doctor. \n \nReporting of side effects \nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \neffects not listed in this leaflet. You can also report side effects directly via the national reporting \nsystem listed in Appendix V. By reporting side effects, you can help provide more information on the \nsafety of this medicine. \n \n \n5. How to store Imatinib Actavis \n \nKeep this medicine out of the sight and reach of children. \nDo not use this medicine after the expiry date which is stated on the carton and blister after EXP. The \nexpiry date refers to the last day of that month. \nDo not store above 25°C. Store in the original package in order to protect from moisture. \nDo not use any pack that is damaged or shows signs of tampering. \nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \nthrow away medicines you no longer use. These measures will help protect the environment. \n \n \n6. Contents of the pack and other information \n \nWhat Imatinib Actavis contains \n- The active substance is imatinib (as mesilate). Each capsule contains 50 mg imatinib (as \n\nmesilate). \n- The other ingredients are: Capsule content: cellulose microcrystalline, copovidone, \n\ncrospovidone, sodium stearyl fumarate, silica (colloidal hydrophobe and colloidal anhydrous). \n\n80 \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\nCapsule shell: hypromellose, titanium dioxide (E171), yellow iron oxide (E172). Printing ink: \nshellac, black iron oxide (E172), propylene glycol, ammonia solution, potassium hydroxide. \n\n \nWhat Imatinib Actavis looks like and contents of the pack \nHard capsule with light yellow cap and light yellow body imprinted with 50 mg in black ink. \nThe capsule contains light yellow powder. \n \nPack sizes: \nThe capsules are supplied in aluminium blister packs of 30 or 90 capsules. \n \nNot all pack sizes may be marketed. \n \nMarketing Authorisation Holder \nActavis Group PTC ehf. \nReykjavíkurvegur 76-78, \nHafnarfjörður \nIceland \n \nManufacturer \nS.C. Sindan-Pharma S.R.L. \n11 Ion Mihalache Blvd \nBucharest \nRomania \n \nFor any information about this medicine, please contact the local representative of the Marketing \nAuthorisation Holder. \n \nBelgië/Belgique/Belgien \nActavis Group PTC ehf. \nIJsland/Islande/Island \nTél/Tel: +354 5503300 \n \n\nLietuva \nUAB Sicor Biotech \nTel: +370 52660203 \n \n\nБългария \nАктавис ЕАД \nTeл: +359 24899585 \n \n\nLuxembourg/Luxemburg \nActavis Group PTC ehf. \nIslande/Island \nTél/Tel: +354 5503300 \n \n\nČeská republika \nTeva Pharmaceuticals CR, s.r.o. \nTel: +420 251007111 \n \n\nMagyarország \nTeva Gyógyszergyár Zrt. \nTel: +36 12886400 \n \n\nDanmark \nTeva Denmark A/S \nTlf: +45 44985511 \n \n\nMalta \nActavis Ltd. \nTel: +356 21693533 \n \n\nDeutschland \nActavis Group PTC ehf. \nIsland \nTel: +354 5503300 \n \n\nNederland \nActavis Group PTC ehf. \nIJsland \nTel: +354 5503300 \n \n\nEesti \nUAB Sicor Biotech Eesti filiaal \nTel: +372 6610801 \n \n\nNorge \nTeva Norway AS \nTlf: +47 66775590 \n \n\n81 \n\n\n\nΕλλάδα \nSpecifar ABEE \nΤηλ: +30 2105401500 \n \n\nÖsterreich \nratiopharm Arzneimittel Vertriebs-GmbH \nTel: +43 1970070 \n \n\nEspaña \nActavis Group PTC ehf. \nIslandia \nTel: +354 5503300 \n \n\nPolska \nTeva Pharmaceuticals Polska Sp. z o.o. \nTel: +48 223459300 \n \n\nFrance \nActavis Group PTC ehf. \nIslande \nTél: +354 5503300 \n \n\nPortugal \nActavis Group PTC ehf. \nIslândia \nTel: +354 5503300 \n \n\nHrvatska \nPliva Hrvatska d.o.o. \nTel: +385 13720000 \n \n\nRomânia \nTeva Pharmaceuticals S.R.L. \nTel: +40 212306524 \n \n\nIreland \nTeva Pharmaceuticals Ireland \nTel: +353 (0)19630330 \n \n\nSlovenija \nPliva Ljubljana d.o.o. \nTel: +386 15890390 \n \n\nÍsland \nActavis Group PTC ehf. \nSími: +354 5503300 \n \n\nSlovenská republika \nTEVA Pharmaceuticals Slovakia s.r.o. \nTel: +421 257267911 \n \n\nItalia \nActavis Group PTC ehf. \nIslanda \nTel: +354 5503300 \n \n\nSuomi/Finland \nratiopharm Oy \nPuh/Tel: +358 201805900 \n \n\nΚύπρος \nSpecifar ABEE \nΕλλάδα \nΤηλ: +30 2105401500 \n \n\nSverige \nTeva Sweden AB \nTel: +46 42121100 \n \n\nLatvija \nUAB Sicor Biotech filiāle Latvijā \nTel: +371 67323666 \n \n\nUnited Kingdom \nActavis UK Limited \nTel: +44 1271385257 \n \n\n \nThis leaflet was last revised in \n \nOther sources of information \n \nDetailed information on this medicine is available on the European Medicines Agency website: \nhttp://www.ema.europa.eu \n \n\n82 \n\nhttp://www.ema.europa.eu/\n\n\nPackage leaflet: Information for the user \n \n\nImatinib Actavis 100 mg hard capsules \nimatinib \n\n \n \nRead all of this leaflet carefully before you start taking this medicine because it contains \nimportant information for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor, pharmacist or nurse. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible \n\nside effects not listed in this leaflet. See section 4. \n \nWhat is in this leaflet \n \n1. What Imatinib Actavis is and what it is used for \n2. What you need to know before you take Imatinib Actavis \n3. How to take Imatinib Actavis \n4. Possible side effects \n5. How to store Imatinib Actavis \n6. Contents of the pack and other information \n \n \n1. What Imatinib Actavis is and what it is used for \n \nImatinib Actavis is a medicine containing an active substance called imatinib. This medicine works by \ninhibiting the growth of abnormal cells in the diseases listed below. These include some types of \ncancer. \n \nImatinib Actavis is a treatment for: \n \n- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white \n\ncells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia \nin which certain abnormal white cells (named myeloid cells) start growing out of control. \n\n \nIn adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast \ncrisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease \n(chronic, accelerated phase and blast crisis). \n \n- Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). \n\nLeukaemia is a cancer of white blood cells. These white cells usually help the body to fight \ninfection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal \nwhite cells (named lymphoblasts) start growing out of control. Imatinib Actavis inhibits the \ngrowth of these cells. \n\n \nImatinib Actavis is also a treatment for adults for: \n \n- Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are a group of blood \n\ndiseases in which some blood cells start growing out of control. Imatinib Actavis inhibits the \ngrowth of these cells in a certain subtype of these diseases. \n\n- Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These \nare blood diseases in which some blood cells (named eosinophils) start growing out of control. \nImatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. \n\n83 \n\n\n\n- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin \nin which some cells start growing out of control. Imatinib Actavis inhibits the growth of these \ncells. \n\n \nIn the rest of this leaflet, we will use the abbreviations when talking about these diseases. \n \nIf you have any questions about how Imatinib Actavis works or why this medicine has been prescribed \nfor you, ask your doctor. \n \n \n2. What you need to know before you take Imatinib Actavis \n \nImatinib Actavis will only be prescribed to you by a doctor with experience in medicines to treat blood \ncancers or solid tumours. \n \nFollow all your doctor’s instructions carefully, even if they differ from the general information \ncontained in this leaflet. \n \nDo not take Imatinib Actavis: \n- if you are allergic to imatinib or any of the other ingredients of this medicine (listed in \n\nsection 6). \n \nIf this applies to you, tell your doctor without taking Imatinib Actavis. \n \nIf you think you may be allergic but are not sure, ask your doctor for advice. \n \nWarnings and precautions \nTalk to your doctor before taking Imatinib Actavis: \n- if you have or have ever had a liver, kidney or heart problem. \n- if you are taking the medicine levothyroxine because your thyroid has been removed. \n- if you have ever had or might now have a hepatitis B infection. This is because Imatinib Actavis \n\ncould cause hepatitis B to become active again, which can be fatal in some cases. Patients will \nbe carefully checked by their doctor for signs of this infection before treatment is started. \n\n- if you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, \ncontact your doctor. This may be a sign of damage to blood vessels known as thrombotic \nmicroangiopathy (TMA). \n\nIf any of these apply to you, tell your doctor before taking Imatinib Actavis. \n \nYou may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun-\nexposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are \nalso applicable to children. \n \nDuring treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very \nquickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). \n \nWhile you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is \nworking. You will also have blood tests and be weighed regularly. \n \nChildren and adolescents \nImatinib Actavis is also a treatment for children with CML. There is no experience in children with \nCML below 2 years of age. There is limited experience in children with Ph-positive ALL and very \nlimited experience in children with MDS/MPD, DFSP and HES/CEL. \n \nSome children and adolescents taking Imatinib Actavis may have slower than normal growth. The \ndoctor will monitor the growth at regular visits. \n \nOther medicines and Imatinib Actavis \n\n84 \n\n\n\nTell your doctor or pharmacist if you are taking, have recently taken or might take any other \nmedicines, including medicines obtained without a prescription (such as paracetamol) and including \nherbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib \nActavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either \nleading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis may do \nthe same to some other medicines. \n \nTell your doctor if you are using medicines that prevent the formation of blood clots. \n \nPregnancy, breast-feeding and fertility \n- If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, \n\nask your doctor for advice before taking this medicine. \n- Imatinib Actavis is not recommended during pregnancy unless clearly necessary as it may harm \n\nyour baby. Your doctor will discuss with you the possible risks of taking Imatinib Actavis \nduring pregnancy. \n\n- Women who might become pregnant are advised to use effective contraception during \ntreatment. \n\n- Do not breast-feed during the treatment with Imatinib Actavis. \n- Patients who are concerned about their fertility while taking Imatinib Actavis are advised to \n\nconsult with their doctor. \n \nDriving and using machines \nYou may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not \ndrive or use any tools or machines until you are feeling well again. \n \nImatinib Actavis contains sodium \nThis medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially \n‘sodium-free’. \n \n \n3. How to take Imatinib Actavis \n \nYour doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib \nActavis can help you to fight this condition. \n \nHowever, always take this medicine exactly as your doctor or pharmacist has told you. It is important \nthat you do this as long as your doctor or pharmacist tells you to. Check with your doctor or \npharmacist if you are not sure. \n \nDo not stop taking Imatinib Actavis unless your doctor tells you to. If you are not able to take the \nmedicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor \nstraight away. \n \nHow much Imatinib Actavis to take \n \nUse in adults \nYour doctor will tell you exactly how many capsules of Imatinib Actavis to take. \n \n- If you are being treated for CML: \n\nThe usual starting dose is 600 mg to be taken as 6 capsules once a day. \n \nYour doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your \ndaily dose is 800 mg (8 capsules), you should take 4 capsules in the morning and 4 capsules in the \nevening. \n \n- If you are being treated for Ph-positive ALL: \n\nThe starting dose is 600 mg to be taken as 6 capsules once a day. \n\n85 \n\n\n\n \n- If you are being treated for MDS/MPD: \n\nThe starting dose is 400 mg to be taken as 4 capsules once a day. \n \n- If you are being treated for HES/CEL: \n\nThe starting dose is 100 mg, to be taken as one capsule once a day. Your doctor may decide to \nincrease the dose to 400 mg, to be taken as 4 capsules once a day, depending on how you \nrespond to treatment. \n\n \n- If you are being treated for DFSP: \n\nThe dose is 800 mg per day (8 capsules), to be taken as 4 capsules in the morning and \n4 capsules in the evening. \n\n \nUse in children and adolescents \nThe doctor will tell you how many capsules of Imatinib Actavis to give to your child. The amount of \nImatinib Actavis given will depend on your child’s condition, body weight and height. \nThe total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The \ntreatment can either be given to your child as a once-daily dose or alternatively the daily dose can be \nsplit into two administrations (half in the morning and half in the evening). \n \nWhen and how to take Imatinib Actavis \n- Take Imatinib Actavis with a meal. This will help protect you from stomach problems when \n\ntaking Imatinib Actavis. \n- Swallow the capsules whole with a large glass of water. Do not open or crush the capsules \n\nunless you have difficulty in swallowing (e.g. in children). \n- If you are unable to swallow the capsules, you can open them up and pour the powder into a \n\nglass of still water or apple juice. \n- If you are a woman who is pregnant or might get pregnant and are trying to open the capsules, \n\nyou should handle the contents with caution in order to avoid skin-eye contact or inhalation. \nYou should wash your hands immediately after opening the capsules. \n\n \nHow long to take Imatinib Actavis \nKeep taking Imatinib Actavis every day for as long as your doctor tells you. \n \nIf you take more Imatinib Actavis than you should \nIf you have accidentally taken too many capsules, talk to your doctor straight away. You may require \nmedical attention. Take the medicine pack with you. \n \nIf you forget to take Imatinib Actavis \n- If you forget a dose, take it as soon as you remember. However if it is nearly time for the next \n\ndose, skip the missed dose. \n- Then continue with your normal schedule. \n- Do not take a double dose to make up a forgotten dose. \n \nIf you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. \n \n \n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. They are \nusually mild to moderate. \n \nSome side effects may be serious. Tell your doctor straight away if you get any of the following: \n \nVery common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): \n- Rapid weight gain. Imatinib Actavis may cause your body to retain water (severe fluid \n\nretention). \n\n86 \n\n\n\n- Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can \nreduce the number of white blood cells, so you might get infections more easily. \n\n- Unexpected bleeding or bruising (when you have not hurt yourself). \n \nUncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): \n- Chest pain, irregular heart rhythm (signs of heart problems). \n- Cough, having difficulty breathing or painful breathing (signs of lung problems). \n- Feeling light-headed, dizzy or fainting (signs of low blood pressure). \n- Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of \n\nliver problems). \n- Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or \n\npurple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). \n- Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of \n\ngastrointestinal disorders). \n- Severely decreased urine output, feeling thirsty (signs of kidney problems). \n- Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel \n\nproblems). \n- Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of \n\nconsciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). \n- Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red \n\nblood cells). \n- Eye pain or deterioration in vision, bleeding in the eyes. \n- Pain in your hips or difficulty walking. \n- Numb or cold toes and fingers (signs of Raynaud’s syndrome). \n- Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). \n- Difficulty hearing. \n- Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of \n\npotassium in your blood). \n- Bruising. \n- Stomach pain with feeling sick (nausea). \n- Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of \n\nmuscle problems). \n- Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling \n\ndizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). \n- Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint \n\ndiscomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and \ncalcium levels and low phosphorous levels in the blood). \n\n- Blood clots in small blood vessels (thrombotic microangiopathy). \n \nNot known (frequency cannot be estimated from the available data): \n- Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood \n\ncells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, \nseverely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic \nreaction). \n\n- Chronic renal failure. \n- Recurrence (reactivation) of Hepatitis B infection when you have had hepatitis B in the past (a \n\nliver infection). \n \nIf you get any of the above, tell your doctor straight away. \n \nOther side effects may include: \n \nVery common (may affect more than 1 in 10 people): \n- Headache or feeling tired. \n- Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. \n- Rash. \n\n87 \n\n\n\n- Muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have \nstopped taking imatinib. \n\n- Swelling such as round your ankles or puffy eyes. \n- Weight gain. \nIf any of these affect you severely, tell your doctor. \n \nCommon (may affect up to 1 in 10 people): \n- Anorexia, weight loss or a disturbed sense of taste. \n- Feeling dizzy or weak. \n- Difficulty in sleeping (insomnia). \n- Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or \n\nhaving blurred vision. \n- Nose bleeds. \n- Pain or swelling in your abdomen, flatulence, heartburn or constipation. \n- Itching. \n- Unusual hair loss or thinning. \n- Numbness of the hands or feet. \n- Mouth ulcers. \n- Joint pain with swelling. \n- Dry mouth, dry skin or dry eye. \n- Decreased or increased skin sensitivity. \n- Hot flushes, chills or night sweats. \nIf any of these affect you severely, tell your doctor. \n \nNot known (frequency cannot be estimated from the available data): \n- Reddening and/or swelling on the palms of the hands and soles of the feet which may be \n\naccompanied by tingling sensation and burning pain. \n- Painful and/or blistering skin lesions. \n- Slowing of growth in children and adolescents. \n- \nIf any of these affect you severely, tell your doctor. \n \nReporting of side effects \nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \neffects not listed in this leaflet. You can also report side effects directly via the national reporting \nsystem listed in Appendix V. By reporting side effects, you can help provide more information on the \nsafety of this medicine. \n \n \n5. How to store Imatinib Actavis \n \nKeep this medicine out of the sight and reach of children. \nDo not use this medicine after the expiry date which is stated on the carton and blister after EXP. The \nexpiry date refers to the last day of that month. \nDo not store above 25°C. Store in the original package in order to protect from moisture. \nDo not use any pack that is damaged or shows signs of tampering. \nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \nthrow away medicines you no longer use. These measures will help protect the environment. \n \n \n6. Contents of the pack and other information \n \nWhat Imatinib Actavis contains \n- The active substance is imatinib (as mesilate). Each capsule contains 100 mg imatinib (as \n\nmesilate). \n- The other ingredients are: Capsule content: cellulose microcrystalline, copovidone, \n\ncrospovidone, sodium stearyl fumarate, silica (colloidal hydrophobe and colloidal anhydrous). \n\n88 \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\nCapsule shell: hypromellose, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide \n(E172). Printing ink: shellac, black iron oxide (E172), propylene glycol, ammonia solution, \npotassium hydroxide. \n\n \nWhat Imatinib Actavis looks like and contents of the pack \nHard capsule with light orange cap and light orange body imprinted with 100 mg in black ink. \nThe capsule contains light yellow powder. \n \nPack sizes: \nThe capsules are supplied in aluminium blister packs of 24, 48, 60, 96, 120 or 180 capsules. \n \nNot all pack sizes may be marketed. \n \nMarketing Authorisation Holder \nActavis Group PTC ehf. \nReykjavíkurvegur 76-78, \nHafnarfjörður \nIceland \n \nManufacturer \nS.C. Sindan-Pharma S.R.L. \n11 Ion Mihalache Blvd \nBucharest \nRomania \n \nFor any information about this medicine, please contact the local representative of the Marketing \nAuthorisation Holder. \n \nBelgië/Belgique/Belgien \nActavis Group PTC ehf. \nIJsland/Islande/Island \nTél/Tel: +354 5503300 \n \n\nLietuva \nUAB Sicor Biotech \nTel: +370 52660203 \n \n\nБългария \nАктавис ЕАД \nTeл: +359 24899585 \n \n\nLuxembourg/Luxemburg \nActavis Group PTC ehf. \nIslande/Island \nTél/Tel: +354 5503300 \n \n\nČeská republika \nTeva Pharmaceuticals CR, s.r.o. \nTel: +420 251007111 \n \n\nMagyarország \nTeva Gyógyszergyár Zrt. \nTel: +36 12886400 \n \n\nDanmark \nTeva Denmark A/S \nTlf: +45 44985511 \n \n\nMalta \nActavis Ltd. \nTel: +356 21693533 \n \n\nDeutschland \nActavis Group PTC ehf. \nIsland \nTel: +354 5503300 \n \n\nNederland \nActavis Group PTC ehf. \nIJsland \nTel: +354 5503300 \n \n\nEesti \nUAB Sicor Biotech Eesti filiaal \nTel: +372 6610801 \n \n\nNorge \nTeva Norway AS \nTlf: +47 66775590 \n \n\n89 \n\n\n\nΕλλάδα \nSpecifar ABEE \nΤηλ: +30 2105401500 \n \n\nÖsterreich \nratiopharm Arzneimittel Vertriebs-GmbH \nTel: +43 1970070 \n \n\nEspaña \nActavis Group PTC ehf. \nIslandia \nTel: +354 5503300 \n \n\nPolska \nTeva Pharmaceuticals Polska Sp. z o.o. \nTel: +48 223459300 \n \n\nFrance \nActavis Group PTC ehf. \nIslande \nTél: +354 5503300 \n \n\nPortugal \nActavis Group PTC ehf. \nIslândia \nTel: +354 5503300 \n \n\nHrvatska \nPliva Hrvatska d.o.o. \nTel: +385 13720000 \n \n\nRomânia \nTeva Pharmaceuticals S.R.L. \nTel: +40 212306524 \n \n\nIreland \nTeva Pharmaceuticals Ireland \nTel: +353 (0)19630330 \n \n\nSlovenija \nPliva Ljubljana d.o.o. \nTel: +386 15890390 \n \n\nÍsland \nActavis Group PTC ehf. \nSími: +354 5503300 \n \n\nSlovenská republika \nTEVA Pharmaceuticals Slovakia s.r.o. \nTel: +421 257267911 \n \n\nItalia \nActavis Group PTC ehf. \nIslanda \nTel: +354 5503300 \n \n\nSuomi/Finland \nratiopharm Oy \nPuh/Tel: +358 201805900 \n \n\nΚύπρος \nSpecifar ABEE \nΕλλάδα \nΤηλ: +30 2105401500 \n \n \n\nSverige \nTeva Sweden AB \nTel: +46 42121100 \n \n\nLatvija \nUAB Sicor Biotech filiāle Latvijā \nTel: +371 67323666 \n \n\nUnited Kingdom \nActavis UK Limited \nTel: +44 1271385257 \n \n\n \nThis leaflet was last revised in \n \nOther sources of information \n \nDetailed information on this medicine is available on the European Medicines Agency website: \nhttp://www.ema.europa.eu \n\n90 \n\nhttp://www.ema.europa.eu/\n\n\nPackage leaflet: Information for the user \n \n\nImatinib Actavis 400 mg hard capsules \nimatinib \n\n \n \nRead all of this leaflet carefully before you start taking this medicine because it contains \nimportant information for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor, pharmacist or nurse. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible \n\nside effects not listed in this leaflet. See section 4. \n \nWhat is in this leaflet \n \n1. What Imatinib Actavis is and what it is used for \n2. What you need to know before you take Imatinib Actavis \n3. How to take Imatinib Actavis \n4. Possible side effects \n5. How to store Imatinib Actavis \n6. Contents of the pack and other information \n \n \n1. What Imatinib Actavis is and what it is used for \n \nImatinib Actavis is a medicine containing an active substance called imatinib. This medicine works by \ninhibiting the growth of abnormal cells in the diseases listed below. These include some types of \ncancer. \n \nImatinib Actavis is a treatment for: \n \n- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white \n\ncells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia \nin which certain abnormal white cells (named myeloid cells) start growing out of control. \n\n \nIn adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast \ncrisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease \n(chronic, accelerated phase and blast crisis). \n \n- Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). \n\nLeukaemia is a cancer of white blood cells. These white cells usually help the body to fight \ninfection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal \nwhite cells (named lymphoblasts) start growing out of control. Imatinib Actavis inhibits the \ngrowth of these cells. \n\n \nImatinib Actavis is also a treatment for adults for: \n \n- Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are a group of blood \n\ndiseases in which some blood cells start growing out of control. Imatinib Actavis inhibits the \ngrowth of these cells in a certain subtype of these diseases. \n\n- Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These \nare blood diseases in which some blood cells (named eosinophils) start growing out of control. \nImatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. \n\n91 \n\n\n\n- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin \nin which some cells start growing out of control. Imatinib Actavis inhibits the growth of these \ncells. \n\n \nIn the rest of this leaflet, we will use the abbreviations when talking about these diseases. \n \nIf you have any questions about how Imatinib Actavis works or why this medicine has been prescribed \nfor you, ask your doctor. \n \n \n2. What you need to know before you take Imatinib Actavis \n \nImatinib Actavis will only be prescribed to you by a doctor with experience in medicines to treat blood \ncancers or solid tumours. \n \nFollow all your doctor’s instructions carefully, even if they differ from the general information \ncontained in this leaflet. \n \nDo not take Imatinib Actavis: \n- if you are allergic to imatinib or any of the other ingredients of this medicine (listed in \n\nsection 6). \n \nIf this applies to you, tell your doctor without taking Imatinib Actavis. \n \nIf you think you may be allergic but are not sure, ask your doctor for advice. \n \nWarnings and precautions \nTalk to your doctor before taking Imatinib Actavis: \n- if you have or have ever had a liver, kidney or heart problem. \n- if you are taking the medicine levothyroxine because your thyroid has been removed. \n- if you have ever had or might now have a hepatitis B infection. This is because Imatinib Actavis \n\ncould cause hepatitis B to become active again, which can be fatal in some cases. Patients will \nbe carefully checked by their doctor for signs of this infection before treatment is started. \n\n- if you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, \ncontact your doctor. This may be a sign of damage to blood vessels known as thrombotic \nmicroangiopathy (TMA). \n\nIf any of these apply to you, tell your doctor before taking Imatinib Actavis. \n \nYou may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun-\nexposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are \nalso applicable to children. \n \nDuring treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very \nquickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). \n \nWhile you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is \nworking. You will also have blood tests and be weighed regularly. \n \nChildren and adolescents \nImatinib Actavis is also a treatment for children with CML. There is no experience in children with \nCML below 2 years of age. There is limited experience in children with Ph-positive ALL and very \nlimited experience in children with MDS/MPD, DFSP and HES/CEL. \n \nSome children and adolescents taking Imatinib Actavis may have slower than normal growth. The \ndoctor will monitor the growth at regular visits. \n \nOther medicines and Imatinib Actavis \n\n92 \n\n\n\nTell your doctor or pharmacist if you are taking, have recently taken or might take any other \nmedicines, including medicines obtained without a prescription (such as paracetamol) and including \nherbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib \nActavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either \nleading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis may do \nthe same to some other medicines. \n \nTell your doctor if you are using medicines that prevent the formation of blood clots. \n \nPregnancy, breast-feeding and fertility \n- If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, \n\nask your doctor for advice before taking this medicine. \n- Imatinib Actavis is not recommended during pregnancy unless clearly necessary as it may harm \n\nyour baby. Your doctor will discuss with you the possible risks of taking Imatinib Actavis \nduring pregnancy. \n\n- Women who might become pregnant are advised to use effective contraception during \ntreatment. \n\n- Do not breast-feed during the treatment with Imatinib Actavis. \n- Patients who are concerned about their fertility while taking Imatinib Actavis are advised to \n\nconsult with their doctor. \n \nDriving and using machines \nYou may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not \ndrive or use any tools or machines until you are feeling well again. \n \nImatinib Actavis contains sodium \nThis medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially \n‘sodium-free’. \n \n \n3. How to take Imatinib Actavis \n \nYour doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib \nActavis can help you to fight this condition. \n \nHowever, always take this medicine exactly as your doctor or pharmacist has told you. It is important \nthat you do this as long as your doctor or pharmacist tells you to. Check with your doctor or \npharmacist if you are not sure. \n \nDo not stop taking Imatinib Actavis unless your doctor tells you to. If you are not able to take the \nmedicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor \nstraight away. \n \nHow much Imatinib Actavis to take \n \nUse in adults \nYour doctor will tell you exactly how many capsules of Imatinib Actavis to take. \n \n- If you are being treated for CML: \n\nThe usual starting dose is 600 mg to be taken as one capsule of 400 mg plus 2 capsules of \n100 mg once a day. \n\n \nYour doctor may prescribe a higher or lower dose depending on how you respond to the treatment. If \nyour daily dose is 800 mg (2 capsules), you should take one capsule in the morning and a second \ncapsule in the evening. \n \n- If you are being treated for Ph-positive ALL: \n\n93 \n\n\n\nThe starting dose is 600 mg to be taken as one capsule of 400 mg plus 2 capsules of 100 mg \nonce a day. \n\n \n- If you are being treated for MDS/MPD: \n\nThe starting dose is 400 mg to be taken as one capsule once a day. \n \n- If you are being treated for HES/CEL: \n\nThe starting dose is 100 mg, to be taken as one capsule of 100 mg once a day. Your doctor may \ndecide to increase the dose to 400 mg, to be taken as one capsule of 400 mg once a day, \ndepending on how you respond to treatment. \n\n \n- If you are being treated for DFSP: \n\nThe dose is 800 mg per day (2 capsules), to be taken as one capsule in the morning and a second \ncapsule in the evening. \n\n \nUse in children and adolescents \nThe doctor will tell you how many capsules of Imatinib Actavis to give to your child. The amount of \nImatinib Actavis given will depend on your child’s condition, body weight and height. \n \nThe total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The \ntreatment can either be given to your child as a once-daily dose or alternatively the daily dose can be \nsplit into two administrations (half in the morning and half in the evening). \n \nWhen and how to take Imatinib Actavis \n- Take Imatinib Actavis with a meal. This will help protect you from stomach problems when \n\ntaking Imatinib Actavis. \n- Swallow the capsules whole with a large glass of water. Do not open or crush the capsules \n\nunless you have difficulty in swallowing (e.g. in children). \n- If you are unable to swallow the capsules, you can open them up and pour the powder into a \n\nglass of still water or apple juice. \n- If you are a woman who is pregnant or might get pregnant and are trying to open the capsules, \n\nyou should handle the contents with caution in order to avoid skin-eye contact or inhalation. \nYou should wash your hands immediately after opening the capsules. \n\n \nHow long to take Imatinib Actavis \nKeep taking Imatinib Actavis every day for as long as your doctor tells you. \n \nIf you take more Imatinib Actavis than you should \nIf you have accidentally taken too many capsules, talk to your doctor straight away. You may require \nmedical attention. Take the medicine pack with you. \n \nIf you forget to take Imatinib Actavis \n- If you forget a dose, take it as soon as you remember. However if it is nearly time for the next \n\ndose, skip the missed dose. \n- Then continue with your normal schedule. \n- Do not take a double dose to make up a forgotten dose. \n \nIf you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. \n \n \n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. They are \nusually mild to moderate. \n \nSome side effects may be serious. Tell your doctor straight away if you get any of the following: \n \n\n94 \n\n\n\nVery common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): \n- Rapid weight gain. Imatinib Actavis may cause your body to retain water (severe fluid \n\nretention). \n- Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can \n\nreduce the number of white blood cells, so you might get infections more easily. \n- Unexpected bleeding or bruising (when you have not hurt yourself). \n \nUncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): \n- Chest pain, irregular heart rhythm (signs of heart problems). \n- Cough, having difficulty breathing or painful breathing (signs of lung problems). \n- Feeling light-headed, dizzy or fainting (signs of low blood pressure). \n- Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of \n\nliver problems). \n- Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or \n\npurple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). \n- Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of \n\ngastrointestinal disorders). \n- Severely decreased urine output, feeling thirsty (signs of kidney problems). \n- Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel \n\nproblems). \n- Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of \n\nconsciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). \n- Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red \n\nblood cells). \n- Eye pain or deterioration in vision, bleeding in the eyes. \n- Pain in your hips or difficulty walking. \n- Numb or cold toes and fingers (signs of Raynaud’s syndrome). \n- Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). \n- Difficulty hearing. \n- Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of \n\npotassium in your blood). \n- Bruising. \n- Stomach pain with feeling sick (nausea). \n- Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of \n\nmuscle problems). \n- Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling \n\ndizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). \n- Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint \n\ndiscomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and \ncalcium levels and low phosphorous levels in the blood). \n\n- Blood clots in small blood vessels (thrombotic microangiopathy). \n \nNot known (frequency cannot be estimated from the available data): \n- Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood \n\ncells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, \nseverely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic \nreaction). \n\n- Chronic renal failure. \n- Recurrence (reactivation) of Hepatitis B infection when you have had hepatitis B in the past (a \n\nliver infection). \n \nIf you get any of the above, tell your doctor straight away. \n \nOther side effects may include: \n \nVery common (may affect more than 1 in 10 people): \n- Headache or feeling tired. \n\n95 \n\n\n\n- Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. \n- Rash. \n- Muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have \n\nstopped taking imatinib. \n- Swelling such as round your ankles or puffy eyes. \n- Weight gain. \nIf any of these affect you severely, tell your doctor. \n \nCommon (may affect up to 1 in 10 people): \n- Anorexia, weight loss or a disturbed sense of taste. \n- Feeling dizzy or weak. \n- Difficulty in sleeping (insomnia). \n- Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or \n\nhaving blurred vision. \n- Nose bleeds. \n- Pain or swelling in your abdomen, flatulence, heartburn or constipation. \n- Itching. \n- Unusual hair loss or thinning. \n- Numbness of the hands or feet. \n- Mouth ulcers. \n- Joint pain with swelling. \n- Dry mouth, dry skin or dry eye. \n- Decreased or increased skin sensitivity. \n- Hot flushes, chills or night sweats. \nIf any of these affect you severely, tell your doctor. \n \nNot known (frequency cannot be estimated from the available data): \n- Reddening and/or swelling on the palms of the hands and soles of the feet which may be \n\naccompanied by tingling sensation and burning pain. \n- Painful and/or blistering skin lesions. \n- Slowing of growth in children and adolescents. \n- \nIf any of these affect you severely, tell your doctor. \n \nReporting of side effects \nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \neffects not listed in this leaflet. You can also report side effects directly via the national reporting \nsystem listed in Appendix V. By reporting side effects, you can help provide more information on the \nsafety of this medicine. \n \n \n5. How to store Imatinib Actavis \n \nKeep this medicine out of the sight and reach of children. \nDo not use this medicine after the expiry date which is stated on the carton and blister after EXP. The \nexpiry date refers to the last day of that month. \nDo not store above 25°C. Store in the original package in order to protect from moisture. \nDo not use any pack that is damaged or shows signs of tampering. \nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \nthrow away medicines you no longer use. These measures will help protect the environment. \n \n \n6. Contents of the pack and other information \n \nWhat Imatinib Actavis contains \n- The active substance is imatinib (as mesilate). Each capsule contains 400 mg imatinib (as \n\nmesilate). \n\n96 \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n- The other ingredients are: \nCapsule content: cellulose microcrystalline, copovidone, crospovidone, sodium stearyl \nfumarate, silica (colloidal hydrophobic and colloidal anhydrous). \nCapsule shell: hypromellose, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide \n(E172), black iron oxide (E172). \nPrinting ink: shellac glaze-45%, black iron oxide (E172), propylene glycol, ammonium \nHydroxide 28%. \n\n \nWhat Imatinib Actavis looks like and contents of the pack \nHard capsule with orange opaque cap and body imprinted with 400 mg in black ink. \nThe capsule contains light yellow powder. \n \nPack sizes: \nThe capsules are supplied in aluminium blister packs of 10, 30, 60, or 90 capsules. \n \nNot all pack sizes may be marketed. \n \nMarketing Authorisation Holder \nActavis Group PTC ehf. \nReykjavíkurvegur 76-78, \nHafnarfjörður \nIceland \n \nManufacturer \nS.C. Sindan-Pharma S.R.L. \n11 Ion Mihalache Blvd \nBucharest \nRomania \n \nFor any information about this medicine, please contact the local representative of the Marketing \nAuthorisation Holder. \n \nBelgië/Belgique/Belgien \nActavis Group PTC ehf. \nIJsland/Islande/Island \nTél/Tel: +354 5503300 \n \n\nLietuva \nUAB Sicor Biotech \nTel: +370 52660203 \n \n\nБългария \nАктавис ЕАД \nTeл: +359 24899585 \n \n\nLuxembourg/Luxemburg \nActavis Group PTC ehf. \nIslande/Island \nTél/Tel: +354 5503300 \n \n\nČeská republika \nTeva Pharmaceuticals CR, s.r.o. \nTel: +420 251007111 \n \n\nMagyarország \nTeva Gyógyszergyár Zrt. \nTel: +36 12886400 \n \n\nDanmark \nTeva Denmark A/S \nTlf: +45 44985511 \n \n\nMalta \nActavis Ltd. \nTel: +356 21693533 \n \n\nDeutschland \nActavis Group PTC ehf. \nIsland \nTel: +354 5503300 \n \n\nNederland \nActavis Group PTC ehf. \nIJsland \nTel: +354 5503300 \n \n\n97 \n\n\n\nEesti \nUAB Sicor Biotech Eesti filiaal \nTel: +372 6610801 \n \n\nNorge \nTeva Norway AS \nTlf: +47 66775590 \n \n\nΕλλάδα \nSpecifar ABEE \nΤηλ: +30 2105401500 \n \n\nÖsterreich \nratiopharm Arzneimittel Vertriebs-GmbH \nTel: +43 1970070 \n \n\nEspaña \nActavis Group PTC ehf. \nIslandia \nTel: +354 5503300 \n \n\nPolska \nTeva Pharmaceuticals Polska Sp. z o.o. \nTel: +48 223459300 \n \n\nFrance \nActavis Group PTC ehf. \nIslande \nTél: +354 5503300 \n \n\nPortugal \nActavis Group PTC ehf. \nIslândia \nTel: +354 5503300 \n \n\nHrvatska \nPliva Hrvatska d.o.o. \nTel: +385 13720000 \n \n\nRomânia \nTeva Pharmaceuticals S.R.L. \nTel: +40 212306524 \n \n\nIreland \nTeva Pharmaceuticals Ireland \nTel: +353 (0)19630330 \n \n\nSlovenija \nPliva Ljubljana d.o.o. \nTel: +386 15890390 \n \n\nÍsland \nActavis Group PTC ehf. \nSími: +354 5503300 \n \n\nSlovenská republika \nTEVA Pharmaceuticals Slovakia s.r.o. \nTel: +421 257267911 \n \n\nItalia \nActavis Group PTC ehf. \nIslanda \nTel: +354 5503300 \n \n\nSuomi/Finland \nratiopharm Oy \nPuh/Tel: +358 201805900 \n \n\nΚύπρος \nSpecifar ABEE \nΕλλάδα \nΤηλ: +30 2105401500 \n \n \n\nSverige \nTeva Sweden AB \nTel: +46 42121100 \n \n\nLatvija \nUAB Sicor Biotech filiāle Latvijā \nTel: +371 67323666 \n \n\nUnited Kingdom \nActavis UK Limited \nTel: +44 1271385257 \n \n\n \nThis leaflet was last revised in \n \nOther sources of information \n \nDetailed information on this medicine is available on the European Medicines Agency website: \nhttp://www.ema.europa.eu \n \n\n98 \n\nhttp://www.ema.europa.eu/\n\n\nPackage leaflet: Information for the user \n \n\nImatinib Actavis 100 mg film-coated tablets \nimatinib \n\n \n \nRead all of this leaflet carefully before you start taking this medicine because it contains \nimportant information for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor, pharmacist or nurse. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible \n\nside effects not listed in this leaflet. See section 4. \n \nWhat is in this leaflet \n \n1. What Imatinib Actavis is and what it is used for \n2. What you need to know before you take Imatinib Actavis \n3. How to take Imatinib Actavis \n4. Possible side effects \n5. How to store Imatinib Actavis \n6. Contents of the pack and other information \n \n \n1. What Imatinib Actavis is and what it is used for \n \nImatinib Actavis is a medicine containing an active substance called imatinib. This medicine works by \ninhibiting the growth of abnormal cells in the diseases listed below. These include some types of \ncancer. \n \nImatinib Actavis is a treatment for: \n \n- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white \n\ncells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia \nin which certain abnormal white cells (named myeloid cells) start growing out of control. \n\n \nIn adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast \ncrisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease \n(chronic, accelerated phase and blast crisis). \n \n- Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). \n\nLeukaemia is a cancer of white blood cells. These white cells usually help the body to fight \ninfection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal \nwhite cells (named lymphoblasts) start growing out of control. Imatinib Actavis inhibits the \ngrowth of these cells. \n\n \nImatinib Actavis is also a treatment for adults for: \n \n- Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are a group of blood \n\ndiseases in which some blood cells start growing out of control. Imatinib Actavis inhibits the \ngrowth of these cells in a certain subtype of these diseases. \n\n- Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These \nare blood diseases in which some blood cells (named eosinophils) start growing out of control. \nImatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. \n\n99 \n\n\n\n- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin \nin which some cells start growing out of control. Imatinib Actavis inhibits the growth of these \ncells. \n\n \nIn the rest of this leaflet, we will use the abbreviations when talking about these diseases. \n \nIf you have any questions about how Imatinib Actavis works or why this medicine has been prescribed \nfor you, ask your doctor. \n \n \n2. What you need to know before you take Imatinib Actavis \n \nImatinib Actavis will only be prescribed to you by a doctor with experience in medicines to treat blood \ncancers or solid tumours. \n \nFollow all your doctor’s instructions carefully, even if they differ from the general information \ncontained in this leaflet. \n \nDo not take Imatinib Actavis: \n- if you are allergic to imatinib, soya, peanut or any of the other ingredients of this medicine \n\n(listed in section 6). \n \nIf this applies to you, tell your doctor without taking Imatinib Actavis. \n \nIf you think you may be allergic but are not sure, ask your doctor for advice. \n \nWarnings and precautions \nTalk to your doctor before taking Imatinib Actavis: \n- if you have or have ever had a liver, kidney or heart problem. \n- if you are taking the medicine levothyroxine because your thyroid has been removed. \n- if you have ever had or might now have a hepatitis B infection. This is because Imatinib Actavis \n\ncould cause hepatitis B to become active again, which can be fatal in some cases. Patients will \nbe carefully checked by their doctor for signs of this infection before treatment is started. \n\n- if you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, \ncontact your doctor. This may be a sign of damage to blood vessels known as thrombotic \nmicroangiopathy (TMA). \n\nIf any of these apply to you, tell your doctor before taking Imatinib Actavis. \n \nYou may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun-\nexposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are \nalso applicable to children. \n \nDuring treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very \nquickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). \n \nWhile you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is \nworking. You will also have blood tests and be weighed regularly. \n \nChildren and adolescents \nImatinib Actavis is also a treatment for children with CML. There is no experience in children with \nCML below 2 years of age. There is limited experience in children with Ph-positive ALL and very \nlimited experience in children with MDS/MPD, DFSP and HES/CEL. \n \nSome children and adolescents taking Imatinib Actavis may have slower than normal growth. The \ndoctor will monitor the growth at regular visits. \n \nOther medicines and Imatinib Actavis \n\n100 \n\n\n\nTell your doctor or pharmacist if you are taking, have recently taken or might take any other \nmedicines, including medicines obtained without a prescription (such as paracetamol) and including \nherbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib \nActavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either \nleading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis may do \nthe same to some other medicines. \n \nTell your doctor if you are using medicines that prevent the formation of blood clots. \n \nPregnancy, breast-feeding and fertility \n- If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, \n\nask your doctor for advice before taking this medicine. \n- Imatinib Actavis is not recommended during pregnancy unless clearly necessary as it may harm \n\nyour baby. Your doctor will discuss with you the possible risks of taking Imatinib Actavis \nduring pregnancy. \n\n- Women who might become pregnant are advised to use effective contraception during \ntreatment. \n\n- Do not breast-feed during the treatment with Imatinib Actavis. \n- Patients who are concerned about their fertility while taking Imatinib Actavis are advised to \n\nconsult with their doctor. \n \nDriving and using machines \nYou may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not \ndrive or use any tools or machines until you are feeling well again. \n \nImatinib Actavis contains lecithin (soya) \nIf you are allergic to peanut or soya, do not use this medicinal product. \n \nImatinib Actavis contains sodium \nThis medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say \nessentially ‘sodium-free’. \n \n \n3. How to take Imatinib Actavis \n \nYour doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib \nActavis can help you to fight this condition. \n \nHowever, always take this medicine exactly as your doctor or pharmacist has told you. It is important \nthat you do this as long as your doctor or pharmacist tells you to. Check with your doctor or \npharmacist if you are not sure. \n \nDo not stop taking Imatinib Actavis unless your doctor tells you to. If you are not able to take the \nmedicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor \nstraight away. \n \nHow much Imatinib Actavis to take \n \nUse in adults \nYour doctor will tell you exactly how many tablets of Imatinib Actavis to take. \n \n- If you are being treated for CML: \n\nThe usual starting dose is 600 mg to be taken as 6 tablets once a day. \n \n\nYour doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your \ndaily dose is 800 mg (8 tablets), you should take 4 tablets in the morning and 4 tablets in the evening. \n \n\n101 \n\n\n\n- If you are being treated for Ph-positive ALL: \nThe starting dose is 600 mg to be taken as 6 tablets once a day. \n\n \n- If you are being treated for MDS/MPD: \n\nThe starting dose is 400 mg to be taken as 4 tablets once a day. \n \n- If you are being treated for HES/CEL: \n\nThe starting dose is 100 mg, to be taken as one tablet once a day. Your doctor may decide to \nincrease the dose to 400 mg, to be taken as 4 tablets once a day, depending on how you respond \nto treatment. \n\n \n- If you are being treated for DFSP: \n\nThe dose is 800 mg per day (8 tablets), to be taken as 4 tablets in the morning and 4 tablets in \nthe evening. \n\n \nUse in children and adolescents \nThe doctor will tell you how many tablets of Imatinib Actavis to give to your child. The amount of \nImatinib Actavis given will depend on your child’s condition, body weight and height. \n \nThe total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The \ntreatment can either be given to your child as a once-daily dose or alternatively the daily dose can be \nsplit into two administrations (half in the morning and half in the evening). \n \nWhen and how to take Imatinib Actavis \n- Take Imatinib Actavis with a meal. This will help protect you from stomach problems when \n\ntaking Imatinib Actavis. \n \n- Swallow the tablets whole with a large glass of water. \n The tablet can be divided into equal doses. \n \nIf you are unable to swallow the tablets, you can dissolve them in a glass of still or mineral water or \napple juice: \n- Use about 50 ml for each 100 mg tablet. \n- Stir with a spoon until the tablets have completely dissolved. \n- Once the tablet has dissolved, drink everything in the glass straight away. Traces of the \n\ndissolved tablets may be left behind in the glass. \n \nHow long to take Imatinib Actavis \nKeep taking Imatinib Actavis every day for as long as your doctor tells you. \n \nIf you take more Imatinib Actavis than you should \nIf you have accidentally taken too many tablets, talk to your doctor straight away. You may require \nmedical attention. Take the medicine pack with you. \n \nIf you forget to take Imatinib Actavis \n- If you forget a dose, take it as soon as you remember. However if it is nearly time for the next \n\ndose, skip the missed dose. \n- Then continue with your normal schedule. \n- Do not take a double dose to make up a forgotten dose. \n \nIf you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. \n \n \n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. They are \nusually mild to moderate. \n\n102 \n\n\n\n \nSome side effects may be serious. Tell your doctor straight away if you get any of the following: \n \nVery common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): \n- Rapid weight gain. Imatinib Actavis may cause your body to retain water (severe fluid \n\nretention). \n- Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can \n\nreduce the number of white blood cells, so you might get infections more easily. \n- Unexpected bleeding or bruising (when you have not hurt yourself). \n \nUncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): \n- Chest pain, irregular heart rhythm (signs of heart problems). \n- Cough, having difficulty breathing or painful breathing (signs of lung problems). \n- Feeling light-headed, dizzy or fainting (signs of low blood pressure). \n- Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of \n\nliver problems). \n- Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or \n\npurple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). \n- Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of \n\ngastrointestinal disorders). \n- Severely decreased urine output, feeling thirsty (signs of kidney problems). \n- Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel \n\nproblems). \n- Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of \n\nconsciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). \n- Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red \n\nblood cells). \n- Eye pain or deterioration in vision, bleeding in the eyes. \n- Pain in your hips or difficulty walking. \n- Numb or cold toes and fingers (signs of Raynaud’s syndrome). \n- Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). \n- Difficulty hearing. \n- Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of \n\npotassium in your blood). \n- Bruising. \n- Stomach pain with feeling sick (nausea). \n- Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of \n\nmuscle problems). \n- Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling \n\ndizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). \n- Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint \n\ndiscomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and \ncalcium levels and low phosphorous levels in the blood). \n\n- Blood clots in small blood vessels (thrombotic microangiopathy). \n \nNot known (frequency cannot be estimated from the available data): \n- Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood \n\ncells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, \nseverely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic \nreaction). \n\n- Chronic renal failure. \n- Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a \n\nliver infection). \n \nIf you get any of the above, tell your doctor straight away. \n \nOther side effects may include: \n\n103 \n\n\n\n \nVery common (may affect more than 1 in 10 people): \n- Headache or feeling tired. \n- Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. \n- Rash. \n- Muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have \n\nstopped taking imatinib. \n- Swelling such as round your ankles or puffy eyes. \n- Weight gain. \nIf any of these affect you severely, tell your doctor. \n \nCommon (may affect up to 1 in 10 people): \n- Anorexia, weight loss or a disturbed sense of taste. \n- Feeling dizzy or weak. \n- Difficulty in sleeping (insomnia). \n- Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or \n\nhaving blurred vision. \n- Nose bleeds. \n- Pain or swelling in your abdomen, flatulence, heartburn or constipation. \n- Itching. \n- Unusual hair loss or thinning. \n- Numbness of the hands or feet. \n- Mouth ulcers. \n- Joint pain with swelling. \n- Dry mouth, dry skin or dry eye. \n- Decreased or increased skin sensitivity. \n- Hot flushes, chills or night sweats. \nIf any of these affect you severely, tell your doctor. \n \nNot known (frequency cannot be estimated from the available data): \n- Reddening and/or swelling on the palms of the hands and soles of the feet which may be \n\naccompanied by tingling sensation and burning pain. \n- Painful and/or blistering skin lesions \n- Slowing of growth in children and adolescents. \nIf any of these affect you severely, tell your doctor. \n \nReporting of side effects \nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \neffects not listed in this leaflet. You can also report side effects directly via the national reporting \nsystem listed in Appendix V. By reporting side effects, you can help provide more information on the \nsafety of this medicine. \n \n \n5. How to store Imatinib Actavis \n \nKeep this medicine out of the sight and reach of children. \nDo not use this medicine after the expiry date which is stated on the carton and blister after EXP. The \nexpiry date refers to the last day of that month. \nDo not store above 30°C. Store in the original package in order to protect from moisture. \nDo not use any pack that is damaged or shows signs of tampering. \n \nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \nthrow away medicines you no longer use. These measures will help protect the environment. \n \n \n6. Contents of the pack and other information \n \n\n104 \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\nWhat Imatinib Actavis contains \n- The active substance is imatinib (as mesilate). Each tablet contains 100 mg imatinib (as \n\nmesilate). \n- The other ingredients are cellulose microcrystalline, copovidone, crospovidone, sodium stearyl \n\nfumarate, silica (colloidal hydrophobe and colloidal anhydrous), polyvinyl alcohol partly \nhydrolysed, talc, yellow iron oxide (E172), titanium dioxide (E171), red iron oxide (E172), \nlecithin (soya) (E322), xanthan gum (E415). \n\n \nWhat Imatinib Actavis looks like and contents of the pack \nRound, biconvex dark yellow to brownish film-coated tablet, embossed with company logo on one \nside and “36” with score line on the other side. \n \nPack sizes: \nThe tablets are supplied in aluminium blister packs of 10, 20, 30, 60, 90, 120 or 180 film-coated \ntablets. \n \nNot all pack sizes may be marketed. \n \nMarketing Authorisation Holder \nActavis Group PTC ehf. \nReykjavíkurvegur 76-78, \nHafnarfjörður \nIceland \n \nManufacturer \nS.C. Sindan-Pharma S.R.L. \n11 Ion Mihalache Blvd \nBucharest \nRomania \n \nFor any information about this medicine, please contact the local representative of the Marketing \nAuthorisation Holder. \n \nBelgië/Belgique/Belgien \nActavis Group PTC ehf. \nIJsland/Islande/Island \nTél/Tel: +354 5503300 \n \n\nLietuva \nUAB Sicor Biotech \nTel: +370 52660203 \n \n\nБългария \nАктавис ЕАД \nTeл: +359 24899585 \n \n\nLuxembourg/Luxemburg \nActavis Group PTC ehf. \nIslande/Island \nTél/Tel: +354 5503300 \n \n\nČeská republika \nTeva Pharmaceuticals CR, s.r.o. \nTel: +420 251007111 \n \n\nMagyarország \nTeva Gyógyszergyár Zrt. \nTel: +36 12886400 \n \n\nDanmark \nTeva Denmark A/S \nTlf: +45 44985511 \n \n\nMalta \nActavis Ltd. \nTel: +356 21693533 \n \n\nDeutschland \nActavis Group PTC ehf. \nIsland \nTel: +354 5503300 \n \n\nNederland \nActavis Group PTC ehf. \nIJsland \nTel: +354 5503300 \n \n\n105 \n\n\n\nEesti \nUAB Sicor Biotech Eesti filiaal \nTel: +372 6610801 \n \n\nNorge \nTeva Norway AS \nTlf: +47 66775590 \n \n\nΕλλάδα \nSpecifar ABEE \nΤηλ: +30 2105401500 \n \n\nÖsterreich \nratiopharm Arzneimittel Vertriebs-GmbH \nTel: +43 1970070 \n \n\nEspaña \nActavis Group PTC ehf. \nIslandia \nTel: +354 5503300 \n \n\nPolska \nTeva Pharmaceuticals Polska Sp. z o.o. \nTel: +48 223459300 \n \n\nFrance \nActavis Group PTC ehf. \nIslande \nTél: +354 5503300 \n \n\nPortugal \nActavis Group PTC ehf. \nIslândia \nTel: +354 5503300 \n \n\nHrvatska \nPliva Hrvatska d.o.o. \nTel: +385 13720000 \n \n\nRomânia \nTeva Pharmaceuticals S.R.L. \nTel: +40 212306524 \n \n\nIreland \nTeva Pharmaceuticals Ireland \nTel: +353 (0)19630330 \n \n\nSlovenija \nPliva Ljubljana d.o.o. \nTel: +386 15890390 \n \n\nÍsland \nActavis Group PTC ehf. \nSími: +354 5503300 \n \n\nSlovenská republika \nTEVA Pharmaceuticals Slovakia s.r.o. \nTel: +421 257267911 \n \n\nItalia \nActavis Group PTC ehf. \nIslanda \nTel: +354 5503300 \n \n\nSuomi/Finland \nratiopharm Oy \nPuh/Tel: +358 201805900 \n \n\nΚύπρος \nSpecifar ABEE \nΕλλάδα \nΤηλ: +30 2105401500 \n \n \n\nSverige \nTeva Sweden AB \nTel: +46 42121100 \n \n\nLatvija \nUAB Sicor Biotech filiāle Latvijā \nTel: +371 67323666 \n \n\nUnited Kingdom \nActavis UK Limited \nTel: +44 1271385257 \n \n\n \nThis leaflet was last revised in \n \nOther source of information \n \nDetailed information on this medicine is available on the European Medicines Agency website: \nhttp://www.ema.europa.eu \n \n \n\n106 \n\nhttp://www.ema.europa.eu/\n\n\nPackage leaflet: Information for the user \n \n\nImatinib Actavis 400 mg film-coated tablets \nimatinib \n\n \n \nRead all of this leaflet carefully before you start taking this medicine because it contains \nimportant information for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor, pharmacist or nurse. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible \n\nside effects not listed in this leaflet. See section 4. \n \nWhat is in this leaflet \n \n1. What Imatinib Actavis is and what it is used for \n2. What you need to know before you take Imatinib Actavis \n3. How to take Imatinib Actavis \n4. Possible side effects \n5. How to store Imatinib Actavis \n6. Contents of the pack and other information \n \n \n1. What Imatinib Actavis is and what it is used for \n \nImatinib Actavis is a medicine containing an active substance called imatinib. This medicine works by \ninhibiting the growth of abnormal cells in the diseases listed below. These include some types of \ncancer. \n \nImatinib Actavis is a treatment for: \n \n- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white \n\ncells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia \nin which certain abnormal white cells (named myeloid cells) start growing out of control. \n\n \nIn adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast \ncrisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease \n(chronic, accelerated phase and blast crisis). \n \n- Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). \n\nLeukaemia is a cancer of white blood cells. These white cells usually help the body to fight \ninfection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal \nwhite cells (named lymphoblasts) start growing out of control. Imatinib Actavis inhibits the \ngrowth of these cells. \n\n \nImatinib Actavis is also a treatment for adults for: \n \n- Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are a group of blood \n\ndiseases in which some blood cells start growing out of control. Imatinib Actavis inhibits the \ngrowth of these cells in a certain subtype of these diseases. \n\n- Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These \nare blood diseases in which some blood cells (named eosinophils) start growing out of control. \nImatinib Actavis inhibits the growth of these cells in a certain subtype of these diseases. \n\n107 \n\n\n\n- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin \nin which some cells start growing out of control. Imatinib Actavis inhibits the growth of these \ncells. \n\n \nIn the rest of this leaflet, we will use the abbreviations when talking about these diseases. \n \nIf you have any questions about how Imatinib Actavis works or why this medicine has been prescribed \nfor you, ask your doctor. \n \n \n2. What you need to know before you take Imatinib Actavis \n \nImatinib Actavis will only be prescribed to you by a doctor with experience in medicines to treat blood \ncancers or solid tumours. \n \nFollow all your doctor’s instructions carefully, even if they differ from the general information \ncontained in this leaflet. \n \nDo not take Imatinib Actavis: \n- if you are allergic to imatinib, soya, peanut or any of the other ingredients of this medicine \n\n(listed in section 6). \n \nIf this applies to you, tell your doctor without taking Imatinib Actavis. \n \nIf you think you may be allergic but are not sure, ask your doctor for advice. \n \nWarnings and precautions \nTalk to your doctor before taking Imatinib Actavis: \n- if you have or have ever had a liver, kidney or heart problem. \n- if you are taking the medicine levothyroxine because your thyroid has been removed. \n- if you have ever had or might now have a hepatitis B infection. This is because Imatinib Actavis \n\ncould cause hepatitis B to become active again, which can be fatal in some cases. Patients will \nbe carefully checked by their doctor for signs of this infection before treatment is started. \n\n- if you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, \ncontact your doctor. This may be a sign of damage to blood vessels known as thrombotic \nmicroangiopathy (TMA). \n\nIf any of these apply to you, tell your doctor before taking Imatinib Actavis. \n \nYou may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun-\nexposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are \nalso applicable to children. \n \nDuring treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very \nquickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). \n \nWhile you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is \nworking. You will also have blood tests and be weighed regularly. \n \nChildren and adolescents \nImatinib Actavis is also a treatment for children with CML. There is no experience in children with \nCML below 2 years of age. There is limited experience in children with Ph-positive ALL and very \nlimited experience in children with MDS/MPD, DFSP and HES/CEL. \n \nSome children and adolescents taking Imatinib Actavis may have slower than normal growth. The \ndoctor will monitor the growth at regular visits. \n \nOther medicines and Imatinib Actavis \n\n108 \n\n\n\nTell your doctor or pharmacist if you are taking, have recently taken or might take any other \nmedicines, including medicines obtained without a prescription (such as paracetamol) and including \nherbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib \nActavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either \nleading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis may do \nthe same to some other medicines. \n \nTell your doctor if you are using medicines that prevent the formation of blood clots. \n \nPregnancy, breast-feeding and fertility \n- If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, \n\nask your doctor for advice before taking this medicine. \n- Imatinib Actavis is not recommended during pregnancy unless clearly necessary as it may harm \n\nyour baby. Your doctor will discuss with you the possible risks of taking Imatinib Actavis \nduring pregnancy. \n\n- Women who might become pregnant are advised to use effective contraception during \ntreatment. \n\n- Do not breast-feed during the treatment with Imatinib Actavis. \n- Patients who are concerned about their fertility while taking Imatinib Actavis are advised to \n\nconsult with their doctor. \n \nDriving and using machines \nYou may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not \ndrive or use any tools or machines until you are feeling well again. \n \nImatinib Actavis contains lecithin (soya) \nIf you are allergic to peanut or soya, do not use this medicinal product. \n \nImatinib Actavis contains sodium \nThis medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say \nessentially ‘sodium-free’. \n \n \n3. How to take Imatinib Actavis \n \nYour doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib \nActavis can help you to fight this condition. \n \nHowever, always take this medicine exactly as your doctor or pharmacist has told you. It is important \nthat you do this as long as your doctor or pharmacist tells you to. Check with your doctor or \npharmacist if you are not sure. \n \nDo not stop taking Imatinib Actavis unless your doctor tells you to. If you are not able to take the \nmedicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor \nstraight away. \n \nHow much Imatinib Actavis to take \n \nUse in adults \nYour doctor will tell you exactly how many tablets of Imatinib Actavis to take. \n \n- If you are being treated for CML: \n\nThe recommended starting dose is 600 mg to be taken as one tablet of 400 mg plus 2 tablets of \n100 mg once a day. \n\n \n\n109 \n\n\n\nYour doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your \ndaily dose is 800 mg (2 tablets), you should take one tablet in the morning and a second in the \nevening. \n \n- If you are being treated for Ph-positive ALL: \n\nThe starting dose is 600 mg to be taken as one tablet of 400 mg plus 2 tablets of 100 mg once a \nday. \n\n \n- If you are being treated for MDS/MPD: \n\nThe starting dose is 400 mg to be taken as one tablet once a day. \n \n- If you are being treated for HES/CEL: \n\nThe starting dose is 100 mg, to be taken as one tablet of 100 mg once a day. Your doctor may \ndecide to increase the dose to 400 mg, to be taken as one tablet of 400 mg once a day, \ndepending on how you respond to treatment. \n\n \n- If you are being treated for DFSP: \n\nThe dose is 800 mg per day (2 tablets), to be taken as one tablet in the morning and a second \ntablet in the evening. \n\n \nUse in children and adolescents \nThe doctor will tell you how many tablets of Imatinib Actavis to give to your child. The amount of \nImatinib Actavis given will depend on your child’s condition, body weight and height. \nThe total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The \ntreatment can either be given to your child as a once-daily dose or alternatively the daily dose can be \nsplit into two administrations (half in the morning and half in the evening). \n \nWhen and how to take Imatinib Actavis \n- Take Imatinib Actavis with a meal. This will help protect you from stomach problems when \n\ntaking Imatinib Actavis. \n \n- Swallow the tablets whole with a large glass of water. \n The score line is not intended for breaking the tablet. \n \nIf you are unable to swallow the tablets, you can dissolve them in a glass of still or mineral water or \napple juice: \n Use about 200 ml for each 400 mg tablet. \n- Stir with a spoon until the tablets have completely dissolved. \n- Once the tablet has dissolved, drink everything in the glass straight away. Traces of the \n\ndissolved tablets may be left behind in the glass. \n \nHow long to take Imatinib Actavis \nKeep taking Imatinib Actavis every day for as long as your doctor tells you. \n \nIf you take more Imatinib Actavis than you should \nIf you have accidentally taken too many tablets, talk to your doctor straight away. You may require \nmedical attention. Take the medicine pack with you. \n \nIf you forget to take Imatinib Actavis \n- If you forget a dose, take it as soon as you remember. However if it is nearly time for the next \n\ndose, skip the missed dose. \n- Then continue with your normal schedule. \n- Do not take a double dose to make up a forgotten dose. \n \nIf you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. \n \n \n\n110 \n\n\n\n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. They are \nusually mild to moderate. \n \nSome side effects may be serious. Tell your doctor straight away if you get any of the following: \n \nVery common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): \n- Rapid weight gain. Imatinib Actavis may cause your body to retain water (severe fluid \n\nretention). \n- Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can \n\nreduce the number of white blood cells, so you might get infections more easily. \n- Unexpected bleeding or bruising (when you have not hurt yourself). \n \nUncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): \n- Chest pain, irregular heart rhythm (signs of heart problems). \n- Cough, having difficulty breathing or painful breathing (signs of lung problems). \n- Feeling light-headed, dizzy or fainting (signs of low blood pressure). \n- Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of \n\nliver problems). \n- Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or \n\npurple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). \n- Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of \n\ngastrointestinal disorders). \n- Severely decreased urine output, feeling thirsty (signs of kidney problems). \n- Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel \n\nproblems). \n- Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of \n\nconsciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). \n- Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red \n\nblood cells). \n- Eye pain or deterioration in vision, bleeding in the eyes. \n- Pain in your hips or difficulty walking. \n- Numb or cold toes and fingers (signs of Raynaud’s syndrome). \n- Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). \n- Difficulty hearing. \n- Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of \n\npotassium in your blood). \n- Bruising. \n- Stomach pain with feeling sick (nausea). \n- Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of \n\nmuscle problems). \n- Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling \n\ndizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). \n- Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint \n\ndiscomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and \ncalcium levels and low phosphorous levels in the blood). \n\n- Blood clots in small blood vessels (thrombotic microangiopathy). \n \nNot known (frequency cannot be estimated from the available data): \n- Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood \n\ncells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, \nseverely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic \nreaction). \n\n- Chronic renal failure. \n- Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a \n\nliver infection). \n\n111 \n\n\n\n \nIf you get any of the above, tell your doctor straight away. \n \nOther side effects may include: \n \nVery common (may affect more than 1 in 10 people): \n- Headache or feeling tired. \n- Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. \n- Rash. \n- Muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have \n\nstopped taking imatinib. \n- Swelling such as round your ankles or puffy eyes. \n- Weight gain. \nIf any of these affect you severely, tell your doctor. \n \nCommon (may affect up to 1 in 10 people): \n- Anorexia, weight loss or a disturbed sense of taste. \n- Feeling dizzy or weak. \n- Difficulty in sleeping (insomnia). \n- Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or \n\nhaving blurred vision. \n- Nose bleeds. \n- Pain or swelling in your abdomen, flatulence, heartburn or constipation. \n- Itching. \n- Unusual hair loss or thinning. \n- Numbness of the hands or feet. \n- Mouth ulcers. \n- Joint pain with swelling. \n- Dry mouth, dry skin or dry eye. \n- Decreased or increased skin sensitivity. \n- Hot flushes, chills or night sweats. \nIf any of these affect you severely, tell your doctor. \n \nNot known (frequency cannot be estimated from the available data): \n- Reddening and/or swelling on the palms of the hands and soles of the feet which may be \n\naccompanied by tingling sensation and burning pain. \n- Painful and/or blistering skin lesions \n- Slowing of growth in children and adolescents. \nIf any of these affect you severely, tell your doctor. \n \nReporting of side effects \nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \neffects not listed in this leaflet. You can also report side effects directly via the national reporting \nsystem listed in Appendix V. By reporting side effects, you can help provide more information on the \nsafety of this medicine. \n \n \n5. How to store Imatinib Actavis \n \nKeep this medicine out of the sight and reach of children. \nDo not use this medicine after the expiry date which is stated on the carton and blister after EXP. The \nexpiry date refers to the last day of that month. \nDo not store above 30°C. Store in the original package in order to protect from moisture. \nDo not use any pack that is damaged or shows signs of tampering. \n \nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \nthrow away medicines you no longer use. These measures will help protect the environment. \n\n112 \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n \n \n6. Contents of the pack and other information \n \nWhat Imatinib Actavis contains \n- The active substance is imatinib (as mesilate). Each tablet contains 400 mg imatinib (as \n\nmesilate). \n- The other ingredients are cellulose microcrystalline, copovidone, crospovidone, sodium stearyl \n\nfumarate, silica (colloidal hydrophobe and colloidal anhydrous), polyvinyl alcohol partly \nhydrolysed, talc, yellow iron oxide (E172), titanium dioxide (E171), red iron oxide (E172), \nlecithin (soya) (E322), xanthan gum (E415). \n\n \nWhat Imatinib Actavis looks like and contents of the pack \nOval-shape, biconvex dark yellow to brownish film-coated tablet, embossed with company logo on \none side and “37” with score line on the other side. \n \nPack sizes: \nThe tablets are supplied in aluminium blister packs of 10, 30, 60 or 90 film-coated tablets. \n \nNot all pack sizes may be marketed. \n \nMarketing Authorisation Holder \nActavis Group PTC ehf. \nReykjavíkurvegur 76-78, \nHafnarfjörður \nIceland \n \nManufacturer \nS.C. Sindan-Pharma S.R.L. \n11 Ion Mihalache Blvd \nBucharest \nRomania \n \nFor any information about this medicine, please contact the local representative of the Marketing \nAuthorisation Holder. \n \nBelgië/Belgique/Belgien \nActavis Group PTC ehf. \nIJsland/Islande/Island \nTél/Tel: +354 5503300 \n \n\nLietuva \nUAB Sicor Biotech \nTel: +370 52660203 \n \n\nБългария \nАктавис ЕАД \nTeл: +359 24899585 \n \n\nLuxembourg/Luxemburg \nActavis Group PTC ehf. \nIslande/Island \nTél/Tel: +354 5503300 \n \n\nČeská republika \nTeva Pharmaceuticals CR, s.r.o. \nTel: +420 251007111 \n \n\nMagyarország \nTeva Gyógyszergyár Zrt. \nTel: +36 12886400 \n \n\nDanmark \nTeva Denmark A/S \nTlf: +45 44985511 \n \n\nMalta \nActavis Ltd. \nTel: +356 21693533 \n \n\n113 \n\n\n\nDeutschland \nActavis Group PTC ehf. \nIsland \nTel: +354 5503300 \n \n\nNederland \nActavis Group PTC ehf. \nIJsland \nTel: +354 5503300 \n \n\nEesti \nUAB Sicor Biotech Eesti filiaal \nTel: +372 6610801 \n \n\nNorge \nTeva Norway AS \nTlf: +47 66775590 \n \n\nΕλλάδα \nSpecifar ABEE \nΤηλ: +30 2105401500 \n \n\nÖsterreich \nratiopharm Arzneimittel Vertriebs-GmbH \nTel: +43 1970070 \n \n\nEspaña \nActavis Group PTC ehf. \nIslandia \nTel: +354 5503300 \n \n\nPolska \nTeva Pharmaceuticals Polska Sp. z o.o. \nTel: +48 223459300 \n \n\nFrance \nActavis Group PTC ehf. \nIslande \nTél: +354 5503300 \n \n\nPortugal \nActavis Group PTC ehf. \nIslândia \nTel: +354 5503300 \n \n\nHrvatska \nPliva Hrvatska d.o.o. \nTel: +385 13720000 \n \n\nRomânia \nTeva Pharmaceuticals S.R.L. \nTel: +40 212306524 \n \n\nIreland \nTeva Pharmaceuticals Ireland \nTel: +353 (0)19630330 \n \n\nSlovenija \nPliva Ljubljana d.o.o. \nTel: +386 15890390 \n \n\nÍsland \nActavis Group PTC ehf. \nSími: +354 5503300 \n \n\nSlovenská republika \nTEVA Pharmaceuticals Slovakia s.r.o. \nTel: +421 257267911 \n \n\nItalia \nActavis Group PTC ehf. \nIslanda \nTel: +354 5503300 \n \n\nSuomi/Finland \nratiopharm Oy \nPuh/Tel: +358 201805900 \n \n\nΚύπρος \nSpecifar ABEE \nΕλλάδα \nΤηλ: +30 2105401500 \n \n \n\nSverige \nTeva Sweden AB \nTel: +46 42121100 \n \n\nLatvija \nUAB Sicor Biotech filiāle Latvijā \nTel: +371 67323666 \n \n\nUnited Kingdom \nActavis UK Limited \nTel: +44 1271385257 \n \n\n \nThis leaflet was last revised in \n \nOther source of information \n \nDetailed information on this medicine is available on the European Medicines Agency website: \nhttp://www.ema.europa.eu \n\n114 \n\nhttp://www.ema.europa.eu/\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. PACKAGE LEAFLET"},"Section_1":{"kind":"string","value":"{'Title': '1. what imatinib actavis is and what it is used for', 'Section_Content': 'imatinib actavis is a medicine containing an active substance called imatinib. this medicine works by inhibiting the growth of abnormal cells in the diseases listed below. these include some types of cancer. imatinib actavis is a treatment for: - chronic myeloid leukaemia (cml). leukaemia is a cancer of white blood cells. these white cells usually help the body to fight infection. chronic myeloid leukaemia is a form of leukaemia in which certain abnormal white cells (named myeloid cells) start growing out of control. in adult patients, imatinib actavis is intended for use in the most advanced phase of the disease (blast crisis). in children and adolescents, imatinib actavis can be used in different phases of the disease (chronic, accelerated phase and blast crisis). - philadelphia chromosome positive acute lymphoblastic leukaemia (ph-positive all). leukaemia is a cancer of white blood cells. these white cells usually help the body to fight infection. acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named lymphoblasts) start growing out of control. imatinib actavis inhibits the growth of these cells. imatinib actavis is also a treatment for adults for: - myelodysplastic/myeloproliferative diseases (mds/mpd). these are a group of blood diseases in which some blood cells start growing out of control. imatinib actavis inhibits the growth of these cells in a certain subtype of these diseases. - hypereosinophilic syndrome (hes) and/or chronic eosinophilic leukaemia (cel). these are blood diseases in which some blood cells (named eosinophils) start growing out of control. imatinib actavis inhibits the growth of these cells in a certain subtype of these diseases. - dermatofibrosarcoma protuberans (dfsp). dfsp is a cancer of the tissue beneath the skin in which some cells start growing out of control. imatinib actavis inhibits the growth of these cells. in the rest of this leaflet, we will use the abbreviations when talking about these diseases. if you have any questions about how imatinib actavis works or why this medicine has been prescribed for you, ask your doctor.', 'Entity_Recognition': [{'Text': 'imatinib actavis', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 3, 'BeginOffset': 0, 'EndOffset': 16, 'Score': 0.8410704731941223, 'Text': 'imatinib actavis', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 30}, {'Id': 4, 'BeginOffset': 69, 'EndOffset': 77, 'Score': 0.9929403066635132, 'Text': 'imatinib', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.6062586903572083}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 79, 'EndOffset': 92}, {'Text': 'abnormal cells', 'Type': 'PROBLEM', 'BeginOffset': 127, 'EndOffset': 141}, {'Id': 12, 'BeginOffset': 200, 'EndOffset': 206, 'Score': 0.979072630405426, 'Text': 'cancer', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9652073979377747}]}, {'Id': 5, 'BeginOffset': 208, 'EndOffset': 224, 'Score': 0.6173694133758545, 'Text': 'imatinib actavis', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a treatment', 'Type': 'TREATMENT', 'BeginOffset': 228, 'EndOffset': 239}, {'Text': 'chronic myeloid leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 247, 'EndOffset': 272}, {'Id': 15, 'BeginOffset': 274, 'EndOffset': 277, 'Score': 0.9306449294090271, 'Text': 'cml', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9552603363990784}], 'Attributes': [{'Type': 'ACUITY', 'Score': 0.9321893453598022, 'RelationshipScore': 0.7695040106773376, 'RelationshipType': 'ACUITY', 'Id': 13, 'BeginOffset': 247, 'EndOffset': 254, 'Text': 'chronic', 'Category': 'MEDICAL_CONDITION', 'Traits': []}]}, {'Id': 16, 'BeginOffset': 280, 'EndOffset': 289, 'Score': 0.7859243750572205, 'Text': 'leukaemia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8346947431564331}]}, {'Text': 'a cancer of white blood cells', 'Type': 'PROBLEM', 'BeginOffset': 293, 'EndOffset': 322}, {'Text': 'these white cells', 'Type': 'PROBLEM', 'BeginOffset': 324, 'EndOffset': 341}, {'Text': 'fight infection', 'Type': 'PROBLEM', 'BeginOffset': 367, 'EndOffset': 382}, {'Text': 'chronic myeloid leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 384, 'EndOffset': 409}, {'Id': 21, 'BeginOffset': 423, 'EndOffset': 432, 'Score': 0.7692468762397766, 'Text': 'leukaemia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8415917754173279}]}, {'Text': 'abnormal white cells', 'Type': 'PROBLEM', 'BeginOffset': 450, 'EndOffset': 470}, {'Text': 'myeloid cells', 'Type': 'PROBLEM', 'BeginOffset': 478, 'EndOffset': 491}, {'Id': 6, 'BeginOffset': 542, 'EndOffset': 558, 'Score': 0.5866321325302124, 'Text': 'imatinib actavis', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the disease (blast crisis', 'Type': 'PROBLEM', 'BeginOffset': 609, 'EndOffset': 634}, {'Id': 7, 'BeginOffset': 666, 'EndOffset': 682, 'Score': 0.4144650399684906, 'Text': 'imatinib actavis', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the disease (chronic, accelerated phase and blast crisis', 'Type': 'PROBLEM', 'BeginOffset': 718, 'EndOffset': 774}, {'Text': 'philadelphia chromosome positive acute lymphoblastic leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 779, 'EndOffset': 841}, {'Id': 25, 'BeginOffset': 861, 'EndOffset': 870, 'Score': 0.6213600635528564, 'Text': 'leukaemia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6719663143157959}]}, {'Text': 'a cancer of white blood cells', 'Type': 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'BeginOffset': 1215, 'EndOffset': 1258, 'Score': 0.8416426181793213, 'Text': 'myelodysplastic/myeloproliferative diseases', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9515717029571533}]}, {'Text': 'mds/mpd)', 'Type': 'TREATMENT', 'BeginOffset': 1260, 'EndOffset': 1268}, {'Id': 32, 'BeginOffset': 1291, 'EndOffset': 1305, 'Score': 0.6759859323501587, 'Text': 'blood diseases', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9183557033538818}]}, {'Text': 'some blood cells', 'Type': 'PROBLEM', 'BeginOffset': 1315, 'EndOffset': 1331}, {'Text': 'imatinib actavis', 'Type': 'PROBLEM', 'BeginOffset': 1362, 'EndOffset': 1378}, {'Text': 'these cells', 'Type': 'PROBLEM', 'BeginOffset': 1402, 'EndOffset': 1413}, {'Text': 'these diseases', 'Type': 'PROBLEM', 'BeginOffset': 1438, 'EndOffset': 1452}, {'Id': 33, 'BeginOffset': 1456, 'EndOffset': 1482, 'Score': 0.9578118324279785, 'Text': 'hypereosinophilic syndrome', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9826849102973938}]}, {'Text': 'chronic eosinophilic leukaemia', 'Type': 'PROBLEM', 'BeginOffset': 1496, 'EndOffset': 1526}, {'Id': 36, 'BeginOffset': 1544, 'EndOffset': 1558, 'Score': 0.793354868888855, 'Text': 'blood diseases', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.930968165397644}]}, {'Text': 'some blood cells', 'Type': 'PROBLEM', 'BeginOffset': 1568, 'EndOffset': 1584}, {'Text': 'eosinophils', 'Type': 'TEST', 'BeginOffset': 1592, 'EndOffset': 1603}, {'Text': 'imatinib actavis', 'Type': 'PROBLEM', 'BeginOffset': 1635, 'EndOffset': 1651}, {'Text': 'these cells', 'Type': 'PROBLEM', 'BeginOffset': 1675, 'EndOffset': 1686}, {'Text': 'these diseases', 'Type': 'PROBLEM', 'BeginOffset': 1711, 'EndOffset': 1725}, {'Id': 37, 'BeginOffset': 1729, 'EndOffset': 1760, 'Score': 0.5512913465499878, 'Text': 'dermatofibrosarcoma protuberans', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9398382306098938}]}, {'Id': 38, 'BeginOffset': 1762, 'EndOffset': 1766, 'Score': 0.651717483997345, 'Text': 'dfsp', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7403752207756042}]}, {'Id': 39, 'BeginOffset': 1769, 'EndOffset': 1773, 'Score': 0.48929449915885925, 'Text': 'dfsp', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.4512864947319031}]}, {'Text': 'a cancer of the tissue', 'Type': 'PROBLEM', 'BeginOffset': 1777, 'EndOffset': 1799}, {'Id': 2, 'BeginOffset': 1812, 'EndOffset': 1816, 'Score': 0.9929694533348083, 'Text': 'skin', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'some cells', 'Type': 'PROBLEM', 'BeginOffset': 1826, 'EndOffset': 1836}, {'Id': 10, 'BeginOffset': 1867, 'EndOffset': 1883, 'Score': 0.25586265325546265, 'Text': 'imatinib actavis', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the abbreviations', 'Type': 'TREATMENT', 'BeginOffset': 1961, 'EndOffset': 1978}, {'Text': 'these diseases', 'Type': 'PROBLEM', 'BeginOffset': 1998, 'EndOffset': 2012}, {'Id': 11, 'BeginOffset': 2050, 'EndOffset': 2058, 'Score': 0.3264927864074707, 'Text': 'imatinib', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}]}"},"Section_2":{"kind":"string","value":"{'Title': '2. what you need to know before you take imatinib actavis', 'Section_Content': \"imatinib actavis will only be prescribed to you by a doctor with experience in medicines to treat blood cancers or solid tumours. follow all your doctor's instructions carefully, even if they differ from the general information contained in this leaflet. do not take imatinib actavis: - if you are allergic to imatinib or any of the other ingredients of this medicine (listed in section 6). if this applies to you, tell your doctor without taking imatinib actavis. if you think you may be allergic but are not sure, ask your doctor for advice. warnings and precautions talk to your doctor before taking imatinib actavis: - if you have or have ever had a liver, kidney or heart problem. - if you are taking the medicine levothyroxine because your thyroid has been removed. - if you have ever had or might now have a hepatitis b infection. this is because imatinib actavis could cause hepatitis b to become active again, which can be fatal in some cases. patients will be carefully checked by their doctor for signs of this infection before treatment is started. - if you experience bruising, bleeding, fever, fatigue and confusion when taking imatinib actavis, contact your doctor. this may be a sign of damage to blood vessels known as thrombotic microangiopathy (tma). if any of these apply to you, tell your doctor before taking imatinib actavis. you may become more sensitive to the sun while taking imatinib actavis. it is important to cover sun- exposed areas of skin and use sunscreen with high sun protection factor (spf). these precautions are also applicable to children. during treatment with imatinib actavis, tell your doctor straight away if you put on weight very quickly. imatinib actavis may cause your body to retain water (severe fluid retention). while you are taking imatinib actavis, your doctor will regularly check whether the medicine is working. you will also have blood tests and be weighed regularly. children and adolescents imatinib actavis is also a treatment for children with cml. there is no experience in children with cml below 2 years of age. there is limited experience in children with ph-positive all and very limited experience in children with mds/mpd, dfsp and hes/cel. some children and adolescents taking imatinib actavis may have slower than normal growth. the doctor will monitor the growth at regular visits. other medicines and imatinib actavis 76 tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription (such as paracetamol) and including herbal medicines (such as st. john's wort). some medicines can interfere with the effect of imatinib actavis when taken together. they may increase or decrease the effect of imatinib actavis, either leading to increased side effects or making imatinib actavis less effective. imatinib actavis may do the same to some other medicines. tell your doctor if you are using medicines that prevent the formation of blood clots. pregnancy, breast-feeding and fertility - if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. - imatinib actavis is not recommended during pregnancy unless clearly necessary as it may harm your baby. your doctor will discuss with you the possible risks of taking imatinib actavis during pregnancy. - women who might become pregnant are advised to use effective contraception during treatment. - do not breast-feed during the treatment with imatinib actavis. - patients who are concerned about their fertility while taking imatinib actavis are advised to consult with their doctor. driving and using machines you may feel dizzy or drowsy or get blurred vision while taking this medicine. if this happens, do not drive or use any tools or machines until you are feeling well again. imatinib actavis contains sodium this medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially 'sodium-free'.\", 'Entity_Recognition': [{'Text': 'imatinib actavis', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 7, 'BeginOffset': 0, 'EndOffset': 16, 'Score': 0.8733806610107422, 'Text': 'imatinib actavis', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 79, 'EndOffset': 88}, {'Id': 21, 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prescribe a higher or lower dose depending on how you respond to treatment. if your daily dose is 800 mg (16 capsules), you should take 8 capsules in the morning and 8 capsules in the evening. - if you are being treated for ph-positive all: the starting dose is 600 mg to be taken as 12 capsules once a day. - if you are being treated for mds/mpd: the starting dose is 400 mg, to be taken as 8 capsules once a day. - if you are being treated for hes/cel: the starting dose is 100 mg, to be taken as 2 capsules once a day. your doctor may decide to increase the dose to 400 mg, to be taken as 8 capsules once a day, depending on how you respond to treatment. - if you are being treated for dfsp: the dose is 800 mg per day (16 capsules), to be taken as 8 capsules in the morning and 8 capsules in the evening. use in children and adolescents the doctor will tell you how many capsules of imatinib actavis to give to your child. the amount of imatinib actavis given will depend on your child's condition, body weight and height. the total daily dose in children must not exceed 800 mg with cml and 600 mg with ph+all. the treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening). when and how to take imatinib actavis - take imatinib actavis with a meal. this will help protect you from stomach problems when taking imatinib actavis. - swallow the capsules whole with a large glass of water. do not open or crush the capsules unless you have difficulty in swallowing (e.g. in children). - if you are unable to swallow the capsules, you can open them up and pour the powder into a glass of still water or apple juice. - if you are a woman who is pregnant or might get pregnant and are trying to open the capsules, you should handle the contents with caution in order to avoid skin-eye contact or inhalation. you should wash your hands immediately after opening the capsules. how long to take imatinib actavis keep taking imatinib actavis every day for as long as your doctor tells you. if you take more imatinib actavis than you should if you have accidentally taken too many capsules, talk to your doctor straight away. you may require medical attention. take the medicine pack with you. if you forget to take imatinib actavis - if you forget a dose, take it as soon as you remember. however if it is nearly time for the next dose, skip the missed dose. - then continue with your normal schedule. - do not take a double dose to make up a forgotten dose. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.\", 'Entity_Recognition': [{'Text': 'imatinib actavis', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 27, 'EndOffset': 43, 'Score': 0.8076077699661255, 'Text': 'imatinib actavis', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a serious 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common (may affect up to 1 in 10 people): - rapid weight gain. imatinib actavis may cause your body to retain water (severe fluid retention). - signs of infection such as fever, severe chills, sore throat or mouth ulcers. imatinib actavis can reduce the number of white blood cells, so you might get infections more easily. - unexpected bleeding or bruising (when you have not hurt yourself). uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): - chest pain, irregular heart rhythm (signs of heart problems). - cough, having difficulty breathing or painful breathing (signs of lung problems). - feeling light-headed, dizzy or fainting (signs of low blood pressure). - feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver problems). - rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). - severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders). - severely decreased urine output, feeling thirsty (signs of kidney problems). - feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel problems). - severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). - pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red blood cells). - eye pain or deterioration in vision, bleeding in the eyes. - pain in your hips or difficulty walking. - numb or cold toes and fingers (signs of raynaud's syndrome). - sudden swelling and redness of the skin (signs of a skin infection called cellulitis). - difficulty hearing. - muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood). - bruising. - stomach pain with feeling sick (nausea). - muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems). - pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). - nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorous levels in the blood). - blood clots in small blood vessels (thrombotic microangiopathy). not known (frequency cannot be estimated from the available data): - combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction). - chronic renal failure. - recurrence (reactivation) of hepatitis b infection when you have had hepatitis b in the past (a liver infection). if you get any of the above, tell your doctor straight away. other side effects may include: very common (may affect more than 1 in 10 people): - headache or feeling tired. - feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. - rash. - muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have stopped taking imatinib. - swelling such as round your ankles or puffy eyes. - weight gain. if any of these affect you severely, tell your doctor. common (may affect up to 1 in 10 people): - anorexia, weight loss or a disturbed sense of taste. - feeling dizzy or weak. - difficulty in sleeping (insomnia). - discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision. - nose bleeds. - pain or swelling in your abdomen, flatulence, heartburn or constipation. - itching. - unusual hair loss or thinning. - numbness of the hands or feet. - mouth ulcers. - joint pain with swelling. - dry mouth, dry skin or dry eye. - decreased or increased skin sensitivity. - hot flushes, chills or night sweats. if any of these affect you severely, tell your doctor. not known (frequency cannot be estimated from the available data): - reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain. - painful and/or blistering skin lesions. - slowing of growth in children and adolescents. - if any of these affect you severely, tell your doctor. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects, you can help provide 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0.8562275171279907, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7075908780097961}]}, {'Id': 278, 'BeginOffset': 5208, 'EndOffset': 5219, 'Score': 0.3710387945175171, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6441730260848999}]}, {'Id': 279, 'BeginOffset': 5233, 'EndOffset': 5245, 'Score': 0.9230383038520813, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7609270215034485}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 5302, 'EndOffset': 5315}]}"},"Section_5":{"kind":"string","value":"{'Title': '5. how to store imatinib actavis', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and blister after exp. the expiry date refers to the last day of that month. do not store above 25. store in the original package in order to protect from moisture. do not use any pack that is damaged or shows signs of tampering. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'imatinib actavis', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '25.', 'Type': 'NUMBER', 'BeginOffset': 232, 'EndOffset': 235}, {'Text': 'any pack', 'Type': 'TREATMENT', 'BeginOffset': 312, 'EndOffset': 320}]}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': 'what imatinib actavis contains - the active substance is imatinib (as mesilate). each capsule contains 50 mg imatinib (as mesilate). - the other ingredients are: capsule content: cellulose microcrystalline, copovidone, crospovidone, sodium stearyl fumarate, silica (colloidal hydrophobe and colloidal anhydrous). capsule shell: hypromellose, titanium dioxide (e171), yellow iron oxide (e172). printing ink: shellac, black iron oxide (e172), propylene glycol, ammonia solution, potassium hydroxide. what imatinib actavis looks like and contents of the pack hard capsule with light yellow cap and light yellow body imprinted with 50 mg in black ink. the capsule contains light yellow powder. pack sizes: the capsules are supplied in aluminium blister packs of 30 or 90 capsules. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'imatinib actavis', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 21, 'Score': 0.8558340668678284, 'Text': 'imatinib actavis', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 57, 'EndOffset': 65, 'Score': 0.9895562529563904, 'Text': 'imatinib', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.6507812738418579, 'RelationshipScore': 0.9996672868728638, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 86, 'EndOffset': 93, 'Text': 'capsule', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.933489978313446, 'RelationshipScore': 0.9249637126922607, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 103, 'EndOffset': 108, 'Text': '50 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 2, 'BeginOffset': 70, 'EndOffset': 78, 'Score': 0.39693915843963623, 'Text': 'mesilate', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.6507812738418579, 'RelationshipScore': 0.7610034346580505, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 86, 'EndOffset': 93, 'Text': 'capsule', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '50 mg imatinib', 'Type': 'TREATMENT', 'BeginOffset': 103, 'EndOffset': 117}, {'Id': 6, 'BeginOffset': 122, 'EndOffset': 130, 'Score': 0.3253958821296692, 'Text': 'mesilate', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 179, 'EndOffset': 205, 'Score': 0.9384433627128601, 'Text': 'cellulose microcrystalline', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.933489978313446, 'RelationshipScore': 0.6936525106430054, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 103, 'EndOffset': 108, 'Text': '50 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 8, 'BeginOffset': 207, 'EndOffset': 217, 'Score': 0.9928009510040283, 'Text': 'copovidone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 219, 'EndOffset': 231, 'Score': 0.9858032464981079, 'Text': 'crospovidone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 233, 'EndOffset': 256, 'Score': 0.9976279139518738, 'Text': 'sodium stearyl fumarate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'silica (colloidal hydrophobe and colloidal anhydrous', 'Type': 'TREATMENT', 'BeginOffset': 258, 'EndOffset': 310}, {'Id': 15, 'BeginOffset': 328, 'EndOffset': 340, 'Score': 0.9864158630371094, 'Text': 'hypromellose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.28856033086776733, 'RelationshipScore': 0.9355559349060059, 'RelationshipType': 'FORM', 'Id': 14, 'BeginOffset': 313, 'EndOffset': 320, 'Text': 'capsule', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 16, 'BeginOffset': 342, 'EndOffset': 358, 'Score': 0.9982789754867554, 'Text': 'titanium dioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 17, 'BeginOffset': 367, 'EndOffset': 384, 'Score': 0.3831613063812256, 'Text': 'yellow iron oxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'black iron oxide (e', 'Type': 'TREATMENT', 'BeginOffset': 416, 'EndOffset': 435}, {'Id': 19, 'BeginOffset': 441, 'EndOffset': 457, 'Score': 0.9944520592689514, 'Text': 'propylene glycol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 20, 'BeginOffset': 459, 'EndOffset': 475, 'Score': 0.9333324432373047, 'Text': 'ammonia solution', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 21, 'BeginOffset': 477, 'EndOffset': 496, 'Score': 0.9982799291610718, 'Text': 'potassium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'what imatinib actavis', 'Type': 'PROBLEM', 'BeginOffset': 498, 'EndOffset': 519}, {'Text': 'the pack hard capsule', 'Type': 'TREATMENT', 'BeginOffset': 547, 'EndOffset': 568}, {'Text': 'light yellow cap', 'Type': 'PROBLEM', 'BeginOffset': 574, 'EndOffset': 590}, {'Text': 'light yellow body', 'Type': 'PROBLEM', 'BeginOffset': 595, 'EndOffset': 612}, {'Text': '50', 'Type': 'NUMBER', 'BeginOffset': 628, 'EndOffset': 630}, {'Id': 24, 'BeginOffset': 637, 'EndOffset': 646, 'Score': 0.5032810568809509, 'Text': 'black ink', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.7994753122329712, 'RelationshipScore': 0.9995812773704529, 'RelationshipType': 'DOSAGE', 'Id': 23, 'BeginOffset': 628, 'EndOffset': 633, 'Text': '50 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'the capsule', 'Type': 'TREATMENT', 'BeginOffset': 648, 'EndOffset': 659}, {'Text': 'light yellow powder', 'Type': 'TREATMENT', 'BeginOffset': 669, 'EndOffset': 688}, {'Text': 'the capsules', 'Type': 'TREATMENT', 'BeginOffset': 702, 'EndOffset': 714}, {'Text': 'aluminium blister packs', 'Type': 'TREATMENT', 'BeginOffset': 731, 'EndOffset': 754}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 758, 'EndOffset': 760}, {'Text': '90', 'Type': 'NUMBER', 'BeginOffset': 764, 'EndOffset': 766}]}"}}},{"rowIdx":1052,"cells":{"ID":{"kind":"string","value":"1DA298606E59612D832FFC82E504F91D"},"URL":{"kind":"string","value":"https://www.ema.europa.eu/documents/product-information/anagrelide-mylan-epar-product-information_en.pdf"},"Product_Name":{"kind":"string","value":"Anagrelide Mylan"},"Full_Content":{"kind":"string","value":"1 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX I \n\n \n\nSUMMARY OF PRODUCT CHARACTERISTICS \n\n \n\n\n\n2 \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n \n\nAnagrelide Mylan 0.5 mg hard capsules \n\nAnagrelide Mylan 1 mg hard capsules \n\n \n\n \n\n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \n\nAnagrelide Mylan 0.5 mg hard capsules \n\n \n\nEach hard capsule contains anagrelide hydrochloride monohydrate equivalent to 0.5 mg anagrelide. \n\n \n\nExcipients with known effect \n\n \n\nEach capsule contains approximately 59.5 mg lactose. \n\n \n\n \n\nAnagrelide Mylan 1 mg hard capsules \n\n \n\nEach hard capsule contains anagrelide hydrochloride monohydrate equivalent to 1 mg anagrelide. \n\n \n\nExcipients with known effect \n\n \n\nEach capsule contains approximately 119 mg lactose. \n\n \n\n \n\nFor the full list of excipients, see section 6.1. \n\n \n\n \n\n3. PHARMACEUTICAL FORM \n \n\nHard capsule (capsule). \n\n \n\nAnagrelide Mylan 0.5 mg hard capsules \n\nA capsule size 4 (approximately 14.3 x 5.3 mm) with an opaque white body and cap. The capsule is \n\nfilled with white to off-white powder. \n\n \n\nAnagrelide Mylan 1 mg hard capsules \n\nA capsule size 4 (approximately 14.3 x 5.3 mm) with a grey body and cap. The capsule is filled with \n\nwhite to off-white powder. \n\n \n\n \n\n4. CLINICAL PARTICULARS \n \n\n4.1 Therapeutic indications \n \n\nAnagrelide is indicated for the reduction of elevated platelet counts in at risk essential \n\nthrombocythaemia (ET) patients who are intolerant to their current therapy or whose elevated platelet \n\ncounts are not reduced to an acceptable level by their current therapy. \n\n \n\nAn at-risk patient \n\nAn at-risk essential thrombocythaemia patient is defined by one or more of the following features: \n\n• > 60 years of age or \n\n• a platelet count >1,000 x 109/l or \n\n• a history of thrombo-haemorrhagic events. \n \n\n\n\n3 \n\n \n\n4.2 Posology and method of administration \n \n\nTreatment with anagrelide should be initiated by a clinician with experience in the management of \n\nessential thrombocythaemia. \n\n \n\nPosology \n\n \n\nThe recommended starting dose of anagrelide is 1 mg/day, which should be administered orally in two \n\ndivided doses (0.5 mg/dose). \n\n \n\nThe starting dose should be maintained for at least one week. After one week the dose may be titrated, \n\non an individual basis, to achieve the lowest effective dose required to reduce and/or maintain a \n\nplatelet count below 600 x 109/l and ideally at levels between 150 x 109/l and 400 x 109/l. The dose \n\nincrement must not exceed more than 0.5 mg/day in any one week and the recommended maximum \n\nsingle dose should not exceed 2.5 mg (see section 4.9). During clinical development doses of \n\n10 mg/day have been used. \n\n \n\nThe effects of treatment with anagrelide must be monitored on a regular basis (see section 4.4). If the \n\nstarting dose is > 1 mg/day, platelet counts should be performed every two days during the first week \n\nof treatment and at least weekly thereafter until a stable maintenance dose is reached. Typically, a fall \n\nin the platelet count will be observed within 14 to 21 days of starting treatment and in most patients an \n\nadequate therapeutic response will be observed and maintained at a dose of 1 to 3 mg/day (for further \n\ninformation on the clinical effects refer, to section 5.1). \n\n \n\nElderly \n\nThe observed pharmacokinetic differences between elderly and young patients with ET (see section \n\n5.2) do not warrant using a different starting regimen or different dose titration step to achieve an \n\nindividual patient-optimised anagrelide regimen. \n\n \n\nDuring clinical development, approximately 50% of the patients treated with anagrelide were over \n\n60 years of age and no age specific alterations in dose were required in these patients. However, as \n\nexpected, patients in this age group had twice the incidence of serious adverse events (mainly cardiac). \n\n \n\nRenal impairment \n\nThere are limited pharmacokinetic data for this patient population. The potential risks and benefits of \n\nanagrelide therapy in a patient with impairment of renal function should be assessed before treatment \n\nis commenced (see section 4.3). \n\n \n\nHepatic impairment \n\nThere are limited pharmacokinetic data for this patient population. However, hepatic metabolism \n\nrepresents the major route of anagrelide clearance and liver function may therefore be expected to \n\ninfluence this process. Therefore, it is recommended that patients with moderate or severe hepatic \n\nimpairment are not treated with anagrelide. The potential risks and benefits of anagrelide therapy in a \n\npatient with mild impairment of hepatic function should be assessed before treatment is commenced \n\n(see sections 4.3 and 4.4). \n\n \n\nPaediatric population \n\nThe safety and efficacy of anagrelide in children have not been established. The experience in children \n\nand adolescents is very limited; anagrelide should be used in this patient group with caution. In the \n\nabsence of specific paediatric guidelines, WHO diagnostic criteria for adult diagnosis of ET are \n\nconsidered to be of relevance to the paediatric population. Diagnostic guidelines for essential \n\nthrombocythaemia should be followed carefully and diagnosis reassessed periodically in cases of \n\nuncertainty, with effort made to distinguish from hereditary or secondary thrombocytosis, which may \n\ninclude genetic analysis and bone marrow biopsy. \n\n \n\nTypically, cytoreductive therapy is considered in high-risk paediatric patients. \n\n \n\n\n\n4 \n\n \n\nAnagrelide treatment should only be initiated when the patient shows signs of disease progression or \n\nsuffers from thrombosis. If treatment is initiated, the benefits and risks of treatment with anagrelide \n\nmust be monitored regularly and the need for ongoing treatment evaluated periodically. \n\n \n\nPlatelet targets are assigned on an individual patient basis by the treating physician. \n\n \n\nDiscontinuation of treatment should be considered in paediatric patients who do not have a satisfactory \n\ntreatment response after approximately 3 months. \n\n \n\nCurrently available data are described in sections 4.4, 4.8, 5.1 and 5.2, but no recommendation on a \n\nposology can be made. \n\n \n\nMethod of administration \n\n \n\nFor oral use. The capsules must be swallowed whole. The contents of the capsules should not be \n\ncrushed or diluted in a liquid. \n\n \n\n4.3 Contraindications \n \n\nHypersensitivity to the active substance or to any of the excipients listed in section 6.1. \n\nPatients with moderate or severe hepatic impairment. \n\nPatients with moderate or severe renal impairment (creatinine clearance <50 ml/min). \n\n \n\n4.4 Special warnings and precautions for use \n \n\nHepatic impairment \n\n \n\nThe potential risks and benefits of anagrelide therapy in a patient with mild impairment of hepatic \n\nfunction should be assessed before treatment is commenced. It is not recommended in patients with \n\nelevated transaminases (>5 times the upper limit of normal) (see sections 4.2 and 4.3). \n\n \n\nRenal impairment \n\n \n\nThe potential risks and benefits of anagrelide therapy in a patient with impairment of renal function \n\nshould be assessed before treatment is commenced (see sections 4.2 and 4.3). \n\n \n\nMonitoring \n\n \n\nTherapy requires close clinical supervision of the patient which will include a full blood count \n\n(haemoglobin and white blood cell and platelet counts), assessment of liver function (ALT and AST), \n\nrenal function (serum creatinine and urea) and electrolytes (potassium, magnesium and calcium). \n\n \n\nPlatelets \n\n \n\nThe platelet count will increase within 4 days of stopping treatment with anagrelide and will return to \n\npre-treatment levels within 10 to 14 days, possibly rebounding above baseline values. Therefore, \n\nplatelets should be monitored frequently. \n\n \n\nCardiovascular \n\n \n\nSerious cardiovascular adverse reactions including cases of torsade de pointes, ventricular tachycardia, \n\ncardiomyopathy, cardiomegaly and congestive heart failure have been reported (see section 4.8). \n\n \n\nCaution should be taken when using anagrelide in patients with known risk factors for prolongation of \n\nthe QT interval, such as congenital long QT syndrome, a known history of acquired QTc prolongation, \n\nmedicinal products that can prolong QTc interval and hypokalaemia. \n\n \n\n\n\n5 \n\n \n\nCare should also be taken in populations that may have a higher maximum plasma concentration \n\n(Cmax) of anagrelide or its active metabolite, 3-hydroxy anagrelide, e.g., hepatic impairment or use \n\nwith CYP1A2 inhibitors (see section 4.5). \n\n \n\nClose monitoring for an effect on the QTc interval is advisable. \n\n \n\nA pre-treatment cardiovascular examination, including a baseline ECG and echocardiography is \n\nrecommended for all patients prior to initiating therapy with anagrelide. All patients should be \n\nmonitored regularly during treatment (e.g., ECG or echocardiography) for evidence of cardiovascular \n\neffects that may require further cardiovascular examination and investigation. Hypokalaemia or \n\nhypomagnesaemia must be corrected prior to anagrelide administration and should be monitored \n\nperiodically during therapy. \n\n \n\nAnagrelide is an inhibitor of cyclic AMP phosphodiesterase III and because of its positive inotropic \n\nand chronotropic effects, anagrelide should be used with caution in patients of any age with known or \n\nsuspected heart disease. Moreover, serious cardiovascular adverse events have also occurred in \n\npatients without suspected heart disease and with normal pre-treatment cardiovascular examination. \n\n \n\nAnagrelide should only be used if the potential benefits of therapy outweigh the potential risks. \n\n \n\nPulmonary hypertension \n\n \n\nCases of pulmonary hypertension have been reported in patients treated with anagrelide. Patients \n\nshould be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating \n\nand during anagrelide therapy. \n\n \n\nPaediatric population \n\n \n\nVery limited data are available on the use of anagrelide in the paediatric population and anagrelide \n\nshould be used in this patient group with caution (see sections 4.2, 4.8, 5.1 and 5.2). \n\n \n\nAs with the adult population, a full blood count and assessment of cardiac, hepatic and renal function \n\nshould be undertaken before treatment and regularly during treatment. The disease may progress to \n\nmyelofibrosis or AML. Although the rate of such progression is not known, children have a longer \n\ndisease course and may, therefore, be at increased risk for malignant transformation, relative to adults. \n\nChildren should be monitored regularly for disease progression according to standard clinical \n\npractices, such as physical examination, assessment of relevant disease markers and bone marrow \n\nbiopsy. \n\n \n\nAny abnormalities should be evaluated promptly and appropriate measures taken, which may also \n\ninclude dose reduction, interruption or discontinuation. \n\n \n\nClinically relevant interactions \n\n \n\nAnagrelide is an inhibitor of cyclic AMP phosphodiesterase III (PDE III). Concomitant use of \n\nanagrelide with other PDE III inhibitors such as milrinone, amrinone, enoximone, olprinone and \n\ncilostazol is not recommended. \n\n \n\nUse of concomitant anagrelide and acetylsalicylic acid has been associated with major haemorrhagic \n\nevents (see section 4.5). \n\n \n\nExcipients \n\n \n\nAnagrelide Mylan contains lactose. Patients with rare hereditary problems of galactose intolerance, the \n\ntotal lactase deficiency or glucose-galactose malabsorption should not take this medicine. \n\n \n\nAnagrelide Mylan contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially \n\n\n\n6 \n\n \n\n‘sodium-free’. \n\n \n\n4.5 Interaction with other medicinal products and other forms of interaction \n \n\nLimited pharmacokinetic and/or pharmacodynamic studies investigating possible interactions between \n\nanagrelide and other medicinal products have been conducted. \n\n \n\nEffects of other active substances on anagrelide \n\n \n\n• In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affect \nthe pharmacokinetic properties of anagrelide. \n\n \n\nCYP1A2 inhibitors \n\n• Anagrelide is primarily metabolised by CYP1A2. It is known that CYP1A2 is inhibited by \nseveral medicinal products, including fluvoxamine and enoxacin, and such medicinal products \n\ncould theoretically adversely influence the clearance of anagrelide. \n\n \n\nCYP1A2 inducers \n\n• CYP1A2 inducers (such as omeprazole) could decrease the exposure of anagrelide increasing its \nmain active metabolite. The consequences on the safety and efficacy profile of anagrelide are \n\nnot established. Therefore, clinical and biological monitoring is recommended in patients taking \n\nconcomitant CYP1A2 inducers. If needed, anagrelide dose adjustment could be made. \n\n \n\nEffects of anagrelide on other active substances \n\n \n\n• Anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present \na theoretical potential for interaction with other co-administered medicinal products sharing that \n\nclearance mechanism e.g., theophylline. \n\n• Anagrelide is an inhibitor of PDE III. The effects of medicinal products with similar properties \nsuch as the inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may be \n\nexacerbated by anagrelide. \n\n• In vivo interaction studies in humans have demonstrated that anagrelide does not affect the \npharmacokinetic properties of digoxin or warfarin. \n\n• At the doses recommended for use in the treatment of essential thrombocythaemia, anagrelide \nmay potentiate the effects of other medicinal products that inhibit or modify platelet function \n\ne.g., acetylsalicylic acid. \n\n• A clinical interaction study performed in healthy subjects showed that co-administration of \nrepeat-dose anagrelide 1 mg once daily and acetylsalicylic acid 75 mg once daily may enhance \n\nthe anti-platelet aggregation effects of each active substance compared with administration of \n\nacetylsalicylic acid alone. In some patients with ET concomitantly treated by acetylsalicylic \n\nacid and anagrelide, major haemorrhages occurred. Therefore, the potential risks of the \n\nconcomitant use of anagrelide with acetylsalicylic acid should be assessed, particularly in \n\npatients with a high-risk profile for haemorrhage before treatment is initiated. \n\n• Anagrelide may cause intestinal disturbance in some patients and compromise the absorption of \nhormonal oral contraceptives. \n\n \n\nFood interactions \n\n \n\n• Food delays the absorption of anagrelide, but does not significantly alter systemic exposure. \n\n• The effects of food on bioavailability are not considered clinically relevant to the use of \nanagrelide. \n\n \n\n \n\n \n\nPaediatric population \n\n \n\n\n\n7 \n\n \n\nInteraction studies have only been performed in adults. \n\n \n\n4.6 Fertility, pregnancy and lactation \n \n\nWomen of child-bearing potential \n\n \n\nWomen of child-bearing potential should use adequate birth-control measures during treatment with \n\nanagrelide. \n\n \n\nPregnancy \n\n \n\nThere are no adequate data from the use of anagrelide in pregnant women. Studies in animals have \n\nshown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore, \n\nanagrelide is not recommended during pregnancy. \n\n \n\nIf anagrelide is used during pregnancy, or if the patient becomes pregnant while using the medicinal \n\nproduct, she should be advised of the potential risk to the foetus. \n\n \n\nBreast-feeding \n\n \n\nIt is unknown whether anagrelide/metabolites are excreted in human milk. Available data in animals \n\nhave shown excretion of anagrelide/metabolites in milk. A risk to the newborn/infant cannot be \n\nexcluded. Breast-feeding should be discontinued during treatment with anagrelide. \n\n \n\nFertility \n\n \n\nNo human data on the effect of anagrelide on fertility are available. In male rats, there was no effect \n\non fertility or reproductive performance with anagrelide. In female rats, using doses in excess of the \n\ntherapeutic range, anagrelide disrupted implantation (see section 5.3). \n\n \n\n4.7 Effects on ability to drive and use machines \n \n\nIn clinical development, dizziness was commonly reported. Patients are advised not to drive or operate \n\nmachinery while taking anagrelide if dizziness is experienced. \n\n \n\n4.8 Undesirable effects \n \n\nSummary of the safety profile \n\n \n\nThe safety of anagrelide has been examined in 4 open label clinical studies. In 3 of the studies \n\n942 patients who received anagrelide at a mean dose of approximately 2 mg/day were assessed for \n\nsafety. \n\nIn these studies, 22 patients received anagrelide for up to 4 years. \n\n \n\nIn the later study 3,660 patients who received anagrelide at a mean dose of approximately 2 mg/day \n\nwere assessed for safety. In this study 34 patients received anagrelide for up to 5 years. \n\n \n\nThe most commonly reported adverse reactions associated with anagrelide were headache occurring at \n\napproximately 14%, palpitations occurring at approximately 9%, fluid retention and nausea both \n\noccurring at approximately 6% and diarrhoea occurring at 5%. These adverse drug reactions are \n\nexpected based on the pharmacology of anagrelide (inhibition of PDE III). Gradual dose titration may \n\nhelp diminish these effects (see section 4.2). \n\n \n\n \n\n \n\nTabulated list of adverse reactions \n\n \n\n\n\n8 \n\n \n\nAdverse reactions arising from clinical studies, post-authorisation safety studies and spontaneous \n\nreports are presented in the table below. Within the system organ classes they are listed under the \n\nfollowing headings: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to \n\n<1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000), not known (cannot be estimated from \n\nthe available data). Within each frequency grouping, adverse reactions are presented in order of \n\ndecreasing seriousness. \n\n \n\nMedDRA \n\nSystem Organ \n\nClass \n\nFrequency of adverse reactions \n\nVery \n\ncommon \n\nCommon Uncommon Rare Not known \n\nBlood and \n\nlymphatic \n\nsystem \n\ndisorders \n\n Anaemia Pancytopenia \n\nThrombocytopenia \n\nHaemorrhage \n\nEcchymosis \n\n \n\nMetabolism \n\nand nutrition \n\ndisorders \n\n Fluid retention Oedema \n\nWeight loss \n\nWeight gain \n\nNervous system \n\ndisorders \n\nHeadache Dizziness Depression \n\nAmnesia \n\nConfusion \n\nInsomnia \n\nParaesthesia \n\nHypoaesthesia \n\nNervousness \n\nDry mouth \n\nMigraine \n\nDysarthria \n\nSomnolence \n\nAbnormal \n\ncoordination \n\n \n\nEye disorders Diplopia \n\nVision abnormal \n\n \n\nEar and \n\nlabyrinth \n\ndisorders \n\n Tinnitus \n\nCardiac \n\ndisorders \n\n Tachycardia \n\nPalpitations \n\nVentricular \n\ntachycardia \n\nCongestive heart \n\nfailure \n\nAtrial fibrillation \n\nSupraventricular \n\ntachycardia \n\nArrhythmia \n\nHypertension \n\nSyncope \n\nMyocardial \n\ninfarction \n\nCardiomyopathy \n\nCardiomegaly \n\nPericardial \n\neffusion \n\nAngina pectoris \n\nPostural \n\nhypotension \n\nVasodilation \n\nPrinzmetal \n\nangina \n\nTorsade de \n\npointes \n\nRespiratory, \n\nthoracic and \n\nmediastinal \n\ndisorders \n\n Pulmonary \n\nhypertension \n\nPneumonia \n\nPleural effusion \n\nDyspnoea \n\nEpistaxis \n\nPulmonary \n\ninfiltrates \n\nInterstitial lung \n\ndisease including \n\npneumonitis and \n\nallergic alveolitis \n\nGastrointestina\n\nl disorders \n\n Diarrhoea \n\nVomiting \n\nAbdominal \n\npain \n\nNausea \n\nFlatulence \n\nGastrointestinal \n\nhaemorrhage \n\nPancreatitis \n\nAnorexia \n\nDyspepsia \n\nConstipation \n\nGastrointestinal \n\ndisorder \n\nColitis \n\nGastritis \n\nGingival \n\nbleeding \n\n \n\n\n\n9 \n\n \n\nMedDRA \n\nSystem Organ \n\nClass \n\nFrequency of adverse reactions \n\nVery \n\ncommon \n\nCommon Uncommon Rare Not known \n\nHepatobiliary \n\ndisorders \n\n Hepatic enzymes \n\nincreased \n\n Hepatitis \n\nSkin and \n\nsubcutaneous \n\ntissue \n\ndisorders \n\n Rash Alopecia \n\nPruritus \n\nSkin discolouration \n\nDry skin \n\nMusculoskeleta\n\nl and \n\nconnective \n\ntissue \n\ndisorders \n\n Arthralgia \n\nMyalgia \n\nBack pain \n\n \n\nRenal and \n\nurinary \n\ndisorders \n\n Impotence Renal failure \n\nNocturia \n\nTubulointerstitial \n\nnephritis \n\nGeneral \n\ndisorders and \n\nadministration \n\nsite conditions \n\n Fatigue Chest pain \n\nFever \n\nChills \n\nMalaise \n\nWeakness \n\nFlu-like \n\nsyndrome \n\nPain \n\nAsthenia \n\n \n\nInvestigations Blood creatinine \n\nincreased \n\n \n\n \n\nPaediatric population \n\n \n\n48 patients aged 6 through17 years (19 children and 29 adolescents) have received anagrelide for up to \n\n6.5 years either in clinical studies or as part of a disease registry (see section 5.1). \n\nThe majority of adverse events observed were among those listed in the SmPC. However, safety data \n\nare limited and do not allow a meaningful comparison between adult and paediatric patients to be \n\nmade (see section 4.4). \n\n \n\nReporting of suspected adverse reactions \n\n \n\nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \n\nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \n\nprofessionals are asked to report any suspected adverse reactions via the national reporting system \n\nlisted in Appendix V. \n\n \n\n4.9 Overdose \n \n\nPost-marketing case reports of intentional overdose with anagrelide have been received. Reported \n\nsymptoms include sinus tachycardia and vomiting. Symptoms resolved with conservative \n\nmanagement. \n\n \n\nAnagrelide, at higher than recommended doses, has been shown to produce reductions in blood \n\npressure with occasional instances of hypotension. A single 5-mg dose of anagrelide can lead to a fall \n\nin blood pressure usually accompanied by dizziness. \n\n \n\nA specific antidote for anagrelide has not been identified. In case of overdose, close clinical \n\nsupervision of the patient is required; this includes monitoring of the platelet count for \n\nthrombocytopenia. Dose should be decreased or stopped, as appropriate, until the platelet count returns \n\nto within the normal range. \n\n \n\n \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n10 \n\n \n\n5. PHARMACOLOGICAL PROPERTIES \n\n \n\n5.1 Pharmacodynamic properties \n\n \n\nPharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX35. \n\n \n\nMechanism of action \n\n \n\nThe precise mechanism by which anagrelide reduces blood platelet count is unknown. In cell culture \n\nstudies, anagrelide suppressed expression of transcription factors including GATA-1 and FOG-1 \n\nrequired for megakaryocytopoiesis, ultimately leading to reduced platelet production. \n\n \n\nIn vitro studies of human megakaryocytopoiesis established that anagrelide’s inhibitory actions on \n\nplatelet formation in man are mediated via retardation of maturation of megakaryocytes, and reducing \n\ntheir size and ploidy. Evidence of similar in vivo actions was observed in bone marrow biopsy samples \n\nfrom treated patients. \n\n \n\nAnagrelide is an inhibitor of cyclic AMP phosphodiesterase III. \n\n \n\nClinical efficacy and safety \n\n \n\nThe safety and efficacy of anagrelide as a platelet lowering agent have been evaluated in four open-\n\nlabel, non-controlled clinical trials (study numbers 700-012, 700-014, 700-999 and 13970-301) \n\nincluding more than 4,000 patients with myeloproliferative neoplasms (MPNs). In patients with \n\nessential thrombocythaemia complete response was defined as a decrease in platelet count to \n\n≤600 x 109/l or a ≥50% reduction from baseline and maintenance of the reduction for at least 4 weeks. \n\nIn studies 700-012, 700-014, 700-999 and study 13970-301 the time to complete response ranged from \n\n4 to 12 weeks. Clinical benefit in terms of thrombohaemorrhagic events has not been convincingly \n\ndemonstrated. \n\n \n\nEffects on heart rate and QTc interval \n\n \n\nThe effect of two dose levels of anagrelide (0.5 mg and 2.5 mg single doses) on the heart rate and QTc \n\ninterval was evaluated in a double-blind, randomised, placebo- and active-controlled, cross-over study \n\nin healthy adult men and women. \n\n \n\nA dose-related increase in heart rate was observed during the first 12 hours, with the maximum \n\nincrease occurring around the time of maximal concentrations. The maximum change in mean heart \n\nrate occurred at 2 hours after administration and was +7.8 beats per minute (bpm) for 0.5 mg and \n\n+29.1 bpm for 2.5 mg. \n\n \n\nA transient increase in mean QTc was observed for both doses during periods of increasing heart rate \n\nand the maximum change in mean QTcF (Fridericia correction) was +5.0 msec occurring at 2 hours \n\nfor 0.5 mg and +10.0 msec occurring at 1 hour for 2.5 mg. \n\n \n\nPaediatric population \n\n \n\nIn an open-label clinical study in 8 children and 10 adolescents (including patients who were \n\nanagrelide treatment naïve or who had been receiving anagrelide for up to 5 years pre-study), median \n\nplatelet counts were decreased to controlled levels after 12 weeks of treatment. The average daily dose \n\ntended to be higher in adolescents. \n\n \n\nIn a paediatric registry study, median platelet counts were reduced from diagnosis and maintained for \n\nup to 18 months in 14 paediatric patients with ET (4 children, 10 adolescents) with anagrelide \n\ntreatment. In earlier, open-label studies, median platelet count reductions were observed in 7 children \n\nand 9 adolescents treated for between 3 months and 6.5 years. \n\n \n\n\n\n11 \n\n \n\nThe average total daily dose of anagrelide across all studies in paediatric patients with ET was highly \n\nvariable, but overall the data suggest that adolescents could follow similar starting and maintenance \n\ndoses to adults and that a lower starting dose of 0.5 mg/day would be more appropriate for children \n\nover 6 years (see sections 4.2, 4.4, 4.8, 5.2). In all paediatric patients, careful titration to a patient-\n\nspecific daily dose is needed. \n\n \n\n5.2 Pharmacokinetic properties \n\n \n\nAbsorption \n\n \n\nFollowing oral administration of anagrelide in man, at least 70% is absorbed from the gastrointestinal \n\ntract. In fasted subjects, peak plasma levels occur about 1 hour after administration. Pharmacokinetic \n\ndata from healthy subjects established that food decreases the Cmax of anagrelide by 14%, but increases \n\nthe AUC by 20%. Food also decreased the Cmax of the active metabolite, 3-hydroxy anagrelide, by \n\n29%, although it had no effect on the AUC. \n\n \n\nBiotransformation \n\n \n\nAnagrelide is primarily metabolised by CYP1A2 to form, 3-hydroxy anagrelide, which is further \n\nmetabolised via CYP1A2 to the inactive metabolite, 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline. \n\n \n\nElimination \n\n \n\nThe plasma half-life of anagrelide is short, approximately 1.3 hours and as expected from its half-life, \n\nthere is no evidence for anagrelide accumulation in the plasma. Less than 1% is recovered in the urine \n\nas anagrelide. The mean recovery of 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline in urine is \n\napproximately 18-35% of the administered dose. \n\n \n\nAdditionally these results show no evidence of auto-induction of the anagrelide clearance. \n\n \n\nLinearity \n\n \n\nDose proportionality has been found in the dose range 0.5 mg to 2 mg. \n\n \n\nPaediatric population \n\n \n\nPharmacokinetic data from exposed fasting children and adolescents (age range 7 through 16 years) \n\nwith essential thrombocythaemia indicate that dose normalised exposure, Cmax and AUC, of anagrelide \n\ntended to be higher in children/adolescents compared with adults. There was also a trend to higher \n\ndose-normalised exposure to the active metabolite. \n\n \n\nElderly \n\n \n\nPharmacokinetic data from fasting elderly patients with ET (age range 65 through 75 years) compared \n\nto fasting adult patients (age range 22 through 50 years) indicate that the Cmax and AUC of anagrelide \n\nwere 36% and 61% higher respectively in elderly patients, but that the Cmax and AUC of the active \n\nmetabolite, 3-hydroxy anagrelide, were 42% and 37% lower respectively in the elderly patients. These \n\ndifferences were likely to be caused by lower presystemic metabolism of anagrelide to 3-hydroxy \n\nanagrelide in the elderly patients. \n\n \n\n \n\n5.3 Preclinical safety data \n\n \n\nRepeated dose toxicity \n\n \n\nFollowing repeated oral administration of anagrelide in dogs, subendocardial haemorrhage and focal \n\nmyocardial necrosis was observed at 1 mg/kg/day or higher in males and females with males being \n\n\n\n12 \n\n \n\nmore sensitive. The no observed effect level (NOEL) for male dogs (0.3 mg/kg/day) corresponds to \n\n0.1-, 0.1-, and 1.6-fold the AUC in humans for anagrelide at 2 mg/day, and the metabolites BCH24426 \n\nand RL603, respectively. \n\n \n\nReproductive toxicology \n\n \n\nFertility \n\nIn male rats, anagrelide at oral doses up to 240 mg/kg/day (>1,000 times a 2-mg/day dose, based on \n\nbody surface area) was found to have no effect on fertility and reproductive performance. In female \n\nrats increases in pre- and post-implantation losses and a decrease in the mean number of live embryos \n\nwas observed at 30 mg/kg/day. The NOEL (10 mg/kg/day) to this effect was 143-, 12- and 11-fold \n\nhigher than the AUC in humans administered a dose of anagrelide 2 mg/day, and the metabolites \n\nBCH24426 and RL603, respectively. \n\n \n\nEmbryofoetal development studies \n\nMaternally toxic doses of anagrelide in rats and rabbits were associated with increased embryo \n\nresorption and foetal mortality. \n\n \n\nIn a pre- and post-natal development study in female rats, anagrelide at oral doses of ≥10 mg/kg \n\nproduced a non-adverse increase in gestational duration. At the NOEL dose (3 mg/kg/day), the AUCs \n\nfor anagrelide and the metabolites BCH24426 and RL603 were 14-, 2- and 2-fold higher than the \n\nAUC in humans administered an oral dose of anagrelide 2 mg/day. \n\n \n\nAnagrelide at ≥ 60 mg/kg increased parturition time and mortality in the dam and foetus, respectively. \n\nAt the NOEL dose (30 mg/kg/day), the AUCs for anagrelide and the metabolites BCH24426 and \n\nRL603 were 425-, 31- and 13-fold higher than the AUC in humans administered an oral dose of \n\nanagrelide 2 mg/day, respectively. \n\n \n\nMutagenic and carcinogenic potential \n\n \n\nStudies on the genotoxic potential of anagrelide did not identify any mutagenic or clastogenic effects. \n\n \n\nIn a two-year rat carcinogenicity study, non-neoplastic and neoplastic findings were observed and \n\nrelated or attributed to an exaggerated pharmacological effect. Among them, the incidence of adrenal \n\nphaeochromocytomas was increased relative to control in males at all dose levels (≥3 mg/kg/day) and \n\nin females receiving 10 mg/kg/day and above. The lowest dose in males (3 mg/kg/day) corresponds to \n\n37 times the human AUC exposure after a 1 mg twice daily dose. Uterine adenocarcinomas, of \n\nepigenetic origin, could be related to an enzyme induction of CYP1 family. They were observed in \n\nfemales receiving 30 mg/kg/day, corresponding to 572 times the human AUC exposure after a 1-mg \n\ntwice daily dose. \n\n \n\n \n\n6. PHARMACEUTICAL PARTICULARS \n\n \n\n6.1 List of excipients \n\n \n\nCapsule contents \n\n \n\nLactose \n\nLactose monohydrate \n\nCroscarmellose sodium \n\nPovidone (K29/32) \n\nMicrocrystalline cellulose \n\nMagnesium stearate \n\n \n\nCapsule shell \n\n \n\n\n\n13 \n\n \n\nAnagrelide Mylan 0.5 mg hard capsules \n\nGelatin \n\nTitanium dioxide (E171) \n\n \n\nAnagrelide Mylan 1 mg hard capsules \n\nGelatin \n\nTitanium dioxide (E171) \n\nIron oxide black (E172) \n\n \n\n6.2 Incompatibilities \n\n \n\nNot applicable. \n\n \n\n6.3 Shelf life \n\n \n\n3 years. \n\n \n\n6.4 Special precautions for storage \n\n \n\nAnagrelide 0.5 mg hard capsules \n\nStore in the original package in order to protect from light and moisture. \n\nThis medicinal product does not require any special temperature storage conditions. \n\n \n\nAnagrelide 1 mg hard capsules \n\nStore in the original package in order to protect from moisture. \n\nThis medicinal product does not require any special temperature storage conditions. \n\n \n\n6.5 Nature and contents of container \n\n \n\nHigh-density polyethylene (HDPE) bottle of 30 ml or 75 ml with a tamper evident, child-resistant \n\npolypropylene (PP) closure with a desiccant. \n\n \n\nPack size: 100 hard capsules. \n\n \n\n6.6 Special precautions for disposal \n\n \n\nNo special requirements. \n\n \n\n \n\n7. MARKETING AUTHORISATION HOLDER \n\n \n\nMylan S.A.S \n\n117 Allée des Parcs \n\nSaint-Priest \n\n69800, France \n\n \n\n \n\n8. MARKETING AUTHORISATION NUMBER \n\n \n\nEU/1/17/1256/001 \n\nEU/1/17/1256/002 \n\n \n\n \n\n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n\n \n\nDate of first authorisation: \n\n \n\n\n\n14 \n\n \n\n \n\n10. DATE OF REVISION OF THE TEXT \n\n \n\nDetailed information on this medicinal product is available on the website of the European Medicines \n\nAgency http://www.ema.europa.eu. \n\n \n\nhttp://www.ema.europa.eu/\n\n\n15 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX II \n\n \n\nA. MANUFACTURERS RESPONSIBLE FOR BATCH \n\nRELEASE \n\n \n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY \n\nAND USE \n\n \n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE \n\nMARKETING AUTHORISATION \n\n \n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO \n\nTHE SAFE AND EFFECTIVE USE OF THE MEDICINAL \n\nPRODUCT \n\n \n\n \n\n\n\n16 \n\n \n\nA. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE \n\n \n\nName and address of the manufacturers responsible for batch release \n\nSYNTHON HISPANIA, S.L. \n\nC/ Castello, nº1, Pol. Las Salinas \n\nSant Boi de Llobregat \n\nBarcelona, 08830 \n\nSpain \n\n \n\nSynthon BV \n\nMicroweg 22 \n\n6545 CM Nijmegen \n\nNETHERLANDS \n\n \n\nThe printed package leaflet of the medicinal product must state the name and address of the \n\nmanufacturer responsible for the release of the concerned batch. \n\n \n\n \n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n\n \n\nMedicinal product subject to restricted medical prescription (see Annex I: Summary of Product \n\nCharacteristics, section 4.2). \n\n \n\n \n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n\n \n\n• Periodic safety update reports (PSURs) \n \n\nThe requirements for submission of PSURs for this medicinal product are set out in the list of Union \n\nreference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any \n\nsubsequent updates published on the European medicines web-portal. \n\n \n\n \n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n\n \n\n• Risk Management Plan (RMP) \n \n\nThe marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities \n\nand interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation \n\nand any agreed subsequent updates of the RMP. \n\n \n\nAn updated RMP should be submitted: \n\n \n\n• At the request of the European Medicines Agency; \n\n• Whenever the risk management system is modified, especially as the result of new \ninformation being received that may lead to a significant change to the benefit/risk profile or \n\nas the result of an important (pharmacovigilance or risk minimisation) milestone being \n\nreached. \n\n \n\n \n\n\n\n17 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX III \n\n \n\nLABELLING AND PACKAGE LEAFLET \n\n \n\n\n\n18 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nA. LABELLING \n \n\n\n\n19 \n\n \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE \n\nPACKAGING \n\n \n\nCARTON AND BOTTLE LABEL \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nAnagrelide Mylan 0.5 mg hard capsules \n\nanagrelide \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE \n\n \n\nEach hard capsule contains anagrelide hydrochloride monohydrate equivalent to 0.5 mg anagrelide. \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\nContains lactose. See leaflet for further information. \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\nHard capsule \n\n \n\n100 hard capsules \n\n \n\n \n\n5. METHOD AND ROUTE OF ADMINISTRATION \n\n \n\nOral use. \n\nRead the package leaflet before use. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORE OUT \nOF THE SIGHT AND REACH OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\nStore in the original package in order to protect from light and moisture. \n\n \n\n\n\n20 \n\n \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nMylan S.A.S \n\n117 Allée des Parcs, \n\nSaint-Priest, \n\n69800, France \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/17/1256/001 \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPLY \n\n \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nCarton only: \n\nanagrelide mylan 0.5 mg \n\n \n\n \n\n17. UNIQUE IDENTIFIER – 2D BARCODE \n\n \n\nCarton only: \n\n2D barcode carrying the unique identifier included. \n\n \n\n \n\n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n\n \n\nCarton only: \n\nPC \n\nSN \n\nNN \n\n\n\n21 \n\n \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE \n\nPACKAGING \n\n \n\nCARTON AND BOTTLE LABEL \n\n \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nAnagrelide Mylan 1 mg hard capsules \n\nanagrelide \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE \n\n \n\nEach hard capsule contains anagrelide hydrochloride monohydrate equivalent to 1 mg anagrelide. \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\nContains lactose. See leaflet for further information. \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\nHard capsule \n\n \n\n100 hard capsules \n\n \n\n \n\n5. METHOD AND ROUTE OF ADMINISTRATION \n\n \n\nOral use. \n\n \n\nRead the package leaflet before use. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORE OUT \nOF THE SIGHT AND REACH OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\n\n\n22 \n\n \n\nStore in the original package in order to protect from moisture. \n\n \n\n \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nMylan S.A.S \n\n117 Allée des Parcs, \n\nSaint-Priest, \n\n69800, France \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/17/1256/002 \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPLY \n\n \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nCarton only: \n\nanagrelide mylan 1 mg \n\n \n\n \n\n17. UNIQUE IDENTIFIER – 2D BARCODE \n\n \n\nCarton only: \n\n2D barcode carrying the unique identifier included. \n\n \n\n \n\n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n\n \n\nCarton only: \n\nPC \n\nSN \n\nNN \n\n\n\n23 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nB. PACKAGE LEAFLET \n \n\n\n\n24 \n\n \n\nPackage leaflet: Information for the patient \n\n \n\nAnagrelide Mylan 0.5 mg hard capsules \n\n \n\nanagrelide \n\n \n\nRead all of this leaflet carefully before you start taking this medicine because it contains \n\nimportant information for you. \n\n- Keep this leaflet. You may need to read it again. \n- If you have further questions, ask your doctor or pharmacist. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n\n- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side \neffects not listed in this leaflet. See section 4. \n\n \n\nWhat is in this leaflet \n\n1. What Anagrelide Mylan is and what it is used for \n\n2. What you need to know before you take Anagrelide Mylan \n\n3. How to take Anagrelide Mylan \n\n4. Possible side effects \n\n5. How to store Anagrelide Mylan \n\n6. Contents of the pack and other information \n\n \n\n \n\n1. What Anagrelide Mylan is and what it is used for \n \n\nAnagrelide Mylan contains the active substance, anagrelide. Anagrelide is a medicine which interferes \n\nwith the development of platelets. It reduces the number of platelets produced by the bone marrow, \n\nwhich results in a decrease in the platelet count in the blood towards a more normal level. For this \n\nreason, it is used to treat patients with essential thrombocythaemia. \n\n \n\nEssential thrombocythaemia is a condition which occurs when the bone marrow produces too many of \n\nthe blood cells known as platelets. Large numbers of platelets in the blood can cause serious problems \n\nwith blood circulation and clotting. \n\n \n\n \n\n2. What you need to know before you take Anagrelide Mylan \n \n\nDo not take Anagrelide Mylan \n\n• If you are allergic to anagrelide or any of the other ingredients of this medicine (listed in \nsection 6). An allergic reaction may be recognised as a rash, itching, swollen face or lips, or \n\nshortness of breath; \n\n• If you have moderate or severe liver problems; \n\n• If you have moderate or severe kidney problems. \n \n\nWarnings and precautions \n\nTalk to your doctor before taking Anagrelide Mylan: \n\n• If you have or think you might have a problem with your heart; \n\n• If you were born with or have family history of prolonged QT interval (seen on ECG, electrical \nrecording of the heart), or you are taking other medicines that result in abnormal ECG changes \n\nor if you have low levels of electrolytes e.g., potassium, magnesium or calcium (see section \n\n“Other medicines and Anagrelide Mylan”); \n\n• If you have any problems with your liver or kidneys. \n \n\nIn combination with acetylsalicylic acid (a substance present in many medicines used to relieve pain \n\nand lower fever, as well as to prevent blood clotting, also known as aspirin), there is an increased risk \n\n\n\n25 \n\n \n\nof major haemorrhages (bleeding) (see section “Other medicines and Anagrelide Mylan”). \n\n \n\nChildren and adolescents \n\nThere is limited information on the use of anagrelide in children and adolescents and therefore this \n\nmedicine should be used with caution. \n\n \n\nOther medicines and Anagrelide Mylan \n\nTell your doctor or pharmacist if you are taking or have recently taken or might take any other \n\nmedicines. \n\n \n\nTell your doctor if you are taking any of the following medicines: \n\n• Medicines that can alter your heart rhythm e.g., sotalol, amiodarone; \n\n• Fluvoxamine, used to treat depression; \n\n• Certain types of antibiotic, such as enoxacin, used to treat infections; \n\n• Theophylline, used to treat severe asthma and breathing problems; \n\n• Medicines used to treat heart disorders, for example, milrinone, enoximone, amrinone, \nolprinone and cilostazol; \n\n• Acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower \nfever, as well as to prevent blood clotting, also known as aspirin); \n\n• Other medicines used to treat conditions affecting the platelets in your blood, e.g., clopidogrel; \n\n• Omeprazole, used to reduce the amount of acid produced in the stomach; \n\n• Oral contraceptives: If you experience bad diarrhoea whilst taking this medicine, it may reduce \nhow well the oral contraceptive works and use of an extra method of contraception is \n\nrecommended (e.g., condom). See the instructions in the patient leaflet of the contraceptive pill \n\nyou are taking. \n\n \n\nAnagrelide or these medicines may not work properly if taken together. \n\n \n\nIf you are not sure, speak to your doctor or pharmacist for advice. \n\n \n\nPregnancy and breast-feeding \n\nTell your doctor if you are pregnant or are planning to become pregnant. Anagrelide Mylan should not \n\nbe taken by pregnant women. Women who are at risk of becoming pregnant should make sure that \n\nthey are using effective contraception when taking anagrelide. Speak to your doctor if you need advice \n\nwith contraception. \n\n \n\nTell your doctor if you are breast-feeding or if you are planning to breast-feed your baby. Anagrelide \n\nMylan should not be taken while breast-feeding. You must stop breast-feeding if you are taking \n\nAnagrelide Mylan. \n\n \n\nDriving and using machines \n\nDizziness has been reported by some patients taking anagrelide. Do not drive or use machines if you \n\nfeel dizzy. \n\n \n\nAnagrelide Mylan contains lactose and sodium \n\nThis medicine contains lactose. If you have been told by your doctor that you have an intolerance to \n\nsome sugars, contact your doctor before taking this medicine. \n\n \n\nThis medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially \n\n‘sodium-free’. \n\n \n\n \n\n3. How to take Anagrelide Mylan \n \n\nAlways take Anagrelide Mylan exactly as your doctor has told you. Check with your doctor or \n\npharmacist if you are not sure. \n\n\n\n26 \n\n \n\n \n\nThe amount of anagrelide that people take can be different, and this depends on your condition. Your \n\ndoctor will prescribe the best dose for you. \n\n \n\nThe usual starting dose of this medicine is 1 mg. You take this dose as one capsule of 0.5 mg twice a \n\nday, for at least a week. After this time, your doctor may either increase or decrease the number of \n\ncapsules that you take to find the dose best suited to you and which treats your condition most \n\neffectively. \n\n \n\nYour capsules should be swallowed whole with a glass of water. Do not crush the capsules or dilute \n\nthe contents in a liquid. You can take the capsules with food or after a meal or on an empty stomach. It \n\nis best to take the capsule(s) at the same time every day. \n\n \n\nDo not take more capsules than your doctor has recommended. \n\n \n\nYour doctor will ask you to have blood tests at regular intervals to check that your medicine is \n\nworking effectively and that your liver and kidneys are working well. \n\n \n\nIf you take more Anagrelide Mylan than you should \n\nIf you take more Anagrelide Mylan than you should or if someone else has taken your medicine, tell a \n\ndoctor or pharmacist immediately. Show them the pack of Anagrelide Mylan. \n\n \n\nIf you forget to take Anagrelide Mylan \n\nTake your capsules as soon as you remember. Take your next dose at the usual time. Do not take a \n\ndouble dose to make up for a forgotten dose. \n\n \n\n \n\n4. Possible side effects \n \n\nLike all medicines, this medicine can cause side effects, although not everybody gets them. If you are \n\nworried, speak to your doctor. \n\n \n\nSerious side effects \n\nUncommon: Heart failure (signs include shortness of breath, chest pain, swelling of the legs due to \n\nfluid build-up), severe problem with the rate or rhythm of the heartbeat (ventricular tachycardia, \n\nsupraventricular tachycardia or atrial fibrillation), inflammation of the pancreas which causes severe \n\nabdominal and back pain (pancreatitis), vomiting blood or passing bloody or black stools, severe \n\nreduction in blood cells which can cause weakness, bruising, bleeding or infections (pancytopenia), \n\nincreased pressure in the lung arteries (signs include shortness of breath, swelling in legs or ankles and \n\nlips and skin can turn bluish colour). \n\nRare: Kidney failure (when you pass little or no urine), heart attack. \n\n \n\nIf you notice any of these side effects, contact your doctor immediately. \n\n \n\nVery common side effects: may affect more than 1 in 10 people \n\nHeadache. \n\n \n\nCommon side effects: may affect up to 1 in 10 people \n\nDizziness, tiredness, rapid heartbeat, irregular or strong heartbeat (palpitations), feeling sick (nausea), \n\ndiarrhoea, stomach pain, wind, being sick (vomiting), reduction in red blood cell count (anaemia), \n\nfluid retention or rash. \n\n \n\nUncommon side effects: may affect up to 1 in 100 people \n\nA feeling of weakness or feeling unwell, high blood pressure, irregular heartbeat, fainting, chills or \n\nfever, indigestion, loss of appetite, constipation, bruising, bleeding, swelling (oedema), weight loss, \n\nmuscle aches, painful joints, back pain, decreased or loss of feeling or sensation such as numbness, \n\nespecially in the skin, abnormal feeling or sensation such as tingling and ‘pins and needles’, \n\n\n\n27 \n\n \n\nsleeplessness, depression, confusion, nervousness, dry mouth, loss of memory, breathlessness, \n\nnosebleed, serious lung infection with fever, shortness of breath, cough, phlegm; hair loss, skin itching \n\nor discolouration, impotence, chest pain, reduction in blood platelets, which increases the risk of \n\nbleeding or bruising (thrombocytopenia), accumulation of fluid around the lungs or an increase in liver \n\nenzymes. Your doctor may do a blood test which may show an increase in your liver enzymes. \n\n \n\nRare side effects: may affect up to 1 in 1,000 people \n\nBleeding gums, weight gain, severe chest pain (angina pectoris), heart muscle disease, (signs include \n\nfatigue, chest pain and palpitations), enlarged heart, accumulation of fluid around the heart, painful \n\nspasm of the blood vessels on the heart (while resting, usually at night or early morning) (Prinzmetal \n\nangina), loss of coordination, difficulty in speaking, dry skin, migraine, visual disturbances or double \n\nvision, ringing in the ears, dizziness on standing up (especially when getting up from a sitting or lying \n\nposition), increased need to pass water at night, pain, ‘flu-like’ symptoms, sleepiness, widening of \n\nblood vessels, inflammation of the large bowel (signs include: diarrhoea, usually with blood and \n\nmucus, stomach pain, fever), inflammation of the stomach (signs include: pain, nausea, vomiting), \n\narea of abnormal density in the lung, increased creatinine level in blood tests, which may be a sign of \n\nkidney problems. \n\n \n\nThe following side effects have been reported but it is not known exactly how often they occur: \n\n• Potentially life-threatening, irregular heartbeat (Torsade de pointes); \n\n• Inflammation of the liver, symptoms include nausea, vomiting, itching, yellowing of the skin \nand eyes, discoloration of stool and urine (hepatitis); \n\n• Lung inflammation (signs include fever, coughing, difficulty breathing, wheezing; which causes \nscaring of the lungs) (allergic alveolitis, including interstitial lung disease, pneumonitis); \n\n• Inflammation of the kidneys (tubulointerstitial nephritis). \n \n\nReporting of side effects \n\nIf you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects \n\nnot listed in this leaflet. You can also report side effects directly via the national reporting system \n\nlisted in Appendix V. By reporting side effects, you can help provide more information on the safety \n\nof this medicine. \n\n \n\n \n\n5. How to store Anagrelide Mylan \n \n\nKeep this medicine out of the sight and reach of children. \n\n \n\nDo not use this medicine after the expiry date which is stated on the carton and bottle label after EXP. \n\nThe expiry date refers to the last day of that month. \n\n \n\nStore in the original package in order to protect from light and moisture. \n\nThis medicinal product does not require any special temperature storage conditions. \n\n \n\nIf your doctor stops your medicine, do not keep any leftover capsules unless your doctor tells you to. \n\nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \n\nthrow away medicines you no longer use. These measures will help protect the environment. \n\n \n\n \n\n6. Contents of the pack and other information \n \n\nWhat Anagrelide Mylan contains \n\nThe active substance is anagrelide. Each capsule contains anagrelide hydrochloride monohydrate \n\nequivalent to 0.5 mg anagrelide. \n\nThe other ingredients are lactose, croscarmellose sodium, povidone, microcrystalline cellulose, \n\nmagnesium stearate, gelatin and titanium dioxide(E171). See section 2 ‘Anagrelide Mylan contains \n\nlactose and sodium’. \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n28 \n\n \n\n \n\n \n\nWhat Anagrelide Mylan looks like and contents of the pack \n\nAnagrelide Mylan 0.5 mg hard capsules have a white body and cap. The capsule is filled with a white \n\nto off-white powder. \n\nThe capsule size is approximately 14.3 x 5.3 mm. \n\n \n\nAnagrelide Mylan is available in plastic bottles of 30 ml or 75 ml with a tamper evident, \n\nchild-resistant closure and a desiccant. Each bottle contains 100 hard capsules. \n\n \n\nMarketing Authorisation Holder \n\nMylan S.A.S \n\n117 Allée des Parcs \n\nSaint-Priest \n\n69800, France \n\n \n\nManufacturer \n\nSynthon Hispania SL \n\nC/ Castelló no1 \n\nPOL. Las Salinas \n\nSant Boi de Llobregat \n\n08830 Barcelona \n\nSpain \n\n \n\nSynthon BV \n\nMicroweg 22 \n\n6545 CM Nijmegen \n\nThe Netherlands \n\n \n\nFor any information about this medicine, please contact the local representative of the Marketing \n\nAuthorisation Holder: \n\n \n\nBelgië/Belgique/Belgien \n\nMylan bvba/sprl \n\nTél/Tel: + 32 (0)2 658 61 00 \n\n \n\nLietuva \n\nBGP Products UAB \n\nTel: +370 5 205 1288 \n\n \n\nБългария \n\nМайлан ЕООД \n\nТел: +359 2 44 55 400 \n\n \n\nLuxembourg/Luxemburg \n\nMylan bvba/sprl \n\nTel: + 32 (0)2 658 61 00 \n\n(Belgique/Belgien) \n\n \n\nČeská republika \n\nMylan Healthcare CZ.s.r.o. \n\nTel: +420 222 004 400 \n\n \n\nMagyarország \n\nMylan EPD Kft \n\nTel: + 36 1 465 2100 \n\nDanmark \n\nMylan Denmark ApS \n\nTel: +45 28 11 69 32 \n\nMalta \n\nV.J. Salomone Pharma Ltd \n\nTel: + 356 21 22 01 74 \n\nDeutschland \n\nMylan Healthcare GmbH \n\nTel: +49 800 0700 800 \n\nNederland \n\nMylan BV \n\nTel: +31 (0)20 426 3300 \n\nEesti \n\nBGP Products Switzerland GmbH Eesti \n\nfiliaal \n\nTel: + 372 6363 052 \n\n \n\nNorge \n\nMylan Healthcare Norge AS \n\nTel: + 47 66 75 33 00 \n\n \n\n\n\n29 \n\n \n\nΕλλάδα \n\nGenerics Pharma Hellas ΕΠΕ \n\nΤηλ: +30 210 993 6410 \n\n \n\nÖsterreich \n\nArcana Arzneimittel GmbH \n\nTel: +43 1 416 2418 \n\n \n\nEspaña \n\nMylan Pharmaceuticals, S.L \n\nTel: + 34 900 102 712 \n\n \n\nPolska \n\nMylan Healthcare Sp. z o.o. \n\nTel: + 48 22 546 64 00 \n\n \n\nFrance \n\nMylan S.A.S \n\nTel: +33 4 37 25 75 00 \n\n \n\nPortugal \n\nMylan, Lda. \n\nTel: + 351 21 412 72 56 \n\n \n\nHrvatska \n\nMylan Hrvatska d.o.o. \n\nTel: +385 1 23 50 599 \n\n \n\nRomânia \n\nBGP Products SRL \n\nTel: +40 372 579 000 \n\n \n\nIreland \n\nMylan Ireland Limited \n\nTel: +353 (0) 87 1694982 \n\nSlovenija \n\nMylan Healthcare d.o.o. \n\nTel: + 386 1 23 63 180 \n\n \n\nÍsland \n\nIcepharma hf \n\nTel: +354 540 8000 \n\n \n\nSlovenská republika \n\nMylan s.r.o. \n\nTel: ++421 2 32 199 100 \n\nItalia \n\nMylan Italia S.r.l. \n\nTel: + 39 02 612 46921 \n\n \n\nSuomi/Finland \n\nMylan Finland OY \n\nPuh/Tel: +358 20 720 9555 \n\n \n\nΚύπρος \n\nVarnavas Hadjipanayis Ltd \n\nΤηλ: +357 2220 7700 \n\n \n\nSverige \n\nMylan AB \n\nTel: + 46 855 522 750 \n\n \n\nLatvija \n\nMylan Healthcare SIA \n\nTel: +371 676 055 80 \n\nUnited Kingdom \n\nGenerics [UK] Ltd \n\nTel: +44 1707 853000 \n\n \n\nThis leaflet was last revised in \n\n \n\n \n\nDetailed information on this medicine is available on the European Medicines Agency web site: \n\nhttp://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. \n\n \n\n \n\nhttp://www.ema.europa.eu/\n\n\n30 \n\n \n\nPackage leaflet: Information for the patient \n\n \n\nAnagrelide Mylan 1 mg hard capsules \n\n \n\nanagrelide \n\n \n\nRead all of this leaflet carefully before you start taking this medicine because it contains \n\nimportant information for you. \n\n- Keep this leaflet. You may need to read it again. \n- If you have further questions, ask your doctor or pharmacist. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n\n- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side \neffects not listed in this leaflet. See section 4. \n\n \n\nWhat is in this leaflet \n\n1. What Anagrelide Mylan is and what it is used for \n\n2. What you need to know before you take Anagrelide Mylan \n\n3. How to take Anagrelide Mylan \n\n4. Possible side effects \n\n5. How to store Anagrelide Mylan \n\n6. Contents of the pack and other information \n\n \n\n \n\n1. What Anagrelide Mylan is and what it is used for \n \n\nAnagrelide Mylan contains the active substance, anagrelide. Anagrelide is a medicine which interferes \n\nwith the development of platelets. It reduces the number of platelets produced by the bone marrow, \n\nwhich results in a decrease in the platelet count in the blood towards a more normal level. For this \n\nreason, it is used to treat patients with essential thrombocythaemia. \n\n \n\nEssential thrombocythaemia is a condition which occurs when the bone marrow produces too many of \n\nthe blood cells known as platelets. Large numbers of platelets in the blood can cause serious problems \n\nwith blood circulation and clotting. \n\n \n\n \n\n2. What you need to know before you take Anagrelide Mylan \n \n\nDo not take Anagrelide Mylan \n\n• If you are allergic to anagrelide or any of the other ingredients of this medicine (listed in \nsection 6). An allergic reaction may be recognised as a rash, itching, swollen face or lips, or \n\nshortness of breath; \n\n• If you have moderate or severe liver problems; \n\n• If you have moderate or severe kidney problems. \n \n\nWarnings and precautions \n\nTalk to your doctor before taking Anagrelide Mylan: \n\n• If you have or think you might have a problem with your heart; \n\n• If you were born with or have family history of prolonged QT interval (seen on ECG, electrical \nrecording of the heart), or you are taking other medicines that result in abnormal ECG changes \n\nor if you have low levels of electrolytes e.g., potassium, magnesium or calcium (see section \n\n“Other medicines and Anagrelide Mylan”); \n\n• If you have any problems with your liver or kidneys. \n \n\nIn combination with acetylsalicylic acid (a substance present in many medicines used to relieve pain \n\nand lower fever, as well as to prevent blood clotting, also known as aspirin), there is an increased risk \n\n\n\n31 \n\n \n\nof major haemorrhages (bleeding) (see section “Other medicines and Anagrelide Mylan”). \n\n \n\nChildren and adolescents \n\nThere is limited information on the use of anagrelide in children and adolescents and therefore this \n\nmedicine should be used with caution. \n\n \n\nOther medicines and Anagrelide Mylan \n\nTell your doctor or pharmacist if you are taking or have recently taken or might take any other \n\nmedicines. \n\n \n\nTell your doctor if you are taking any of the following medicines: \n\n• Medicines that can alter your heart rhythm e.g., sotalol, amiodarone; \n\n• Fluvoxamine, used to treat depression; \n\n• Certain types of antibiotic, such as enoxacin, used to treat infections; \n\n• Theophylline, used to treat severe asthma and breathing problems; \n\n• Medicines used to treat heart disorders, for example, milrinone, enoximone, amrinone, \nolprinone and cilostazol; \n\n• Acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower \nfever, as well as to prevent blood clotting, also known as aspirin); \n\n• Other medicines used to treat conditions affecting the platelets in your blood, e.g., clopidogrel; \n\n• Omeprazole, used to reduce the amount of acid produced in the stomach; \n\n• Oral contraceptives: If you experience bad diarrhoea whilst taking this medicine, it may reduce \nhow well the oral contraceptive works and use of an extra method of contraception is \n\nrecommended (e.g., condom). See the instructions in the patient leaflet of the contraceptive pill \n\nyou are taking. \n\n \n\nAnagrelide or these medicines may not work properly if taken together. \n\n \n\nIf you are not sure, speak to your doctor or pharmacist for advice. \n\n \n\nPregnancy and breast-feeding \n\nTell your doctor if you are pregnant or are planning to become pregnant. Anagrelide Mylan should not \n\nbe taken by pregnant women. Women who are at risk of becoming pregnant should make sure that \n\nthey are using effective contraception when taking anagrelide. Speak to your doctor if you need advice \n\nwith contraception. \n\n \n\nTell your doctor if you are breast-feeding or if you are planning to breast-feed your baby. Anagrelide \n\nMylan should not be taken while breast-feeding. You must stop breast-feeding if you are taking \n\nAnagrelide Mylan. \n\n \n\nDriving and using machines \n\nDizziness has been reported by some patients taking anagrelide. Do not drive or use machines if you \n\nfeel dizzy. \n\n \n\nAnagrelide Mylan contains lactose and sodium \n\nThis medicine contains lactose. If you have been told by your doctor that you have an intolerance to \n\nsome sugars, contact your doctor before taking this medicine. \n\n \n\nThis medicine contains less than 1mmol sodium (23 mg) per capsule, that is to say essentially \n\n‘sodium-free’. \n\n \n\n \n\n3. How to take Anagrelide Mylan \n \n\nAlways take Anagrelide Mylan exactly as your doctor has told you. Check with your doctor or \n\npharmacist if you are not sure. \n\n\n\n32 \n\n \n\n \n\nThe amount of anagrelide that people take can be different, and this depends on your condition. Your \n\ndoctor will prescribe the best dose for you. \n\n \n\nThe usual starting dose of anagrelide is 1 mg. You take this dose as one capsule of 0.5 mg twice a day, \n\nfor at least a week. After this time, your doctor may either increase or decrease the number of capsules \n\nthat you take to find the dose best suited to you and which treats your condition most effectively. \n\n \n\nYour capsules should be swallowed whole with a glass of water. Do not crush the capsules or dilute \n\nthe contents in a liquid. You can take the capsules with food or after a meal or on an empty stomach. It \n\nis best to take the capsule(s) at the same time every day. \n\n \n\nDo not take more capsules than your doctor has recommended. \n\n \n\nYour doctor will ask you to have blood tests at regular intervals to check that your medicine is \n\nworking effectively and that your liver and kidneys are working well. \n\n \n\nIf you take more Anagrelide Mylan than you should \n\nIf you take more Anagrelide Mylan than you should or if someone else has taken your medicine, tell a \n\ndoctor or pharmacist immediately. Show them the pack of Anagrelide Mylan. \n\n \n\nIf you forget to take Anagrelide Mylan \n\nTake your capsules as soon as you remember. Take your next dose at the usual time. Do not take a \n\ndouble dose to make up for a forgotten dose. \n\n \n\n \n\n4. Possible side effects \n \n\nLike all medicines, this medicine can cause side effects, although not everybody gets them. If you are \n\nworried, speak to your doctor. \n\n \n\nSerious side effects: \n\nUncommon: Heart failure (signs include shortness of breath, chest pain, swelling of the legs due to \n\nfluid build-up), severe problem with the rate or rhythm of the heartbeat (ventricular tachycardia, \n\nsupraventricular tachycardia or atrial fibrillation), inflammation of the pancreas which causes severe \n\nabdominal and back pain (pancreatitis), vomiting blood or passing bloody or black stools, severe \n\nreduction in blood cells which can cause weakness, bruising, bleeding or infections (pancytopenia), \n\nincreased pressure in the lung arteries (signs include shortness of breath, swelling in legs or ankles and \n\nlips and skin can turn bluish colour). \n\nRare: Kidney failure (when you pass little or no urine), heart attack. \n\n \n\nIf you notice any of these side effects, contact your doctor immediately. \n\n \n\nVery common side effects: may affect more than 1 in 10 people \n\nHeadache. \n\n \n\nCommon side effects: may affect up to 1 in 10 people \n\nDizziness, tiredness, rapid heartbeat, irregular or strong heartbeat (palpitations), feeling sick (nausea), \n\ndiarrhoea, stomach pain, wind, being sick (vomiting), reduction in red blood cell count (anaemia), \n\nfluid retention or rash. \n\n \n\nUncommon side effects: may affect up to 1 in 100 people \n\nA feeling of weakness or feeling unwell, high blood pressure, irregular heartbeat, fainting, chills or \n\nfever, indigestion, loss of appetite, constipation, bruising, bleeding, swelling (oedema), weight loss, \n\nmuscle aches, painful joints, back pain, decreased or loss of feeling or sensation such as numbness, \n\nespecially in the skin, abnormal feeling or sensation such as tingling and ‘pins and needles’, \n\nsleeplessness, depression, confusion, nervousness, dry mouth, loss of memory, breathlessness, \n\n\n\n33 \n\n \n\nnosebleed, serious lung infection with fever, shortness of breath, cough, phlegm; hair loss, skin itching \n\nor discolouration, impotence, chest pain, reduction in blood platelets, which increases the risk of \n\nbleeding or bruising (thrombocytopenia), accumulation of fluid around the lungs or an increase in liver \n\nenzymes. Your doctor may do a blood test which may show an increase in your liver enzymes. \n\n \n\nRare side effects: may affect up to 1 in 1,000 people \n\nBleeding gums, weight gain, severe chest pain (angina pectoris), heart muscle disease, (signs include \n\nfatigue, chest pain and palpitations), enlarged heart, accumulation of fluid around the heart, painful \n\nspasm of the blood vessels on the heart (while resting, usually at night or early morning) (Prinzmetal \n\nangina), loss of coordination, difficulty in speaking, dry skin, migraine, visual disturbances or double \n\nvision, ringing in the ears, dizziness on standing up (especially when getting up from a sitting or lying \n\nposition), increased need to pass water at night, pain, ‘flu-like’ symptoms, sleepiness, widening of \n\nblood vessels, inflammation of the large bowel (signs include: diarrhoea, usually with blood and \n\nmucus, stomach pain, fever), inflammation of the stomach (signs include: pain, nausea, vomiting), \n\narea of abnormal density in the lung, increased creatinine level in blood tests, which may be a sign of \n\nkidney problems. \n\n \n\nThe following side effects have been reported but it is not known exactly how often they occur: \n\n• Potentially life-threatening, irregular heartbeat (Torsade de pointes); \n\n• Inflammation of the liver, symptoms include nausea, vomiting, itching, yellowing of the skin \nand eyes, discoloration of stool and urine (hepatitis); \n\n• Lung inflammation (signs include fever, coughing, difficulty breathing, wheezing; which causes \nscaring of the lungs) (allergic alveolitis, including interstitial lung disease, pneumonitis); \n\n• Inflammation of the kidneys (tubulointerstitial nephritis). \n \n\nReporting of side effects \n\nIf you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects \n\nnot listed in this leaflet. You can also report side effects directly via the national reporting system \n\nlisted in Appendix V. By reporting side effects, you can help provide more information on the safety \n\nof this medicine. \n\n \n\n \n\n5. How to store Anagrelide Mylan \n \n\nKeep this medicine out of the sight and reach of children. \n\n \n\nDo not use this medicine after the expiry date which is stated on the carton and bottle label after EXP. \n\nThe expiry date refers to the last day of that month. \n\n \n\nStore in the original package in order to protect from moisture. \n\nThis medicinal product does not require any special temperature storage conditions. \n\nIf your doctor stops your medicine, do not keep any leftover capsules unless your doctor tells you to. \n\nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \n\nthrow away medicines you no longer use. These measures will help protect the environment. \n\n \n\n \n\n6. Contents of the pack and other information \n \n\nWhat Anagrelide Mylan contains \n\nThe active substance is anagrelide. Each capsule contains anagrelide hydrochloride monohydrate \n\nequivalent to 1 mg anagrelide. \n\n \n\nThe other ingredients are lactose, croscarmellose sodium, povidone, microcrystalline cellulose, \n\nmagnesium stearate, gelatin, titanium dioxide (E171) and iron oxide black (E172). See section 2 \n\n‘Anagrelide Mylan contains lactose and sodium’. \n\n \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n34 \n\n \n\nWhat Anagrelide Mylan looks like and contents of the pack \n\nAnagrelide Mylan 1 mg hard capsules have a grey body and cap. The capsule is filled with a white to \n\noff-white powder. \n\nThe capsule size is approximately 14.3 x 5.3 mm. \n\n \n\nAnagrelide Mylan is available in plastic bottles of 30 ml or 75 ml with a tamper evident, \n\nchild-resistant closure and a desiccant. Each bottle contains 100 hard capsules. \n\n \n\nMarketing Authorisation Holder \n\nMylan S.A.S \n\n117 Allée des Parcs, \n\nSaint-Priest, \n\n69800, France \n\n \n\nManufacturer \n\nSynthon Hispania SL, \n\nC/ Castelló no1, \n\nPOL. Las Salinas, \n\nSant Boi de Llobregat, \n\n08830 Barcelona, \n\nSpain. \n\n \n\nSynthon BV \n\nMicroweg 22 \n\n6545 CM Nijmegen \n\nThe Netherlands \n\n \n\nFor any information about this medicine, please contact the local representative of the Marketing \n\nAuthorisation Holder: \n\n \n\n \n\nBelgië/Belgique/Belgien \n\nMylan bvba/sprl \n\nTél/Tel: + 32 (0)2 658 61 00 \n\n \n\nLietuva \n\nBGP Products UAB \n\nTel: +370 5 205 1288 \n\n \n\nБългария \n\nМайлан ЕООД \n\nТел: +359 2 44 55 400 \n\n \n\nLuxembourg/Luxemburg \n\nMylan bvba/sprl \n\nTel: + 32 (0)2 658 61 00 \n\n(Belgique/Belgien) \n\n \n\nČeská republika \n\nMylan Healthcare CZ.s.r.o. \n\nTel: +420 222 004 400 \n\n \n\nMagyarország \n\nMylan EPD Kft \n\nTel: + 36 1 465 2100 \n\nDanmark \n\nMylan Denmark ApS \n\nTel: +45 28 11 69 32 \n\nMalta \n\nV.J. Salomone Pharma Ltd \n\nTel: + 356 21 22 01 74 \n\n \n\nDeutschland \n\nMylan Healthcare GmbH \n\nTel: +49 800 0700 800 \n\nNederland \n\nMylan BV \n\nTel: + 31 (0)20 426 3300 \n\nEesti \n\nBGP Products Switzerland GmbH Eesti \n\nfiliaal \n\nTel: + 372 6363 052 \n\n \n\nNorge \n\nMylan Healthcare Norge AS \n\nTel: + 47 66 75 33 00 \n\n \n\n \n\n\n\n35 \n\n \n\nΕλλάδα \n\nGenerics Pharma Hellas ΕΠΕ \n\nΤηλ: +30 210 993 6410 \n\n \n\nÖsterreich \n\nArcana Arzneimittel GmbH \n\nTel: +43 1 416 2418 \n\n \n\nEspaña \n\nMylan Pharmaceuticals, S.L \n\nTel: + 34 900 102 712 \n\n \n\nPolska \n\nMylan Healthcare Sp. z o.o. \n\nTel: + 48 22 546 64 00 \n\n \n\nFrance \n\nMylan S.A.S \n\nTel: +33 4 37 25 75 00 \n\n \n\nPortugal \n\nMylan, Lda. \n\nTel: + 351 21 412 72 56 \n\n \n\nHrvatska \n\nMylan Hrvatska d.o.o. \n\nTel: +385 1 23 50 599 \n\nRomânia \n\nBGP Products SRL \n\nTel: +40 372 579 000 \n\n \n\nIreland \n\nMylan Ireland Limited \n\nTel: +353 (0) 87 1694982 \n\nSlovenija \n\nMylan Healthcare d.o.o. \n\nTel: + 386 1 23 63 180 \n\n \n\nÍsland \n\nIcepharma hf \n\nTel: +354 540 8000 \n\n \n\nSlovenská republika \n\nMylan s.r.o. \n\nTel: ++421 2 32 199 100 \n\nItalia \n\nMylan Italia S.r.l. \n\nTel: + 39 02 612 46921 \n\n \n\nSuomi/Finland \n\nMylan Finland OY \n\nPuh/Tel: +358 20 720 9555 \n\n \n\nΚύπρος \n\nVarnavas Hadjipanayis Ltd \n\nΤηλ: +357 2220 7700 \n\n \n\nSverige \n\nMylan AB \n\nTel: + 46 855 522 750 \n\n \n\nLatvija \n\nMylan Healthcare SIA \n\nTel: +371 676 055 80 \n\n \n\nUnited Kingdom \n\nGenerics [UK] Ltd \n\nTel: +44 1707 853000 \n\n \n\nThis leaflet was last revised in \n\n \n\nDetailed information on this medicine is available on the European Medicines Agency web site: \n\nhttp://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. \n\nhttp://www.ema.europa.eu/\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. 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heart), or you are taking other medicines that result in abnormal ecg changes or if you have low levels of electrolytes e.g., potassium, magnesium or calcium (see section \"other medicines and anagrelide mylan\"); if you have any problems with your liver or kidneys. in combination with acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever, as well as to prevent blood clotting, also known as aspirin), there is an increased risk 25 of major haemorrhages (bleeding) (see section \"other medicines and anagrelide mylan\"). children and adolescents there is limited information on the use of anagrelide in children and adolescents and therefore this medicine should be used with caution. other medicines and anagrelide mylan tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines. tell your doctor if you are taking any of the following medicines: medicines that can alter your heart rhythm e.g., sotalol, amiodarone; fluvoxamine, used to treat depression; certain types of antibiotic, such as enoxacin, used to treat infections; theophylline, used to treat severe asthma and breathing problems; medicines used to treat heart disorders, for example, milrinone, enoximone, amrinone, olprinone and cilostazol; acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever, as well as to prevent blood clotting, also known as aspirin); other medicines used to treat conditions affecting the platelets in your blood, e.g., clopidogrel; omeprazole, used to reduce the amount of acid produced in the stomach; oral contraceptives: if you experience bad diarrhoea whilst taking this medicine, it may reduce how well the oral contraceptive works and use of an extra method of contraception is recommended (e.g., condom). see the instructions in the patient leaflet of the contraceptive pill you are taking. anagrelide or these medicines may not work properly if taken together. if you are not sure, speak to your doctor or pharmacist for advice. pregnancy and breast-feeding tell your doctor if you are pregnant or are planning to become pregnant. anagrelide mylan should not be taken by pregnant women. women who are at risk of becoming pregnant should make sure that they are using effective contraception when taking anagrelide. speak to your doctor if you need advice with contraception. tell your doctor if you are breast-feeding or if you are planning to breast-feed your baby. anagrelide mylan should not be taken while breast-feeding. you must stop breast-feeding if you are taking anagrelide mylan. driving and using machines dizziness has been reported by some patients taking anagrelide. do not drive or use machines if you feel dizzy. anagrelide mylan contains lactose and sodium this medicine contains lactose. if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. this medicine contains 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or pharmacist if you are not sure. the amount of anagrelide that people take can be different, and this depends on your condition. your doctor will prescribe the best dose for you. the usual starting dose of this medicine is 1 mg. you take this dose as one capsule of 0.5 mg twice a day, for at least a week. after this time, your doctor may either increase or decrease the number of capsules that you take to find the dose best suited to you and which treats your condition most effectively. your capsules should be swallowed whole with a glass of water. do not crush the capsules or dilute the contents in a liquid. you can take the capsules with food or after a meal or on an empty stomach. it is best to take the capsule(s) at the same time every day. do not take more capsules than your doctor has recommended. your doctor will ask you to have blood tests at regular intervals to check that your medicine is working effectively and that your liver and kidneys are working well. if you take more anagrelide mylan than you should if you take more anagrelide mylan than you should or if someone else has taken your medicine, tell a doctor or pharmacist immediately. show them the pack of anagrelide mylan. if you forget to take anagrelide mylan take your capsules as soon as you remember. take your next dose at the usual time. do not take a double dose to make up for a forgotten dose.', 'Entity_Recognition': [{'Text': 'anagrelide mylan', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'anagrelide mylan', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 28}, {'Id': 4, 'BeginOffset': 138, 'EndOffset': 148, 'Score': 0.9815389513969421, 'Text': 'anagrelide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 297, 'EndOffset': 310}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 314, 'EndOffset': 315}, {'Text': 'this dose', 'Type': 'TREATMENT', 'BeginOffset': 329, 'EndOffset': 338}, {'Text': 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tachycardia or atrial fibrillation), inflammation of the pancreas which causes severe abdominal and back pain (pancreatitis), vomiting blood or passing bloody or black stools, severe reduction in blood cells which can cause weakness, bruising, bleeding or infections (pancytopenia), increased pressure in the lung arteries (signs include shortness of breath, swelling in legs or ankles and lips and skin can turn bluish colour). rare: kidney failure (when you pass little or no urine), heart attack. if you notice any of these side effects, contact your doctor immediately. very common side effects: may affect more than 1 in 10 people headache. common side effects: may affect up to 1 in 10 people dizziness, tiredness, rapid heartbeat, irregular or strong heartbeat (palpitations), feeling sick (nausea), diarrhoea, stomach pain, wind, being sick (vomiting), reduction in red blood cell count (anaemia), fluid retention or rash. uncommon side effects: may affect up to 1 in 100 people a feeling of weakness or feeling unwell, high blood pressure, irregular heartbeat, fainting, chills or fever, indigestion, loss of appetite, constipation, bruising, bleeding, swelling (oedema), weight loss, muscle aches, painful joints, back pain, decreased or loss of feeling or sensation such as numbness, especially in the skin, abnormal feeling or sensation such as tingling and 'pins and needles', 27 sleeplessness, depression, confusion, nervousness, dry mouth, loss of memory, breathlessness, nosebleed, serious lung infection with fever, shortness of breath, cough, phlegm; hair loss, skin itching or discolouration, impotence, chest pain, reduction in blood platelets, which increases the risk of bleeding or bruising (thrombocytopenia), accumulation of fluid around the lungs or an increase in liver enzymes. your doctor may do a blood test which may show an increase in your liver enzymes. rare side effects: may affect up to 1 in 1,000 people bleeding gums, weight gain, severe chest pain (angina pectoris), heart muscle disease, (signs include fatigue, chest pain and palpitations), enlarged heart, accumulation of fluid around the heart, painful spasm of the blood vessels on the heart (while resting, usually at night or early morning) (prinzmetal angina), loss of coordination, difficulty in speaking, dry skin, migraine, visual disturbances or double vision, ringing in the ears, dizziness on standing up (especially when getting up from a sitting or lying position), increased need to pass water at night, pain, 'flu-like' symptoms, sleepiness, widening of blood vessels, inflammation of the large bowel (signs include: diarrhoea, usually with blood and mucus, stomach pain, fever), inflammation of the stomach (signs include: pain, nausea, vomiting), area of abnormal density in the lung, increased creatinine level in blood tests, which may be a sign of kidney problems. the following side effects have been reported but it is not known exactly how often they occur: potentially life-threatening, irregular heartbeat (torsade de pointes); inflammation of the liver, symptoms include nausea, vomiting, itching, yellowing of the skin and eyes, discoloration of stool and urine (hepatitis); lung inflammation (signs include fever, coughing, difficulty breathing, wheezing; which causes scaring of the lungs) (allergic alveolitis, including interstitial lung disease, pneumonitis); inflammation of the kidneys (tubulointerstitial nephritis). reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects, you can help provide more information on the safety of this medicine.\", 'Entity_Recognition': [{'Text': 'anagrelide mylan', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 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'Text': 'pneumonitis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9680280685424805}]}, {'Text': 'inflammation of the kidneys', 'Type': 'PROBLEM', 'BeginOffset': 3756, 'EndOffset': 3783}, {'Id': 201, 'BeginOffset': 3785, 'EndOffset': 3813, 'Score': 0.8070409297943115, 'Text': 'tubulointerstitial nephritis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.957181990146637}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.978255569934845, 'RelationshipScore': 0.9966359734535217, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 135, 'BeginOffset': 3776, 'EndOffset': 3783, 'Text': 'kidneys', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 202, 'BeginOffset': 3829, 'EndOffset': 3841, 'Score': 0.927201509475708, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6405333280563354}]}, {'Id': 203, 'BeginOffset': 3857, 'EndOffset': 3869, 'Score': 0.9016119241714478, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7168055772781372}]}, {'Id': 214, 'BeginOffset': 3933, 'EndOffset': 3945, 'Score': 0.9335864186286926, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5424249172210693}, {'Name': 'NEGATION', 'Score': 0.7177737951278687}]}, {'Id': 215, 'BeginOffset': 3994, 'EndOffset': 4006, 'Score': 0.8480466604232788, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6411871910095215}]}, {'Id': 216, 'BeginOffset': 4060, 'EndOffset': 4071, 'Score': 0.3641791343688965, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5545737147331238}]}, {'Id': 217, 'BeginOffset': 4085, 'EndOffset': 4097, 'Score': 0.9221882820129395, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7188360095024109}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 4154, 'EndOffset': 4167}]}"},"Section_5":{"kind":"string","value":"{'Title': '5. how to store anagrelide mylan', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and bottle label after exp. the expiry date refers to the last day of that month. store in the original package in order to protect from light and moisture. this medicinal product does not require any special temperature storage conditions. if your doctor stops your medicine, do not keep any leftover capsules unless your doctor tells you to. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': \"what anagrelide mylan contains the active substance is anagrelide. each capsule contains anagrelide hydrochloride monohydrate equivalent to 0.5 mg anagrelide. the other ingredients are lactose, croscarmellose sodium, povidone, microcrystalline cellulose, magnesium stearate, gelatin and titanium dioxide(e171). see section 2 'anagrelide mylan contains lactose and sodium'. what anagrelide mylan looks like and contents of the pack anagrelide mylan 0.5 mg hard capsules have a white body and cap. the capsule is filled with a white to off-white powder. the capsule size is approximately 14.3 x 5.3 mm. anagrelide mylan is available in plastic bottles of 30 ml or 75 ml with a tamper evident, child-resistant closure and a desiccant. each bottle contains 100 hard capsules.\", 'Entity_Recognition': [{'Text': 'anagrelide mylan', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'anagrelide mylan', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 21}, {'Id': 2, 'BeginOffset': 55, 'EndOffset': 65, 'Score': 0.9853469133377075, 'Text': 'anagrelide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.6096318364143372, 'RelationshipScore': 0.9952360987663269, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 72, 'EndOffset': 79, 'Text': 'capsule', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'anagrelide hydrochloride monohydrate equivalent', 'Type': 'TREATMENT', 'BeginOffset': 89, 'EndOffset': 136}, {'Text': '0.5', 'Type': 'NUMBER', 'BeginOffset': 140, 'EndOffset': 143}, {'Id': 6, 'BeginOffset': 147, 'EndOffset': 157, 'Score': 0.9950590133666992, 'Text': 'anagrelide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9190890789031982, 'RelationshipScore': 0.9793552756309509, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 140, 'EndOffset': 146, 'Text': '0.5 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'lactose', 'Type': 'TREATMENT', 'BeginOffset': 185, 'EndOffset': 192}, {'Id': 7, 'BeginOffset': 194, 'EndOffset': 215, 'Score': 0.9704983234405518, 'Text': 'croscarmellose sodium', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 217, 'EndOffset': 225, 'Score': 0.8732883334159851, 'Text': 'povidone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 227, 'EndOffset': 253, 'Score': 0.9962660670280457, 'Text': 'microcrystalline cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 255, 'EndOffset': 273, 'Score': 0.9933165311813354, 'Text': 'magnesium stearate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'gelatin and titanium dioxide', 'Type': 'TREATMENT', 'BeginOffset': 275, 'EndOffset': 303}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 323, 'EndOffset': 324}, {'Id': 12, 'BeginOffset': 326, 'EndOffset': 342, 'Score': 0.5562722086906433, 'Text': 'anagrelide mylan', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'lactose', 'Type': 'TREATMENT', 'BeginOffset': 352, 'EndOffset': 359}, {'Text': 'sodium', 'Type': 'TREATMENT', 'BeginOffset': 364, 'EndOffset': 370}, {'Text': 'anagrelide mylan', 'Type': 'TREATMENT', 'BeginOffset': 378, 'EndOffset': 394}, {'Text': 'the pack anagrelide mylan', 'Type': 'TREATMENT', 'BeginOffset': 422, 'EndOffset': 447}, {'Text': '0.5', 'Type': 'NUMBER', 'BeginOffset': 448, 'EndOffset': 451}, {'Text': 'the capsule', 'Type': 'TREATMENT', 'BeginOffset': 496, 'EndOffset': 507}, {'Text': 'white powder', 'Type': 'TREATMENT', 'BeginOffset': 538, 'EndOffset': 550}, {'Text': 'the capsule size', 'Type': 'TEST', 'BeginOffset': 552, 'EndOffset': 568}, {'Text': '14.3', 'Type': 'NUMBER', 'BeginOffset': 586, 'EndOffset': 590}, {'Text': '5.3', 'Type': 'NUMBER', 'BeginOffset': 593, 'EndOffset': 596}, {'Text': 'anagrelide mylan', 'Type': 'TREATMENT', 'BeginOffset': 601, 'EndOffset': 617}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 653, 'EndOffset': 655}, {'Text': '75', 'Type': 'NUMBER', 'BeginOffset': 662, 'EndOffset': 664}, {'Text': 'child-resistant closure', 'Type': 'TREATMENT', 'BeginOffset': 691, 'EndOffset': 714}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 753, 'EndOffset': 756}]}"}}},{"rowIdx":1053,"cells":{"ID":{"kind":"string","value":"1B231D72EFCF1289444C70AA9FE3F436"},"URL":{"kind":"string","value":"https://www.ema.europa.eu/documents/product-information/zoely-epar-product-information_en.pdf"},"Product_Name":{"kind":"string","value":"Zoely"},"Full_Content":{"kind":"string","value":"1\n\nANNEX I\n\nSUMMARY OF PRODUCT CHARACTERISTICS\n\n \n\n\n\n2\n\nThis medicinal product is subject to additional monitoring. This will allow quick identification of \nnew safety information. Healthcare professionals are asked to report any suspected adverse reactions. \nSee section 4.8 for how to report adverse reactions.\n\n1. NAME OF THE MEDICINAL PRODUCT\n\nZoely 2.5 mg/1.5 mg film-coated tablets\n\n2. QUALITATIVE AND QUANTITATIVE COMPOSITION\n\nWhite active film-coated tablets: Each film-coated tablet contains 2.5 mg nomegestrol acetate and \n1.5 mg estradiol (as hemihydrate).\nYellow placebo film-coated tablets: The tablet does not contain active substances.\n\nExcipients with known effect\nEach white active film-coated tablet contains 57.71 mg of lactose monohydrate.\nEach yellow placebo film-coated tablet contains 61.76 mg of lactose monohydrate.\n\nFor the full list of excipients, see section 6.1.\n\n3. PHARMACEUTICAL FORM\n\nFilm-coated tablet (tablet).\nActive film-coated tablets: white, round and coded ‘ne’ on both sides.\nPlacebo film-coated tablets: yellow, round and coded ‘p’ on both sides.\n\n4. CLINICAL PARTICULARS\n\n4.1 Therapeutic indications\n\nOral contraception.\n\nThe decision to prescribe Zoely should take into consideration the individual woman’s current risk \nfactors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Zoely \ncompares with other combined hormonal contraceptives (CHCs) (see sections 4.3 and 4.4).\n\n4.2 Posology and method of administration\n\nPosology\n\nOne tablet is to be taken daily for 28 consecutive days. Each pack starts with 24 white active tablets, \nfollowed by 4 yellow placebo tablets. A subsequent pack is started immediately after finishing the \nprevious pack, without a break in daily tablet intake and irrespective of presence or absence of \nwithdrawal bleeding. Withdrawal bleeding usually starts on day 2-3 after intake of the last white tablet \nand may not have finished before the next pack is started. See ‘Cycle control’ in section 4.4.\n\nSpecial populations\n\nRenal impairment\nAlthough data in renal impaired patients are not available, renal impairment is unlikely to affect the \nelimination of nomegestrol acetate and estradiol.\n\n \n\n\n\n3\n\nHepatic impairment\nNo clinical studies have been performed in patients with hepatic insufficiency. Since the metabolism \nof steroid hormones might be impaired in patients with severe hepatic disease, the use of Zoely in \nthese women is not indicated as long as liver function values have not returned to normal (see \nsection 4.3).\n\nMethod of administration\n\nOral use.\n\nHow to take Zoely\nTablets must be taken every day at about the same time without regard to meals. Tablets should be \ntaken with some liquid as needed, and in the order as directed on the blister. Stickers marked with the \n7 days of the week are provided. The woman should choose the sticker that starts with the day she \nbegins taking the tablets and stick it on the blister.\n\nHow to start Zoely\nNo preceding hormonal contraceptive use (in the past month)\nTablet-taking has to start on day 1 of the woman’s natural cycle (i.e. the first day of her menstrual \nbleeding). When doing so, no additional contraceptive measures are necessary.\n\nChanging from a combined hormonal contraceptive (combined oral contraceptive (COC), vaginal \nring or transdermal patch)\nThe woman should start with Zoely preferably on the day after the last active tablet (the last tablet \ncontaining the active substances) of her previous COC, but at the latest on the day following the usual \ntablet-free or placebo tablet interval of her previous COC. In case a vaginal ring or transdermal patch \nhas been used, the woman should start using Zoely preferably on the day of removal, but at the latest \nwhen the next application would have been due.\n\nChanging from a progestogen-only-method (minipill, implant, injectable) or from a \nhormone-medicated intra uterine system (IUS)\nThe woman may switch any day from the minipill and Zoely should be started on the next day. An \nimplant or IUS may be removed any day, and Zoely should be started on the day of its removal. When \nchanging from an injectable, Zoely should be started on the day when the next injection would have \nbeen due. In all of these cases, the woman should be advised to additionally use a barrier method until \nshe has completed 7 days of uninterrupted white active tablet-taking.\n\nFollowing first-trimester abortion\nThe woman may start immediately. When doing so, no additional contraceptive measures are necessary.\n\nFollowing delivery or second-trimester abortion\nWomen should be advised to start between day 21 and 28 after delivery or second-trimester abortion. \nWhen starting later, the woman should be advised to additionally use a barrier method until she has \ncompleted 7 days of uninterrupted white active tablet-taking. However, if intercourse has already \noccurred, pregnancy should be excluded before the actual start of COC use or the woman has to wait \nfor her first menstrual period.\nFor breast-feeding women see section 4.6.\n\nManagement of missed tablets\n\nThe following advice only refers to missed white active tablets:\n\nIf the woman is less than 24 hours late in taking any active tablet, contraceptive protection is not \nreduced. The woman should take the tablet as soon as she remembers and should take further tablets at \nthe usual time.\n\n \n\n\n\n4\n\nIf she is 24 or more hours late in taking any active tablet, contraceptive protection may be reduced. \nThe management of missed tablets can be guided by the following two basic rules:\n 7 days of uninterrupted ‘white active tablet’-taking are required to attain adequate suppression \n\nof the hypothalamic-pituitary-ovarian-axis.\n The more ‘white active tablets’ are missed and the closer the missed tablets are to the 4 yellow \n\nplacebo tablets, the higher the risk of a pregnancy.\n\nDay 1-7\nThe user should take the last missed white tablet as soon as she remembers, even if this means taking \ntwo tablets at the same time. She then continues to take tablets at her usual time. In addition, a barrier \nmethod such as a condom should be used until she has completed 7 days of uninterrupted white tablet-\ntaking. If intercourse took place in the preceding 7 days, the possibility of a pregnancy should be \nconsidered.\nDay 8-17\nThe user should take the last missed white tablet as soon as she remembers, even if this means taking \ntwo tablets at the same time. She then continues to take tablets at her usual time. Provided that the \nwoman has taken her tablets correctly in the 7 days preceding the first missed tablet, there is no need \nto use extra contraceptive precautions. However, if she has missed more than 1 tablet, the woman \nshould be advised to use extra precautions until she has completed 7 days of uninterrupted white \ntablet-taking.\nDay 18-24\nThe risk of reduced reliability is imminent because of the forthcoming yellow placebo tablet phase. \nHowever, by adjusting the tablet-intake schedule, reduced contraceptive protection can still be \nprevented. By adhering to either of the following two options, there is therefore no need to use extra \ncontraceptive precautions, provided that in the 7 days preceding the first missed tablet the woman has \ntaken all tablets correctly. If this is not the case, she should follow the first of these two options and \nuse extra precautions for the next 7 days as well.\n1. The user should take the last missed tablet as soon as she remembers, even if this means taking \n\ntwo tablets at the same time. She then continues to take tablets at her usual time until the active \ntablets are used up. The 4 placebo tablets from the last row must be discarded. The next blister \npack must be started right away. The user is unlikely to have a withdrawal bleed until the end of \nthe active tablets section of the second pack, but she may experience spotting or breakthrough \nbleeding on tablet-taking days.\n\n2. The woman may also be advised to discontinue active tablet-taking from the current blister \npack. She should then take placebo tablets from the last row for a maximum of 3 days such that \nthe total number of placebo plus missed white active tablets is not more than 4, and \nsubsequently continue with the next blister pack.\n\nIf the woman missed tablets and subsequently has no withdrawal bleed in the placebo tablet phase, the \npossibility of a pregnancy should be considered.\n\nPlease note: If the user is not sure about the number or colour of tablets missed and what advice to \nfollow, a barrier method should be used until she has completed 7 days of uninterrupted white active \ntablet-taking.\n\nYellow placebo tablets missed\n\nContraceptive protection is not reduced. Yellow tablets from the last (4th) row of the blister can be \ndisregarded. However, the missed tablets should be discarded to avoid unintentionally prolonging the \nplacebo tablet phase.\n\nAdvice in case of gastro-intestinal disturbances\n\nIn case of severe gastro-intestinal disturbance (e.g., vomiting or diarrhoea), absorption of the active \nsubstances may not be complete and additional contraceptive measures should be taken.\nIf vomiting occurs within 3-4 hours after white tablet-taking, the tablet should be considered as missed \nand a new tablet should be taken as soon as possible. The new tablet should be taken within 24 hours \n\n \n\n\n\n5\n\nof the usual time of tablet-taking if possible. The next tablet should then be taken at the usual time. If \n24 or more hours have passed since last tablet intake, the advice concerning missed tablets, as given in \nsection 4.2 \"Management of missed tablets\", is applicable. If the woman does not want to change her \nnormal tablet-taking schedule, she has to take the extra white tablet(s) from another pack.\n\nHow to shift periods or how to delay a period\n\nTo delay a period the woman should continue with another blister pack of Zoely without taking the \nyellow placebo tablets from her current pack. The extension can be carried on for as long as wished \nuntil the end of the white active tablets in the second pack. Regular intake of Zoely is then resumed \nafter the yellow placebo tablets have been taken of the second pack. During the extension the woman \nmay experience breakthrough-bleeding or spotting.\n\nTo shift her periods to another day of the week than the woman is used to with her current scheme, she \ncan be advised to shorten her forthcoming yellow placebo tablet phase with a maximum of 4 days. The \nshorter the interval, the higher the risk that she does not have a withdrawal bleed and may experience \nbreakthrough-bleeding and spotting during the subsequent pack (just as when delaying a period).\n\n4.3 Contraindications\n\nCombined hormonal contraceptives (CHCs) must not be used in the following conditions. As no \nepidemiological data are yet available with 17β-estradiol containing CHCs, the contraindications for \nethinylestradiol containing CHCs are considered applicable to the use of Zoely. Should any of the \nconditions appear for the first time during Zoely use, the medicinal product should be stopped\nimmediately.\n\n Presence or risk of venous thromboembolism (VTE)\no Venous thromboembolism - current VTE (on anticoagulants) or history of (e.g. deep \n\nvenous thrombosis [DVT] or pulmonary embolism [PE]).\no Known hereditary or acquired predisposition for venous thromboembolism, such as \n\nAPC-resistance (including Factor V Leiden), antithrombin-III-deficiency, protein C \ndeficiency, protein S deficiency.\n\no Major surgery with prolonged immobilisation (see section 4.4).\no A high risk of venous thromboembolism due to the presence of multiple risk factors (see \n\nsection 4.4).\n Presence or risk of arterial thromboembolism (ATE)\n\no Arterial thromboembolism - current arterial thromboembolism, history of arterial \nthromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. angina \npectoris).\n\no Cerebrovascular disease – current stroke, history of stroke or prodromal condition (e.g.\ntransient ischaemic attack, TIA).\n\no Known hereditary or acquired predisposition for arterial thromboembolism, such as \nhyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies, \nlupus anticoagulant).\n\no History of migraine with focal neurological symptoms.\no A high risk of arterial thromboembolism due to multiple risk factors (see section 4.4) or \n\nto the presence of one serious risk factor such as:\n diabetes mellitus with vascular symptoms\n severe hypertension\n severe dyslipoproteinaemia.\n\n Pancreatitis or a history thereof if associated with severe hypertriglyceridaemia.\n Presence or history of severe hepatic disease as long as liver function values have not returned \n\nto normal.\n Presence or history of liver tumours (benign or malignant).\n Known or suspected sex steroid-influenced malignancies (e.g., of the genital organs or the \n\nbreasts).\n\n \n\n\n\n6\n\n Presence or history of meningioma.\n Undiagnosed vaginal bleeding.\n Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.\n\n4.4 Special warnings and precautions for use\n\nWarnings\nIf any of the conditions or risk factors mentioned below is present, the suitability of Zoely should be \ndiscussed with the woman.\n\nIn the event of aggravation, or first appearance of any of these conditions or risk factors, the woman \nshould be advised to contact her doctor to determine whether the use of Zoely should be discontinued. \nAll data presented below are based upon epidemiological data obtained with CHCs containing \nethinylestradiol. Zoely contains 17β-estradiol. As no epidemiological data are yet available with \nestradiol containing-CHCs, the warnings are considered applicable to the use of Zoely.\n\nRisk of venous thromboembolism (VTE)\n The use of any combined hormonal contraceptive (CHC) increases the risk of venous \n\nthromboembolism (VTE) compared with no use. Products that contain levonorgestrel,\nnorgestimate or norethisterone are associated with the lowest risk of VTE. It is not yet \nknown how the risk with Zoely compares with these lower risk products. The decision to \nuse any product other than one known to have the lowest VTE risk should be taken only \nafter a discussion with the woman to ensure she understands the risk of VTE with CHCs, \nhow her current risk factors influence this risk, and that her VTE risk is highest in the \nfirst ever year of use. There is also some evidence that the risk is increased when a CHC is \nre-started after a break in use of 4 weeks or more.\n\n In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a \nVTE over the period of one year. However, in any individual woman, the risk may be far \nhigher, depending on her underlying risk factors (see below).\n\n Epidemiological studies in women who use low dose (< 50 µg ethinylestradiol) combined \nhormonal contraceptives have found that out of 10,000 women between 6 and 12 will develop a \nVTE in one year.\n\n It is estimated that out of 10,000 women who use a levonorgestrel-containing CHC about 61 will \ndevelop a VTE in one year.\n\n It is not yet known how the risk of VTE with CHCs that contain nomegestrol acetate in \ncombination with estradiol compares with the risk with low dose levonorgestrel-containing \nCHCs.\n\n The number of VTEs per year with low dose CHCs is fewer than the number expected in \nwomen during pregnancy or in the postpartum period.\n\n VTE may be fatal in 1-2 % of cases.\n Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, \n\ne.g. hepatic, mesenteric, renal, or retinal veins and arteries.\n\nRisk factors for VTE\nThe risk for venous thromboembolic complications in CHC users may increase substantially in a \nwoman with additional risk factors, particularly if there are multiple risk factors (see table).\n\nZoely is contraindicated if a woman has multiple risk factors that put her at high risk of venous \nthrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increase \nin risk is greater than the sum of the individual factors – in this case her total risk of VTE should be \nconsidered. If the balance of benefits and risks is considered to be negative, a CHC should not be\nprescribed (see section 4.3).\n\n \n1\n\nMid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6\n\n \n\n\n\n7\n\nTable: Risk factors for VTE\nRisk factor Comment\n\nObesity (body mass index over 30 kg/m²) Risk increases substantially as BMI rises.\n\nParticularly important to consider if other risk \nfactors also present.\n\nProlonged immobilisation, major surgery, any \nsurgery to the legs or pelvis, neurosurgery, or \nmajor trauma\n\nNote: Temporary immobilisation including air \ntravel > 4 hours can also be a risk factor for VTE, \nparticularly in women with other risk factors.\n\nIn these situations it is advisable to discontinue \nuse of the pill (in the case of elective surgery at \nleast four weeks in advance) and not resume until \ntwo weeks after complete remobilisation. Another\nmethod of contraception should be used to avoid \nunintentional pregnancy.\n\nAntithrombotic treatment should be considered if \nZoely has not been discontinued in advance.\n\nPositive family history (venous thromboembolism \never in a sibling or parent especially at a \nrelatively early age, e.g., before 50)\n\nIf a hereditary predisposition is suspected, the \nwoman should be referred to a specialist for \nadvice before deciding about any CHC use.\n\nOther medical conditions associated with VTE Cancer, systemic lupus erythematosus, \nhaemolytic uraemic syndrome, chronic \ninflammatory bowel disease (Crohn's disease or \nulcerative colitis) and sickle cell disease\n\nIncreasing age Particularly above 35 years\n\n There is no consensus about the possible role of varicose veins and superficial thrombophlebitis \nin the onset or progression of venous thrombosis.\n\n The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of the \npuerperium, must be considered (for information on \"Pregnancy and lactation\" see section 4.6).\n\nSymptoms of VTE (deep vein thrombosis and pulmonary embolism)\nIn the event of symptoms women should be advised to seek urgent medical attention and to inform the \nhealthcare professional that she is taking a CHC.\nSymptoms of deep vein thrombosis (DVT) can include:\n\n- unilateral swelling of the leg and/or foot or along a vein in the leg;\n- pain or tenderness in the leg which may be felt only when standing or walking;\n- increased warmth in the affected leg; red or discoloured skin on the leg.\n\nSymptoms of pulmonary embolism (PE) can include:\n- sudden onset of unexplained shortness of breath or rapid breathing;\n- sudden coughing which may be associated with haemoptysis;\n- sharp chest pain;\n- severe light headedness or dizziness;\n- rapid or irregular heartbeat.\n\nSome of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be \nmisinterpreted as more common or less severe events (e.g. respiratory tract infections).\nOther signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of \nan extremity.\nIf the occlusion occurs in the eye symptoms can range from painless blurring of vision which can \nprogress to loss of vision. Sometimes loss of vision can occur almost immediately.\n\n \n\n\n\n8\n\nRisk of arterial thromboembolism (ATE)\nEpidemiological studies have associated the use of CHCs with an increased risk for arterial \nthromboembolism (myocardial infarction) or for cerebrovascular accident (e.g., transient ischaemic \nattack, stroke). Arterial thromboembolic events may be fatal.\n\nRisk factors for ATE\nThe risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users \nincreases in women with risk factors (see table). Zoely is contraindicated if a woman has one serious \nor multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). If a \nwoman has more than one risk factor, it is possible that the increase in risk is greater than the sum of \nthe individual factors – in this case her total risk should be considered. If the balance of benefits and \nrisks is considered to be negative a CHC should not be prescribed (see section 4.3).\n\nTable: Risk factors for ATE\nRisk factor Comment\nIncreasing age Particularly above 35 years\n\nSmoking Women should be advised not to smoke if they \nwish to use a CHC. Women over 35 who continue \nto smoke should be strongly advised to use a \ndifferent method of contraception.\n\nHypertension\n\nObesity (body mass index over 30 kg/m2) Risk increases substantially as BMI increases.\n\nParticularly important in women with\nadditional risk factors\n\nPositive family history (arterial thromboembolism \never in a sibling or parent especially at relatively \nearly age, e.g., below 50)\n\nIf a hereditary predisposition is suspected, the \nwoman should be referred to a specialist for \nadvice before deciding about any CHC use.\n\nMigraine An increase in frequency or severity of migraine \nduring CHC use (which may be prodromal of a \ncerebrovascular event) may be a reason for \nimmediate discontinuation.\n\nOther medical conditions associated with\nadverse vascular events\n\nDiabetes mellitus, hyperhomocysteinaemia,\nvalvular heart disease and atrial fibrillation,\ndyslipoproteinaemia and systemic lupus\nerythematosus\n\nSymptoms of ATE\nIn the event of symptoms women should be advised to seek urgent medical attention and to inform the \nhealthcare professional that she is taking a CHC.\nSymptoms of a cerebrovascular accident can include:\n\n- sudden numbness or weakness of the face, arm or leg, especially on one side of the body;\n- sudden trouble walking, dizziness, loss of balance or coordination;\n- sudden confusion, trouble speaking or understanding;\n- sudden trouble seeing in one or both eyes;\n- sudden, severe or prolonged headache with no known cause;\n- loss of consciousness or fainting with or without seizure.\n\nTemporary symptoms suggest the event is a transient ischaemic attack (TIA).\n\n \n\n\n\n9\n\nSymptoms of a myocardial infarction (MI) can include:\n- pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or\n\nbelow the breastbone;\n- discomfort radiating to the back, jaw, throat, arm, stomach;\n- feeling of being full, having indigestion or choking;\n- sweating, nausea, vomiting or dizziness;\n- extreme weakness, anxiety, or shortness of breath;\n- rapid or irregular heartbeats.\n\nTumours\n An increased risk of cervical cancer in long-term users of COCs (> 5 years) has been reported in \n\nsome epidemiological studies, but there continues to be controversy about the extent to which \nthis finding is attributable to the confounding effects of sexual behaviour and other factors such \nas human papilloma virus (HPV). No epidemiological data on the risk of cervical cancer in \nusers of Zoely are available.\n\n With the use of the higher-dosed COCs (50 g ethinylestradiol) the risk of endometrial and \novarian cancer is reduced. Whether this also applies to 17β-estradiol-containing COCs remains \nto be confirmed.\n\n A meta-analysis from 54 epidemiological studies reported that there is a slightly increased \nrelative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using \nCOCs. The excess risk gradually disappears during the course of the 10 years after cessation of \nCOC use. Because breast cancer is rare in women under 40 years of age, the excess number of \nbreast cancer diagnoses in current and recent COC users is small in relation to the overall risk of \nbreast cancer. The breast cancers diagnosed in ever-users tend to be less advanced clinically \nthan the cancers diagnosed in never-users. The observed pattern of increased risk may be due to \nan earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a \ncombination of both.\n\n In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been \nreported in users of COCs. In isolated cases, these tumours have led to life-threatening \nintra-abdominal haemorrhages. Therefore, a hepatic tumour should be considered in the \ndifferential diagnosis when severe upper abdominal pain, liver enlargement or signs of \nintra-abdominal haemorrhage occur in women taking COCs.\n\nMeningioma\nThe occurrence of meningioma (single and multiple) has been reported with prolonged use (several \nyears) of nomegestrol monotherapy at doses of 3.75 mg or 5 mg daily and higher. If a meningioma is \ndiagnosed in a patient treated with Zoely, treatment should be stopped (see section 4.3).\n\nHepatitis C\n During clinical trials with the Hepatitis C virus (HCV) combination drug regimen \n\nombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times \nthe upper limit of normal (ULN) were significantly more frequent in women using\nethinylestradiol-containing medications such as CHCs. Women using medications containing\noestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to \nthose not receiving any oestrogens; however, due to the limited number of women taking these \nother oestrogens, caution is warranted for co-administration with the combination drug regimen\nombitasvir/paritaprevir/ritonavir with or without dasabuvir. See section 4.5.\n\nOther conditions\n Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of \n\npancreatitis when using COCs.\n Although small increases in blood pressure have been reported in many women taking COCs, \n\nclinically relevant increases are rare. A relationship between COC use and clinical hypertension \nhas not been established. However, if a sustained clinically significant hypertension develops \nduring the use of a COC, then it is prudent for the physician to suspend the intake of the tablets \nand treat the hypertension. Where considered appropriate, COC use may be resumed if \nnormotensive values can be achieved with antihypertensive therapy.\n\n \n\n\n\n10\n\n The following conditions have been reported to occur or deteriorate with both pregnancy and \nCOC use, but the evidence of an association with COC use is inconclusive: jaundice and/or \npruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; \nhaemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related \nhearing loss.\n\n In women with hereditary angioedema, exogenous oestrogens may induce or exacerbate \nsymptoms of angioedema.\n\n Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use \nuntil markers of liver function return to normal. Recurrence of cholestatic jaundice which occurred \nfirst during pregnancy or previous use of sex steroids necessitates the discontinuation of COCs.\n\n Although COCs may have an effect on peripheral insulin resistance and glucose tolerance, there \nis no evidence for a need to alter the therapeutic regimen in diabetics using low-dose COCs \n(containing 0.05 mg ethinylestradiol). However, diabetic women should be carefully observed \nwhile taking a COC, especially in the first months of use.\n\n Crohn’s disease, ulcerative colitis, and worsening of depression have been associated with COC \nuse.\n\n Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. \nWomen with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation \nwhilst taking COCs.\n\n Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or \nglucose-galactose malabsorption should not take this medicinal product.\n\n Depressed mood and depression are well-known undesirable effects of hormonal contraceptive \nuse (see section 4.8). Depression can be serious and is a well-known risk factor for suicidal \nbehaviour and suicide. Women should be advised to contact their physician in case of mood \nchanges and depressive symptoms, including shortly after initiating the treatment.\n\nMedical examination/consultation\nPrior to the initiation or reinstitution of Zoely use a complete medical history (including family \nhistory) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a \nphysical examination should be performed, guided by the contraindications (see section 4.3) and \nwarnings (see section 4.4). It is important to draw a woman’s attention to the information on venous \nand arterial thrombosis, including the risk of Zoely compared with other CHCs, the symptoms of VTE \nand ATE, the known risk factors and what to do in the event of a suspected thrombosis.\n\nThe woman should also be instructed to carefully read the user leaflet and to adhere to the advice \ngiven. The frequency and nature of examinations should be based on established practice guidelines \nand be adapted to the individual woman.\n\nWomen should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) \nand other sexually transmitted diseases.\n\nReduced efficacy\nThe efficacy of COCs may be reduced in the event of e.g., missed tablets (see section 4.2), \ngastro-intestinal disturbances during active tablet-taking (see section 4.2) or use of concomitant \nmedicinal products that decrease the plasma concentrations of nomegestrol acetate and/or estradiol \n(see section 4.5).\n\nCycle control\nWith all COCs, irregular bleeding (spotting or breakthrough bleeding) may occur, especially during \nthe first months of use. Therefore, the evaluation of any irregular bleeding is only meaningful after an \nadaptation interval of about 3 cycles. The percentage of women using Zoely experiencing intracyclic \nbleeding after this adaptation period ranged from 15-20 %.\n\nIf bleeding irregularities persist or occur after previously regular cycles, then non-hormonal causes \nshould be considered and adequate diagnostic measures are indicated to exclude malignancy or \npregnancy. These may include curettage.\n\n \n\n\n\n11\n\nThe duration of the withdrawal bleeding in women using Zoely is on average 3-4 days. Users of Zoely \nmay also miss their withdrawal bleeding although not being pregnant. During clinical trials, absence of \nwithdrawal bleeding ranged over the cycles 1-12 from 18 % to 32 %. In such cases, absence of \nwithdrawal bleeding was not associated with a higher occurrence of breakthrough bleeding/spotting in \nthe subsequent cycles. 4.6 % of the women did not have a withdrawal bleeding in the first three cycles \nof use and the occurrences of absence of withdrawal bleeding in the later cycles of use were high in \nthis subgroup, ranging from 76 % to 87 % of women. 28 % of the women experienced absence of \nwithdrawal bleeding in at least one of the cycles 2, 3 and 4, associated with higher occurrences of \nabsence of withdrawal bleeding in the later cycles of use, ranging from 51 % to 62 %.\n\nIf absence of withdrawal bleeding occurs and Zoely has been taken according to the instructions as \ndescribed in section 4.2, it is unlikely that the woman is pregnant. However, pregnancy must be ruled \nout before Zoely use is continued, if Zoely has not been taken as directed or if two consecutive \nwithdrawal bleedings are missed.\n\nPaediatric population\nIt is unknown whether the amount of estradiol in Zoely is sufficient to maintain adequate levels of \nestradiol in adolescents, especially for bone mass accrual (see section 5.2).\n\nLaboratory tests\nThe use of contraceptive steroids may influence the results of certain laboratory tests, including \nbiochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) \nproteins, e.g., corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of \ncarbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain \nwithin the normal laboratory range.\n\n4.5 Interaction with other medicinal products and other forms of interaction\n\nInteractions\nNote: The prescribing information of concomitant medications should be consulted to identify \npotential interactions.\n\nInfluence of other medicinal products on Zoely\nInteractions between oral contraceptives and enzyme-inducing medicinal products may lead to \nbreakthrough bleeding and/or contraceptive failure.\n\nHepatic metabolism: Interactions can occur with substances that induce CYP450 enzymes, resulting in\nreduced concentrations of sex hormones and decreased effectiveness of combined oral contraceptives, \nincluding Zoely. These substances are represented mostly with anticonvulsants (e.g. carbamazepine,\ntopiramate, phenytoin, phenobarbital, primidone, oxcarbazepine, felbamate); anti-infective drugs (e.g. \nrifampicin, rifabutin, griseofulvin); St. John’s wort; bosentan and HIV or Hepatitis C virus (HCV) \nprotease inhibitors (e.g. ritonavir, boceprevir, telaprevir) and non-nucleoside reverse transcriptase \ninhibitors (e.g. efavirenz).\n\nEnzyme induction can occur after a few days of treatment. Maximal enzyme induction is generally \nobserved within a few weeks. After drug therapy is discontinued, enzyme induction can last for about \n28 days.\n\nA barrier contraceptive method should also be used during the concomitant use of an enzyme inducer,\nand for 28 days after its discontinuation. In case of long-term treatment with hepatic enzyme-inducing \nsubstances another method of contraception should be considered.\n\nIf concomitant drug administration runs beyond the end of the active tablets in the current blister pack, \nthe next blister pack should be started right away without the usual placebo tablet interval.\n\n \n\n\n\n12\n\nConcomitant administration of strong (e.g. ketoconazole, itraconazole, clarithromycin) or moderate \n(e.g. fluconazole, diltiazem, erythromycin) CYP3A4 inhibitors may increase the serum concentrations \nof oestrogens or progestogens.\n\nMedicinal product interaction studies were not performed with Zoely, but two studies with rifampicin \nand ketoconazole, respectively, were performed with a higher dosed nomegestrol acetate-estradiol \ncombination (nomegestrol acetate 3.75 mg + 1.5 mg estradiol) in post-menopausal women. \nConcomitant use of rifampicin decreases the AUC0-∞ of nomegestrol acetate by 95 % and increases the \nAUC0-tlast of estradiol by 25 %. Concomitant use of ketoconazole (200 mg single dose) does not \nmodify estradiol metabolism whereas increases in the peak concentration (85 %) and AUC0-∞ (115 %) \nof nomegestrol acetate were observed, which were of no clinical relevance. Similar conclusions are \nexpected in women of childbearing potential.\n\nInfluence of Zoely on other medicinal products\nContraceptives containing ethinylestradiol may decrease the concentrations of lamotrigine by \napproximately 50%. Attention should be paid, notably when introducing a combined contraceptive, \neven with estradiol, in a well-equilibrated woman given lamotrigine.\n\nOther interactions\nDuring clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir with \nand without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were \nsignificantly more frequent in women using ethinylestradiol-containing medications such as CHCs. \nWomen using medications containing oestrogens other than ethinylestradiol, such as estradiol, had a \nrate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited \nnumber of women taking these other oestrogens, caution is warranted for co-administration with the \ncombination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir.\n\n4.6 Fertility, pregnancy and lactation\n\nPregnancy\nZoely is not indicated during pregnancy.\n\nIf pregnancy occurs while taking Zoely, further intake should be stopped. Most epidemiological \nstudies have revealed neither an increased risk of birth defects in infants born to women who used \nethinylestradiol-containing COCs prior to pregnancy, nor a teratogenic effect when \nethinylestradiol-containing COCs were taken inadvertently during early pregnancy.\n\nClinical data on a limited number of exposed pregnancies indicate no adverse effect of Zoely on the \nfoetus or neonate.\n\nIn animal studies, reproductive toxicity has been observed with the nomegestrol acetate / estradiol \ncombination (see preclinical safety data in section 5.3).\n\nThe increased risk of VTE during the postpartum period should be considered when re-starting Zoely \n(see section 4.2 and 4.4).\n\nBreast-feeding\nSmall amounts of the contraceptive steroids and/or their metabolites may be excreted with the breast \nmilk, but there is no evidence that this adversely affects infant health.\n\nBreastfeeding may be influenced by COCs as they may reduce the quantity and change the \ncomposition of breast milk. Therefore, the use of COCs should not be recommended until the breast-\nfeeding mother has completely weaned her child and an alternative contraceptive method should be \nproposed to women wishing to breastfeed.\n\n \n\n\n\n13\n\nFertility\nZoely is indicated for the prevention of pregnancy. For information on return to fertility, see \nsection 5.1.\n\n4.7 Effects on ability to drive and use machines\n\nZoely has no or negligible influence on the ability to drive and use machines.\n\n4.8 Undesirable effects\n\nSummary of the safety profile\nSix multi-centre clinical trials of up to one year duration were used to evaluate safety of Zoely. In total \n3,434 women, aged 18-50, were enrolled and completed 33,828 cycles.\n\nTabulated list of adverse reactions\nPossibly related adverse reactions that have been reported in clinical trials or during postmarketing use \nwith Zoely are listed in the table below.\n\nAll adverse reactions are listed by system organ class and frequency; very common ( 1/10), common \n( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100) and rare ( 1/10,000 to < 1/1,000).\n\nSystem organ class\nAdverse reaction in MedDRA Term1\n\nVery common Common Uncommon Rare\nMetabolism and \nnutrition disorders\n\nincreased \nappetite, fluid \nretention\n\ndecreased \nappetite\n\nPsychiatric disorders decreased libido, \ndepression/ \ndepressed mood, \nmood altered\n\nincreased libido\n\nNervous system \ndisorders\n\nheadache, \nmigraine\n\ncerebrovascular \naccident,\ntransient \nischaemic attack, \ndisturbance in \nattention\n\nEye disorders contact lens \nintolerance/dry \neye\n\nVascular disorders hot flush venous \nthromboembolism\n\nGastrointestinal \ndisorders\n\nnausea abdominal \ndistension\n\ndry mouth\n\nHepatobiliary \ndisorders\n\ncholelithiasis, \ncholecystitis\n\nSkin and subcutaneous \ntissue disorders\n\nacne hyperhydrosis, \nalopecia, \npruritus, dry \nskin, seborrhea\n\nchloasma, \nhypertrichosis\n\nMusculoskeletal and \nconnective tissue \ndisorders\n\nsensation of \nheaviness\n\n \n\n\n\n14\n\nSystem organ class\nAdverse reaction in MedDRA Term1\n\nVery common Common Uncommon Rare\nReproductive system \nand breast disorders\n\nabnormal \nwithdrawal \nbleeding\n\nmetrorrhagia, \nmenorrhagia, \nbreast pain, \npelvic pain\n\nhypomenorrhoea, \nbreast swelling, \ngalactorrhoea, \nuterine spasm, \npremenstrual \nsyndrome, breast \nmass, \ndyspareunia, \nvulvovaginal \ndryness\n\nvaginal odour, \nvulvovaginal \ndiscomfort\n\nGeneral disorders and \nadministration site \nconditions\n\nirritability, \noedema\n\nhunger\n\nInvestigations weight increased hepatic enzyme \nincreased\n\n1The most appropriate MedDRA term to describe a certain adverse reaction is listed. Synonyms or related \nconditions are not listed, but should be taken into account as well.\n\nIn addition to the above mentioned adverse reactions, hypersensitivity reactions have been reported in \nZoely users (frequency unknown).\n\nDescription of selected adverse reactions\nAn increased risk of arterial and venous thrombotic and thromboembolic events, including myocardial \ninfarction, stroke, transient ischaemic attacks, venous thrombosis and pulmonary embolism has been \nobserved in women using CHCs, which are discussed in more detail in section 4.4.\n\nReporting of suspected adverse reactions\nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V.\n\n4.9 Overdose\n\nMultiple doses up to five times the daily dose of Zoely and single doses up to 40 times the daily dose \nof nomegestrol acetate alone have been used in women without safety concern. On the basis of general \nexperience with combined oral contraceptives, symptoms that may occur are: nausea, vomiting and, in \nyoung girls, slight vaginal bleeding. There are no antidotes and further treatment should be \nsymptomatic.\n\n5. PHARMACOLOGICAL PROPERTIES\n\n5.1 Pharmacodynamic properties\n\nPharmacotherapeutic group: Sex hormones and modulators of the genital system, progestogens and \noestrogens, fixed combinations, ATC code: G03AA14.\n\nMechanism of action\nNomegestrol acetate is a highly selective progestogen derived from the naturally occurring steroid \nhormone, progesterone. Nomegestrol acetate has a strong affinity for the human progesterone receptor \nand has an anti-gonadotropic activity, a progesterone receptor-mediated anti-oestrogenic activity, a \nmoderate anti-androgenic activity, and is devoid of any oestrogenic, androgenic, glucocorticoid or \nmineralocorticoid activity.\n\n \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n15\n\nThe oestrogen contained in Zoely is 17β-estradiol, a natural oestrogen identical to the endogenous \nhuman 17β-estradiol.\n\nThe contraceptive effect of Zoely is based on the interaction of various factors, the most important of \nwhich are seen as the inhibition of ovulation and the changes in the cervical secretion.\n\nClinical efficacy and safety\nIn two randomized, open-label, comparative efficacy-safety trials, more than 3,200 women have been \ntreated for up to 13 consecutive cycles with Zoely and more than 1,000 women with drospirenone \n3 mg – ethinylestradiol 30 μg (21/7 regimen).\nIn the Zoely group, acne was reported by 15.4 % of the women (versus 7.9 % in the comparator \ngroup), weight increased was reported by 8.6 % of the women (versus 5.7 % in the comparator group), \nand abnormal withdrawal bleeding (predominantly absence of withdrawal bleeding) was reported by \n10.5 % of the women (versus 0.5 % in the comparator group).\n\nIn the clinical trial performed with Zoely in the European Union the following Pearl Indices for the \nage class 18-35 years were calculated:\n\nMethod failure: 0.40 (upper limit 95 % confidence interval 1.03)\nMethod and user failure: 0.38 (upper limit 95 % confidence interval 0.97)\n\nIn the clinical trial performed with Zoely in the United States the following Pearl Indices for the age \nclass 18-35 years were calculated:\n\nMethod failure: 1.22 (upper limit 95 % confidence interval 2.18)\nMethod and user failure: 1.16 (upper limit 95 % confidence interval 2.08)\n\nIn a randomized, open label trial, 32 women were treated for 6 cycles with Zoely.\nAfter discontinuation of Zoely, return to ovulation in the first 28 days after last tablet intake was \nobserved in 79 % of the women.\n\nEndometrial histology was investigated in a subgroup of women (n=32) in one clinical study after \n13 cycles of treatment. There were no abnormal results.\n\nPaediatric population\nNo data on efficacy and safety are available in adolescents below 18 years. Available pharmacokinetic \ndata are described in section 5.2.\n\n5.2 Pharmacokinetic properties\n\nNomegestrol acetate\n\nAbsorption\nOrally administered nomegestrol acetate is rapidly absorbed.\nMaximum plasma concentrations of nomegestrol acetate of about 7 ng/mL are reached at 2 h after \nsingle administration. The absolute bioavailability of nomegestrol acetate after a single dose is 63 %. \nNo clinically relevant effect of food was observed on the bioavailability of nomegestrol acetate.\n\nDistribution\nNomegestrol acetate is extensively bound to albumin (97-98 %), but does not bind to sex hormone \nbinding globulin (SHBG) or corticoid binding globulin (CBG). The apparent volume of distribution of \nnomegestrol acetate at steady-state is 1,645 576 L.\n\nBiotransformation\nNomegestrol acetate is metabolized into several inactive hydroxylated metabolites by liver \ncytochrome P450 enzymes, mainly CYP3A4 and CYP3A5 with possible contribution of CYP2C19 \nand CYP2C8. Nomegestrol acetate and its hydroxylated metabolites undergo extensive phase 2 \n\n \n\n\n\n16\n\nmetabolism to form glucuronide- and sulphate conjugates. The apparent clearance at steady state is \n26 L/h.\n\nElimination\nThe elimination half-life (t1/2) is 46 h (ranging from 28-83 h) at steady state. The elimination half-life \nof metabolites was not determined.\nNomegestrol acetate is excreted via urine and faeces. Approximately 80 % of the dose is excreted in \nurine and faeces within 4 days. Excretion of nomegestrol acetate was nearly complete after 10 days \nand amounts excreted were higher in faeces than in urine.\n\nLinearity\nDose-linearity was observed in the range 0.625-5 mg (assessed in fertile and post-menopausal \nwomen).\n\nSteady-state conditions\nThe pharmacokinetics of nomegestrol acetate are not influenced by SHBG.\nSteady-state is achieved after 5 days. Maximum plasma concentrations of nomegestrol acetate of about \n12 ng/mL are reached 1.5 h after dosing. Average steady state plasma concentrations are 4 ng/mL.\n\nDrug drug interactions\nNomegestrol acetate causes in vitro no notable induction or inhibition of any cytochrome P450 \nenzymes and has no clinically relevant interaction with the P-gp transporter.\n\nEstradiol\n\nAbsorption\nEstradiol is subject to a substantial first-pass effect after oral administration. The absolute \nbioavailability is about 1 %. No clinically relevant effect of food was observed on the bioavailability \nof estradiol.\n\nDistribution\nThe distribution of exogenous and endogenous estradiol is similar. Oestrogens are widely distributed \nin the body and are generally found in higher concentrations in the sex hormone target organs. \nEstradiol circulates in the blood bound to SHBG (37 %) and to albumin (61 %), while only \napproximately 1-2 % is unbound.\n\nBiotransformation\nOral exogenous estradiol is extensively metabolized. The metabolism of exogenous and endogenous \nestradiol is similar. Estradiol is rapidly transformed in the gut and the liver in several metabolites, \nmainly estrone, which are subsequently conjugated and undergo entero-hepatic circulation. There is a \ndynamic equilibrium between estradiol, estrone and estrone-Sulfate due to various enzymatic activities \nincluding estradiol-dehydrogenases, sulfotransferases and aryl sulfatases. Oxidation of estrone and \nestradiol involves cytochrome P450 enzymes, mainly CYP1A2, CYP1A2 (extra hepatic), CYP3A4, \nCYP3A5, and CYP1B1 and CYP2C9.\n\nElimination\nEstradiol is rapidly cleared from the circulation. Due to metabolism and enterohepatic circulation, a \nlarge circulating pool of oestrogen sulfates and glucuronides is present. This results in a highly \nvariable baseline-corrected elimination half-life of estradiol, which is calculated to be 3.6 ± 1.5 h, after \nintravenous administration.\n\nSteady-state conditions\nMaximum serum concentrations of estradiol are about 90 pg/mL and are reached 6 h after dosing. \nAverage serum concentrations are 50 pg/mL and these estradiol levels correspond with the early and \nlate phase of a woman’s menstrual cycle.\n\n \n\n\n\n17\n\nSpecial populations\n\nPaediatric population\nThe pharmacokinetics of nomegestrol acetate (primary objective) after single oral dosing of Zoely in \nhealthy postmenarcheal female adolescents and adult subjects were similar. However, after single oral \ndosing, for the estradiol component (secondary objective), the exposure was 36 % lower in adolescents \nversus adult subjects. The clinical relevance of this result is unknown.\n\nEffect of renal impairment\nNo studies were performed to evaluate the effect of renal disease on the pharmacokinetics of Zoely.\n\nEffect of hepatic impairment\nNo studies were conducted to evaluate the effect of hepatic disease on the pharmacokinetics of Zoely. \nHowever, steroid hormones may be poorly metabolized in women with impaired liver function.\n\nEthnic groups\nNo formal studies were performed to assess pharmacokinetics in ethnic groups.\n\n5.3 Preclinical safety data\n\nRepeat dose toxicity studies with estradiol, nomegestrol acetate or combination have indicated \nexpected oestrogenic and gestagen effects.\nReproductive toxicity studies performed with the combination have shown foetotoxicity which is \nconsistent with estradiol exposure.\nGenotoxicity and carcinogenicity studies were not conducted with the combination. Nomegestrol \nacetate is not genotoxic.\nHowever, it must be borne in mind that sex steroids can promote the growth of certain \nhormone-dependent tissues and tumours.\n\n6. PHARMACEUTICAL PARTICULARS\n\n6.1 List of excipients\n\nTablet core (white active and yellow placebo film-coated tablets)\nLactose monohydrate\nMicrocrystalline cellulose (E460)\nCrospovidone (E1201)\nTalc (E553b)\nMagnesium stearate (E572)\nColloidal anhydrous silica\n\nTablet coat (white active film-coated tablets)\nPoly(vinyl alcohol) (E1203)\nTitanium dioxide (E171)\nMacrogol 3350\nTalc (E553b)\n\nTablet coating (yellow placebo film-coated tablets)\nPoly(vinyl alcohol) (E1203)\nTitanium dioxide (E171)\nMacrogol 3350\nTalc (E553b)\nIron oxide yellow (E172)\nIron oxide black (E172)\n\n \n\n\n\n18\n\n6.2 Incompatibilities\n\nNot applicable.\n\n6.3 Shelf life\n\n3 years\n\n6.4 Special precautions for storage\n\nThis medicinal product does not require any special storage conditions.\n\n6.5 Nature and contents of container\n\nPVC/aluminium blister containing 28 film-coated tablets (24 white film-coated tablets and 4 yellow \nfilm-coated tablets).\nPack sizes: 28, 84, 168 and 364 film-coated tablets.\nNot all pack sizes may be marketed.\n\n6.6 Special precautions for disposal\n\nCOC tablets (including Zoely tablets) no longer required should not be disposed via wastewater or the \nmunicipal sewage system. The hormonal active compounds in the tablet may have harmful effects if \nreaching the aquatic environment. The tablets should be returned to a pharmacy or disposed of in \nanother safe way according to local requirements. These measures will help to protect the \nenvironment.\n\n7. MARKETING AUTHORISATION HOLDER\n\nTheramex Ireland Limited\n3rd Floor, Kilmore House,\nPark Lane, Spencer Dock,\nDublin 1\nD01 YE64\nIreland\n\n8. MARKETING AUTHORISATION NUMBER(S)\n\nEU/1/11/690/001\nEU/1/11/690/002\nEU/1/11/690/003\nEU/1/11/690/004\n\n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION\n\nDate of first authorisation: 27 July 2011\nDate of latest renewal: 21 April 2016\n\n10. DATE OF REVISION OF THE TEXT\n\nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency: http://www.ema.europa.eu.\n\n \n\n\n\n19\n\nANNEX II\n\nA. MANUFACTURERS RESPONSIBLE FOR BATCH \nRELEASE\n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY \nAND USE\n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE \nMARKETING AUTHORISATION\n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO \nTHE SAFE AND EFFECTIVE USE OF THE MEDICINAL \nPRODUCT\n\n \n\n\n\n20\n\nA. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE\n\nName and address of the manufacturers responsible for batch release\n\nDelpharm Lille S.A.S.\nParc d’Activités Roubaix-Est\n22 Rue de Toufflers\nCS 50070\n59452 LYS-LEZ-LANNOY\nFrance\n\nTeva Operations Poland Sp. z o.o.\nul. Mogilska 80\n31-546 Krakow\nPoland\n\nN.V. Organon\nKloosterstraat 6\n5349 AB Oss\nThe Netherlands\n\nMerck Sharp & Dohme B.V.\nWaarderweg 39\n2031 BN Haarlem\nThe Netherlands\n\nThe printed package leaflet of the medicinal product must state the name and address of the \nmanufacturer responsible for the release of the concerned batch.\n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\nMedicinal product subject to medical prescription.\n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \nAUTHORISATION\n\n Periodic safety update reports (PSURs)\n\nThe requirements for submission of PSURs for this medicinal product are set out in the list of Union \nreference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any \nsubsequent updates published on the European medicines web-portal.\n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \nEFFECTIVE USE OF THE MEDICINAL PRODUCT\n\n Risk management plan (RMP)\n\nThe marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities \nand interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation \nand any agreed subsequent updates of the RMP.\n\nAn updated RMP should be submitted:\n At the request of the European Medicines Agency;\n\n \n\n\n\n21\n\n Whenever the risk management system is modified, especially as the result of new information \nbeing received that may lead to a significant change to the benefit/risk profile or as the result of \nan important (pharmacovigilance or risk minimisation) milestone being reached.\n\n Obligation to conduct post-authorisation measures\n\nThe MAH shall complete, within the stated timeframe, the below measures:\n\nDescription Due date\nNon-interventional post-authorisation safety study (PASS):\nA prospective observational study to assess in particular the risk of Venous \nthromboembolic events (VTE) and ATE in nomegestrol/estradiol users compared \nwith the VTE risk in users of combined oral contraceptives containing \nlevonorgestrel.\nSubmission of final study report\n\n30 April 2021\n\n \n\n\n\n22\n\nANNEX III\n\nLABELLING AND PACKAGE LEAFLET\n\n \n\n\n\n23\n\nA. LABELLING\n\n \n\n\n\n24\n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING\n\nCARTON\n\n1. NAME OF THE MEDICINAL PRODUCT\n\nZoely 2.5 mg/1.5 mg film-coated tablets\nnomegestrol acetate/estradiol\n\n2. STATEMENT OF ACTIVE SUBSTANCE(S)\n\nEach white active tablet contains 2.5 mg nomegestrol acetate and 1.5 mg estradiol (as hemihydrate).\n\n3. LIST OF EXCIPIENTS\n\nContains lactose monohydrate\n\nSee leaflet for further information.\n\n4. PHARMACEUTICAL FORM AND CONTENTS\n\n28 film-coated tablets\n84 film-coated tablets\n168 film-coated tablets\n364 film-coated tablets\n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION\n\nRead the package leaflet before use.\nOral use\n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \nOF THE SIGHT AND REACH OF CHILDREN\n\nKeep out of the sight and reach of children.\n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY\n\n8. EXPIRY DATE\n\nEXP\n\n9. SPECIAL STORAGE CONDITIONS\n\n \n\n\n\n25\n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE\n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER\n\nTheramex Ireland Limited\n3rd Floor, Kilmore House,\nPark Lane, Spencer Dock,\nDublin 1\nD01 YE64\nIreland\n\n12. MARKETING AUTHORISATION NUMBER(S)\n\nEU/1/11/690/001 28 film-coated tablets\nEU/1/11/690/002 84 film-coated tablets\nEU/1/11/690/003 168 film-coated tablets\nEU/1/11/690/004 364 film-coated tablets\n\n13. BATCH NUMBER\n\nLot\n\n14. GENERAL CLASSIFICATION FOR SUPPLY\n\n15. INSTRUCTIONS ON USE\n\n16. INFORMATION IN BRAILLE\n\nzoely\n\n17. UNIQUE IDENTIFIER – 2D BARCODE\n\n2D barcode carrying the unique identifier included.\n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA\n\nPC\nSN\nNN\n\n \n\n\n\n26\n\nMINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS\n\nBLISTER\n\n1. NAME OF THE MEDICINAL PRODUCT\n\nZoely 2.5 mg/1.5 mg tablets\nnomegestrol acetate/estradiol\n\n2. NAME OF THE MARKETING AUTHORISATION HOLDER\n\nTheramex Ireland Limited\n\n3. EXPIRY DATE\n\nEXP\n\n4. BATCH NUMBER\n\nLot\n\n5. OTHER\n\n[Box for placing day label stating:] Place day label here\n[Day numbering for each individual tablet:] Start,2, ….28\n[Arrows indicating the sequence of the tablets:] \n\n \n\n\n\n27\n\nDAY LABEL SHEET INCLUDING STICKERS PROVIDED WITH THE LEAFLET\n\nDay label sheet\nChoose the day label that begins with your starting day.\nPlace the label on the blister over the words ‘Place day label here’.\n\nSUN MON TUE WED THU FRI SAT\nMON TUE WED THU FRI SAT SUN\nTUE WED THU FRI SAT SUN MON\nWED THU FRI SAT SUN MON TUE\nTHU FRI SAT SUN MON TUE WED\nFRI SAT SUN MON TUE WED THU\nSAT SUN MON TUE WED THU FRI\n\n[Second day label sheet for box of 3 blisters stating, twice:]\n\nSUN MON TUE WED THU FRI SAT\nMON TUE WED THU FRI SAT SUN\nTUE WED THU FRI SAT SUN MON\nWED THU FRI SAT SUN MON TUE\nTHU FRI SAT SUN MON TUE WED\nFRI SAT SUN MON TUE WED THU\nSAT SUN MON TUE WED THU FRI\n\n[In front of day labels intended for second blister:] Blister 2\n[In front of day labels intended for third blister:] Blister 3\n\n \n\n\n\n28\n\nB. PACKAGE LEAFLET\n\n \n\n\n\n29\n\nPackage leaflet: Information for the user\n\nZoely 2.5 mg/1.5 mg film-coated tablets\nnomegestrol acetate/estradiol\n\nThis medicine is subject to additional monitoring. This will allow quick identification of new \nsafety information. You can help by reporting any side effects you may get. See the end of section 4 \nfor how to report side effects.\n\nImportant things to know about combined hormonal contraceptives (CHCs):\n They are one of the most reliable reversible methods of contraception if used correctly.\n They slightly increase the risk of having a blood clot in the veins and arteries, especially in the \n\nfirst year or when restarting a combined hormonal contraceptive following a break of 4 or more \nweeks.\n\n Please be alert and see your doctor if you think you may have symptoms of a blood clot (see \nsection 2 “Blood clots”).\n\nRead all of this leaflet carefully before you start using this medicine because it contains \nimportant information for you.\n- Keep this leaflet. You may need to read it again.\n- If you have any further questions, ask your doctor, pharmacist or nurse.\n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them.\n- If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible \n\nside effects not listed in this leaflet. See section 4.\n\nWhat is in this leaflet\n\n1. What Zoely is and what it is used for\n2. What you need to know before you use Zoely\n3. How to use Zoely\n4. Possible side effects\n5. How to store Zoely\n6. Contents of the pack and other information\n\n1. What Zoely is and what it is used for\n\nZoely is a contraceptive pill that is used to prevent pregnancy.\n\n All 24 white film-coated tablets are active tablets that contain a small amount of two different \nfemale hormones. These are nomegestrol acetate (a progestogen) and estradiol (an oestrogen).\n\n The 4 yellow tablets are inactive tablets that do not contain hormones and are called placebo \ntablets.\n\n Contraceptive pills that contain two different hormones, like Zoely, are called ‘combined pills’.\n Estradiol, the oestrogen in Zoely, is identical to the hormone produced by your ovaries during a \n\nmenstrual cycle.\n Nomegestrol acetate, the progestogen in Zoely, is derived from the hormone progesterone. \n\nProgesterone is produced by your ovaries during a menstrual cycle.\n\n2. What you need to know before you use Zoely\n\nGeneral notes\n\nBefore you start using Zoely you should read the information on blood clots (thrombosis) in section 2.\nIt is particularly important to read the symptoms of a blood clot – see section 2 “Blood clots”.\n\n \n\n\n\n30\n\nBefore you can begin taking Zoely, your doctor will ask you some questions about your personal \nhealth history and that of your close relatives. The doctor will also measure your blood pressure and, \ndepending upon your personal situation, may also carry out some other tests.\n\nIn this leaflet, several situations are described where you should stop taking the pill, or where the \nreliability of the pill may be decreased. In such situations you should not have sexual intercourse or \nyou should take extra non-hormonal contraceptive precautions, e.g., use a condom or another barrier \nmethod. Do not use rhythm or temperature methods. These methods can be unreliable because the pill \nalters the usual changes in temperature and cervical mucus that occur during the menstrual cycle.\n\nZoely, like other hormonal contraceptives, does not protect against HIV infection (AIDS) or any \nother sexually transmitted disease.\n\nDo not use Zoely\nYou must not use Zoely if you have any of the conditions listed below. If you do have any of the \nconditions listed below, you must tell your doctor. Your doctor will discuss with you what other form \nof birth control would be more appropriate.\n\n if you have (or have ever had) a blood clot in a blood vessel of your legs (deep vein thrombosis,\nDVT), your lungs (pulmonary embolus, PE) or other organs;\n\n if you know you have a disorder affecting your blood clotting - for instance, protein C \ndeficiency, protein S deficiency, antithrombin – III deficiency, Factor V Leiden or \nantiphospholipid antibodies;\n\n if you need an operation or if you are off your feet for a long time (see section ‘Blood clots);\n if you have ever had a heart attack or a stroke;\n if you have (or have ever had) angina pectoris (a condition that causes severe chest pain and\n\nmay be a first sign of a heart attack) or transient ischaemic attack (TIA – temporary stroke\nsymptoms);\n\n if you have any of the following diseases that may increase your risk of a clot in the arteries:\n– severe diabetes with blood vessel damage\n– very high blood pressure\n– a very high level of fat in the blood (cholesterol or triglycerides);\n– a condition known as hyperhomocysteinaemia\n\n if you have (or have ever had) a type of migraine called ‘migraine with aura’;\n if you have (had) inflammation of the pancreas (pancreatitis) associated with high levels of fat \n\nin your blood;\n if you have (had) severe liver disease and your liver is not yet working normally;\n if you have (had) a benign or malignant tumour in the liver;\n if you have (had), or if you may have, cancer of the breast or the genital organs;\n in case of presence or history of meningioma (generally benign tumour of the tissue located \n\nbetween the brain and the skull). In case of doubt, contact your doctor.\n if you have any unexplained bleeding from the vagina;\n if you are allergic to estradiol or nomegestrol acetate, or any of the other ingredients of this \n\nmedicine (listed in section 6).\n\nIf any of these conditions appear for the first time while using Zoely, stop taking it at once and tell \nyour doctor. In the meantime, use a non-hormonal contraceptive. See also ‘General Notes’ in section 2 \nabove.\n\n \n\n\n\n31\n\nWhen to take special care with Zoely\n\nWhen should you contact your doctor?\n\nSeek urgent medical attention\n\n if you notice possible signs of a blood clot that may mean you are suffering from a blood clot in \nthe leg (i.e., deep vein thrombosis), a blood clot in the lung (i.e., pulmonary embolism), a heart \nattack or a stroke (see “Blood clots” section below).\n\nFor a description of the symptoms of these serious side effects please go to “How to recognise a blood \nclot”.\n if you notice any changes in your own health, especially involving any of the items mentioned \n\nin this leaflet (see also in section 2 ‘Do not use Zoely’; do not forget about the changes in the \nhealth of your immediate family);\n\n if you feel a lump in your breast;\n if you experience symptoms of angioedema such as swollen face, tongue and/or throat and/or \n\ndifficulty swallowing or hives together with difficulty breathing;\n if you are going to use other medicines (see also in section 2 ‘Other medicines and Zoely’);\n if you are to be immobilised or are to have surgery (tell your doctor at least four weeks in \n\nadvance);\n if you have unusual, heavy vaginal bleeding;\n if you forgot one or more tablets in the first week of the blister pack and had unprotected \n\nintercourse in the seven days before (see also in section 3 ‘If you forget to take Zoely’);\n if you have severe diarrhoea or experience severe vomiting;\n if you miss periods and suspect you may be pregnant (do not start the next blister pack until \n\nyour doctor tells you, see also in section 3 ‘If you have missed one or more periods’).\n\nTell your doctor if any of the following conditions apply to you.\nIf the condition develops, or gets worse while you are using Zoely, you should also tell your doctor.\n if you have hereditary angioedema. Consult your doctor immediately if you experience \n\nsymptoms of angioedema such as swollen face, tongue and/or throat and/or difficulty \nswallowing or hives, together with difficulty breathing. Products containing oestrogens may \ninduce or worsen symptoms of angioedema;\n\n if a close relative has or has ever had breast cancer;\n if you have epilepsy (see in section 2 ‘Other medicines and Zoely’);\n if you have liver disease (for instance jaundice) or gallbladder disease (for instance gallstones);\n if you have diabetes;\n if you have depression;\n if you have Crohn’s disease or ulcerative colitis (chronic inflammatory bowel disease);\n if you have systemic lupus erythematosus (SLE - a disease affecting your natural defence \n\nsystem);\n if you have haemolytic uraemic syndrome (HUS - a disorder of blood clotting causing failure of \n\nthe kidneys);\n if you have sickle cell anaemia (an inherited disease of the red blood cells);\n if you have elevated levels of fat in the blood (hypertriglyceridaemia) or a positive family \n\nhistory for this condition. Hypertriglyceridaemia has been associated with an increased risk of \ndeveloping pancreatitis (inflammation of the pancreas);\n\n if you need an operation or if you are off your feet for a long time (see in section 2 ‘Blood\nclots).\n\n if you have just given birth you are at an increased risk of blood clots. You should ask your \ndoctor how soon after delivery you can start taking Zoely.\n\n if you have an inflammation in the veins under the skin (superficial thrombophlebitis);\n if you have varicose veins.\n if you have a condition that occurred for the first time or worsened during pregnancy or\n\nprevious use of sex hormones (e.g. hearing loss, porphyria [a disease of the blood], herpes \n\n \n\n\n\n32\n\ngestationis [skin rash with vesicles during pregnancy], Sydenham’s chorea [a disease of the \nnerves in which sudden movements of the body occur] (see in section 2 ‘When should you \ncontact your doctor’);\n\n if you have (or have ever had) chloasma [yellowish-brown pigment patches, so called \n‘pregnancy patches’, particularly on the face]. If so, avoid too much exposure to the sun or \nultraviolet light;\n\nBLOOD CLOTS\n\nUsing a combined hormonal contraceptive such as Zoely increases your risk of developing a blood \nclot compared with not using one. In rare cases a blood clot can block blood vessels and cause serious \nproblems.\n\nBlood clots can develop\n in veins (referred to as ‘venous thrombosis’, ‘venous thromboembolism’ or VTE)\n in the arteries (referred to as an ‘arterial thrombosis’, ‘arterial thromboembolism’ or ATE).\nRecovery from blood clots is not always complete. Rarely, there may be serious lasting effects or, very \nrarely, they may be fatal.\n\nIt is important to remember that the overall risk of a harmful blood clot due to Zoely is small.\n\nHOW TO RECOGNISE A BLOOD CLOT\n\nSeek urgent medical attention if you notice any of the following signs or symptoms.\n\nAre you experiencing any of these signs? What are you possibly \nsuffering from?\n\n swelling of one leg or along a vein in the leg or foot especially when \naccompanied by:\n\n pain or tenderness in the leg which may be felt only when \nstanding or walking\n\n increased warmth in the affected leg\n change in colour of the skin on the leg e.g. turning pale, red or \n\nblue\n\nDeep vein thrombosis\n\n sudden unexplained breathlessness or rapid breathing;\n sudden cough without an obvious cause, which may bring up blood;\n sharp chest pain which may increase with deep breathing;\n severe light headedness or dizziness;\n rapid or irregular heartbeat;\n severe pain in your stomach;\n\nIf you are unsure, talk to a doctor as some of these symptoms such as \ncoughing or being short of breath may be mistaken for a milder condition \nsuch as a respiratory tract infection (e.g., a ‘common cold’).\n\nPulmonary embolism\n\nSymptoms most commonly occur in one eye:\n immediate loss of vision or\n painless blurring of vision which can progress to loss of vision\n\nRetinal vein thrombosis\n(blood clot in the eye)\n\n \n\n\n\n33\n\n chest pain, discomfort, pressure, heaviness\n sensation of squeezing or fullness in the chest, arm or below the \n\nbreastbone;\n fullness, indigestion or choking feeling;\n upper body discomfort radiating to the back, jaw, throat, arm and \n\nstomach;\n sweating, nausea, vomiting or dizziness;\n extreme weakness, anxiety, or shortness of breath;\n rapid or irregular heartbeats\n\nHeart attack\n\n sudden weakness or numbness of the face, arm or leg, especially on \none side of the body;\n\n sudden confusion, trouble speaking or understanding;\n sudden trouble seeing in one or both eyes;\n sudden trouble walking, dizziness, loss of balance or coordination;\n sudden, severe or prolonged headache with no known cause;\n loss of consciousness or fainting with or without seizure.\n\nSometimes the symptoms of stroke can be brief with an almost immediate \nand full recovery, but you should still seek urgent medical attention as you \nmay be at risk of another stroke.\n\nStroke\n\n swelling and slight blue discolouration of an extremity;\n severe pain in your stomach (acute abdomen).\n\nBlood clots blocking \nother blood vessels\n\nBLOOD CLOTS IN A VEIN\n\nWhat can happen if a blood clot forms in a vein?\n The use of combined hormonal contraceptives has been connected with an increase in the risk of \n\nblood clots in the vein (venous thrombosis). However, these side effects are rare. Most \nfrequently, they occur in the first year of use of a combined hormonal contraceptive.\n\n If a blood clot forms in a vein in the leg or foot it can cause a deep vein thrombosis (DVT).\n If a blood clot travels from the leg and lodges in the lung it can cause a pulmonary embolism.\n Very rarely a clot may form in a vein in another organ such as the eye (retinal vein thrombosis).\n\nWhen is the risk of developing a blood clot in a vein highest?\nThe risk of developing a blood clot in a vein is highest during the first year of taking a combined \nhormonal contraceptive for the first time. The risk may also be higher if you restart taking a combined \nhormonal contraceptive (the same product or a different product) after a break of 4 weeks or more.\n\nAfter the first year, the risk gets smaller but is always slightly higher than if you were not using a \ncombined hormonal contraceptive.\n\nWhen you stop Zoely your risk of a blood clot returns to normal within a few weeks.\n\nWhat is the risk of developing a blood clot?\nThe risk depends on your natural risk of VTE and the type of combined hormonal contraceptive you \nare taking.\n\nThe overall risk of a blood clot in the leg or lung (DVT or PE) with Zoely is small.\n Out of 10,000 women who are not using any combined hormonal contraceptive and are not \n\npregnant, about 2 will develop a blood clot in a year.\n Out of 10,000 women who are using a combined hormonal contraceptive that contains \n\nlevonorgestrel, norethisterone, or norgestimate, about 5-7 will develop a blood clot in a year.\n\n \n\n\n\n34\n\n It is not yet known how the risk of a blood clot with Zoely compares to the risk with a combined \nhormonal contraceptive that contains levonorgestrel.\n\n The risk of having a blood clot will vary according to your personal medical history (see \n“Factors that increase your risk of a blood clot” below).\n\nRisk of developing a blood clot \nin a year\n\nWomen who are not using a combined hormonal pill and are not \npregnant\n\nAbout 2 out of 10,000 women\n\nWomen using a combined hormonal contraceptive pill containing \nlevonorgestrel, norethisterone or norgestimate\n\nAbout 5-7 out of 10,000 women\n\nWomen using Zoely Not yet known\n\nFactors that increase your risk of a blood clot in a vein\nThe risk of a blood clot with Zoely is small but some conditions will increase the risk. Your risk is \nhigher:\n if you are very overweight (body mass index or BMI over 30 kg/m2);\n if one of your immediate family has had a blood clot in the leg, lung or other organ at a young \n\nage (e.g., below the age of about 50). In this case you could have a hereditary blood clotting \ndisorder;\n\n if you need to have an operation, or if you are off your feet for a long time because of an injury \nor illness, or you have your leg in a cast. The use of Zoely may need to be stopped several \nweeks before surgery or while you are less mobile. If you need to stop Zoely ask your doctor \nwhen you can start using it again.\n\n as you get older (particularly above about 35 years);\n if you gave birth less than a few weeks ago\n\nThe risk of developing a blood clot increases the more conditions you have.\nAir travel (> 4 hours) may temporarily increase your risk of a blood clot, particularly if you have some \nof the other factors listed.\nIt is important to tell your doctor if any of these conditions apply to you, even if you are unsure. Your \ndoctor may decide that Zoely needs to be stopped.\nIf any of the above conditions change while you are using Zoely, for example a close family member \nexperiences a thrombosis for no known reason or you gain a lot of weight, tell your doctor.\n\nBLOOD CLOTS IN AN ARTERY\n\nWhat can happen if a blood clot forms in an artery?\nLike a blood clot in a vein, a clot in an artery can cause serious problems. For example, it can cause a \nheart attack or a stroke.\n\nFactors that increase your risk of a blood clot in an artery\n\nIt is important to note that the risk of a heart attack or stroke from using Zoely is very small but can \nincrease:\n\n with increasing age (beyond about 35 years);\n if you smoke. When using a combined hormonal contraceptive like Zoely you are advised to \n\nstop smoking. If you are unable to stop smoking and are older than 35 your doctor may advise \nyou to use a different type of contraceptive;\n\n if you are overweight;\n if you have high blood pressure;\n if a member of your immediate family has had a heart attack or stroke at a young age (less than \n\nabout 50). In this case you could also have a higher risk of having a heart attack or stroke;\n\n \n\n\n\n35\n\n if you, or someone in your immediate family, have a high level of fat in the blood (cholesterol\nor triglycerides);\n\n if you get migraines, especially migraines with aura;\n if you have a problem with your heart (valve disorder, disturbance of the rhythm called atrial\n\nfibrillation)\n if you have diabetes.\n\nIf you have more than one of these conditions or if any of them are particularly severe, the risk of \ndeveloping a blood clot may be increased even more.\nIf any of the above conditions change while you are using Zoely, for example, you start smoking, a \nclose family member experiences a thrombosis for no known reason or you gain a lot of weight, tell \nyour doctor.\n\nCancer\nBreast cancer has been found slightly more often in women using combined pills, but it is not known \nwhether this is caused by the combined pills. For example, it may be that tumours are found more in \nwomen on combined pills because they are examined by the doctor more often. After stopping the \ncombined pill, the increased risk gradually reduces.\nIt is important to check your breasts regularly and you should contact your doctor if you feel any \nlump. You should also tell your doctor if a close relative has, or ever had breast cancer (see section 2\n“When to take special care with Zoely”).\n\nIn rare cases, benign (noncancerous) liver tumours, and in even fewer cases malignant (cancerous) \nliver tumours have been reported in pill users. Contact your doctor if you have unusual severe \nabdominal pain.\n\nCervical cancer is caused by an infection with the human papilloma virus (HPV). It has been reported \nto occur more often in women using the pill for more than 5 years. It is unknown if this finding is due \nto the use of hormonal contraceptives or to other factors, such as difference in sexual behaviour.\n\nMeningiomas\nCases of meningioma (generally benign tumours of the brain) have been reported with prolonged use \n(several years) of nomegestrol monotherapy (without estradiol) at higher doses of 3.75 and 5 mg and\nmore (see section ‘Do not use Zoely’). If a meningioma is diagnosed, treatment with Zoely should be \nstopped.\n\nPsychiatric disorders\nSome women using hormonal contraceptives including Zoely have reported depression or depressed \nmood. Depression can be serious and may sometimes lead to suicidal thoughts. If you experience \nmood changes and depressive symptoms contact your doctor for further medical advice as soon as \npossible.\n\nLaboratory tests\nIf you are having any blood or urinary test, tell your doctor that you are using Zoely as it may affect \nthe results of some tests.\n\nChildren and adolescents\nNo data on efficacy and safety are available in adolescents below 18 years.\n\nOther medicines and Zoely\nTell your doctor or pharmacist if you are taking, have recently taken or might take any other \nmedicines, including medicines obtained without a prescription and herbal medicines.\nAlso tell any other doctor or dentist who prescribes another medicine (or the dispensing pharmacist) \nthat you use Zoely.\n There are medicines that can make Zoely less effective in preventing pregnancy, or can cause \n\nunexpected bleeding. These include medicines used to treat:\n\n \n\n\n\n36\n\n– epilepsy (e.g. primidone, phenytoin, phenobarbital, carbamazepine, oxcarbazepine, \ntopiramate, felbamate);\n\n– tuberculosis (e.g. rifampicin);\n– HIV infections (e.g. rifabutin, ritonavir, efavirenz);\n– Hepatitis C virus (HCV) infection (e.g. boceprevir, telaprevir);\n– other infectious diseases (e.g. griseofulvin);\n– high blood pressure in the blood vessels in the lungs (bosentan).\n\n The herbal product St. John’s wort may also stop Zoely from working properly. If you want to \nuse herbal products containing St. John’s wort while you are already using Zoely you should \nconsult your doctor first.\n\n If you are taking medicines or herbal products that might make Zoely less effective, a barrier \ncontraceptive method should also be used. Since the effect of another medicine on Zoely may \nlast up to 28 days after stopping the medicine, it is necessary to use the additional barrier \ncontraceptive method for that long.\n\n Some medicines can increase the levels of the active substances of Zoely in the blood. The \neffectiveness of the pill is maintained, but tell your doctor if you are using anti-fungal medicines \ncontaining ketoconazole.\n\n Zoely may also interfere with the working of other medicines – such as the anti-epileptic \nlamotrigine.\n\n The Hepatitis C virus (HCV) combination drug regimen ombitasvir/paritaprevir/ritonavir with or\nwithout dasabuvir may cause increases in liver function blood test results (increase in ALT liver \nenzyme) in women using CHCs containing ethinylestradiol. Zoely contains estradiol instead of \nethinylestradiol. It is not known whether an increase in ALT liver enzyme can occur when using \nZoely with this HCV combination drug regimen. Your doctor will advise you.\n\nPregnancy and breast-feeding\nZoely must not be used by women who are pregnant, or who think they may be pregnant. If you get \npregnant while using Zoely you should stop using Zoely and contact your doctor.\nIf you want to stop Zoely because you want to get pregnant, see in section 3 ‘If you stop taking Zoely’.\n\nZoely is not usually recommended for use during breast-feeding. If you wish to use the pill while \nbreast-feeding, please seek the advice of your doctor.\n\nAsk your doctor or pharmacist for advice before taking any medicine.\n\nDriving and using machines\nZoely has no or negligible effect on your ability to drive and use machines.\n\nZoely contains lactose\nZoely contains lactose. If you have been told by your doctor that you have an intolerance to some \nsugars, contact your doctor before taking this medicine.\n\n3. How to use Zoely\n\nWhen and how to take the tablets\nThe Zoely blister contains 28 tablets: 24 white tablets with the active substances (number 1-24) and \n4 yellow tablets without active substances (number 25-28).\n\nEach time you start a new blister of Zoely, take the number 1 white active tablet in the left-hand top \ncorner (see ‘Start’). Choose from the 7 stickers with day indicators the one in the grey column that \nbegins with your starting day. For example, if you start on a Wednesday, use the day label sticker that \nstarts with ‘WED’. Stick it on the blister, just above the row of white active tablets where it reads \n‘Place day label here’. This allows you to check whether you took your daily tablet.\nTake one tablet each day at about the same time, with some water if necessary.\nFollow the direction of the arrows on the blister, so use the white active tablets first and then the \nyellow placebo tablets.\n\n \n\n\n\n37\n\nYour period will start during the 4 days that you use the yellow placebo tablets (so-called withdrawal \nbleeding). Usually it will start 2-3 days after the last white active tablet and may not have finished \nbefore the next blister is started.\nStart taking your next blister immediately after the last yellow tablet, even if your period hasn’t \nfinished. This means that you will always start a new blister on the same day of the week, and also that \nyou have your period on roughly the same days each month.\nSome users may not have their period every month during the intake of the yellow tablets. If you have \ntaken Zoely every day according to these directions, it is unlikely that you are pregnant (see also \nsection 3 ‘If you have missed one or more periods’).\n\nStarting your first pack of Zoely\n\nWhen no hormonal contraceptive has been used in the past month\nStart taking Zoely on the first day of your cycle (i.e. the first day of your menstrual bleeding). Zoely \nwill work immediately. You do not need to use an additional contraceptive method.\n\nWhen changing from another combined hormonal contraceptive (combined pill, vaginal ring, or \ntransdermal patch)\nYou can start taking Zoely the day after you have taken the last tablet from your present pill blister \n(this means no tablet-free break). If your present pill blister also contains inactive (placebo) tablets you \ncan start Zoely on the day after taking the last active tablet (if you are not sure which this is, ask your \ndoctor or pharmacist). You can also start later, but never later than the day following the tablet-free \nbreak of your present pill (or the day after the last inactive tablet of your present pill). In case you use \na vaginal ring or transdermal patch, it is best to start using Zoely on the day you remove the ring or \npatch. You can also start, at the latest, on the day you would have started using the next ring or patch.\nIf you follow these instructions, it is not necessary to use an additional contraceptive method.\n\nWhen changing from a progestogen-only pill (minipill)\nYou can stop taking the minipill any day and start taking Zoely the next day. But if you are having \nintercourse, make sure you also use a barrier method of contraception for the first 7 days that you are \ntaking Zoely.\n\nWhen changing from a progestogen-only injectable, implant or a hormone-medicated intrauterine \nsystem (IUS)\nStart using Zoely when your next injection is due or on the day that your implant or IUS is removed. \nBut if you are having intercourse, make sure you also use a barrier method of contraception for the \nfirst 7 days that you are taking Zoely.\n\nAfter having a baby\nYou can start Zoely between 21 and 28 days after having a baby. If you start later than day 28, you \nshould also use a barrier method of contraception during the first 7 days of Zoely use. If, after having a \nbaby, you have had sexual intercourse before starting Zoely, be sure that you are not pregnant or wait \nuntil the next menstrual period. If you want to start Zoely after having a baby and are breast-feeding, \nsee also section 2 ‘Pregnancy and Breast-feeding’.\nAsk your doctor what to do if you are not sure when to start.\n\nAfter a miscarriage or an abortion\nFollow the advice of your doctor.\n\nIf you take more Zoely than you should\nThere have been no reports of serious harmful effects from taking too many Zoely tablets at one time. \nIf you have taken several tablets at a time, you may have nausea, vomiting or vaginal bleeding. If you \ndiscover that a child has taken Zoely, ask your doctor for advice.\n\n \n\n\n\n38\n\nIf you forget to take Zoely\n\nThe following advice only refers to missed white active tablets.\n if you are less than 24 hours late in taking a tablet, the reliability of the pill is maintained. Take \n\nthe tablet as soon as you remember and take the next tablets at the usual time.\n if you are 24 or more hours late in taking any tablet, the reliability of the pill may be reduced. \n\nThe more consecutive tablets you have missed, the higher the risk that the contraceptive \nefficacy is decreased. There is a particularly high risk of becoming pregnant if you miss white\nactive tablets at the beginning or at the end of the blister. Therefore you should follow the rules \ngiven below.\n\nDay 1-7 of white active tablet intake (see picture and schedule)\nTake the last white active missed tablet as soon as you remember (even if this means taking two \ntablets at the same time) and take the next tablet at the usual time. However, use a barrier method such \nas a condom as an extra precaution until you have taken your tablets correctly for 7 days in a row.\nIf you had sexual intercourse in the week before missing the tablets, there is a possibility of becoming \nor being pregnant. So contact your doctor immediately.\n\nDay 8-17 of white active tablet intake (see picture and schedule)\nTake the last missed tablet as soon as you remember (even if this means taking two tablets at the same \ntime) and take the next tablets at the usual time. If you have taken your tablets correctly in the 7 days \nprior to the missed tablet, the protection against pregnancy is not reduced, and you do not need to use \nextra precautions. However, if you have missed more than 1 tablet, use a barrier method such as a \ncondom as an extra precaution until you have taken your tablets correctly for 7 days in a row.\n\nDay 18-24 of white active tablet intake (see picture and schedule)\nThere is a particularly high risk of becoming pregnant if you miss white active tablets close to the \nyellow placebo tablet interval. By adjusting your intake schedule this higher risk can be prevented.\n\nThe following two options can be followed. You do not need to use extra precautions if you have \ntaken your tablets correctly in the 7 days prior to the missed tablet. If this is not the case, you should \nfollow the first of these two options and use a barrier method such as a condom as an extra precaution \nuntil you have taken your tablets correctly for 7 days in a row.\nOption 1)\nTake the last missed white active tablet as soon as you remember (even if this means taking two \ntablets at the same time) and take the next tablets at the usual time. Start the next blister as soon as the \nwhite active tablets in the current blister are finished, so skip the yellow placebo tablets. You may \nnot have your period until you take the yellow placebo tablets at the end of the second blister, but you \nmay have spotting (drops or flecks of blood) or breakthrough bleeding while taking the white active \ntablets.\nOption 2)\nStop taking the white active tablets and start taking the yellow placebo tablets for a maximum of 3 \ndays so that the total number of placebo plus missed white active tablets is not more than 4. At the end \nof the placebo tablet interval, start the next blister.\n\nIf you cannot remember how many white active tablets you have missed, follow the first option, use a \nbarrier method such as a condom as an extra precaution until you have taken your tablets correctly for \n7 days in a row, and contact your doctor (as you may not have been protected from being pregnant).\nIf you have forgotten to take white active tablets in a blister, and you do not have the expected \nmonthly period while taking the yellow placebo tablets from the same blister, you may be pregnant. \nConsult your doctor before you start with the next blister.\n\nYellow placebo tablets missed\nThe last 4 yellow tablets of the fourth row are placebo tablets which do not contain active substances. \nIf you forgot to take one of these tablets the reliability of Zoely is maintained. Throw away the yellow \nplacebo tablet(s) you missed and continue taking the next tablets at the usual time.\n\n \n\n\n\n39\n\nPicture\n\nSchedule: if you are 24 or more hours late taking white tablets\n\nIf you vomit or have severe diarrhoea\nIf you vomit within 3-4 hours of taking a white active tablet, or you have severe diarrhoea, the active \ningredients of your Zoely tablet may not have been completely absorbed into your body. The situation \nis similar to if you forget a white active tablet. After vomiting or diarrhoea, you must take another \nwhite active tablet from a reserve blister as soon as possible. If possible take it within 24 hours of \nwhen you normally take your pill. Take the next tablet at the usual time. If this is not possible or 24 or \nmore hours have passed, you should follow the advice given under \"If you forget to take Zoely\". If \nyou have severe diarrhoea, please tell your doctor.\nThe yellow tablets are placebo tablets which do not contain active substances. If you vomit or have \nsevere diarrhoea within 3-4 hours of taking a yellow tablet, the reliability of Zoely is maintained.\n\nIf you want to delay your period\nYou can delay your period by not taking the yellow placebo tablets and going straight to a new blister \nof Zoely. You may experience light or menstruation-like bleeding while using this second blister. \nWhen you wish your period to begin during the second blister, stop taking the white active tablets and \nstart taking the yellow placebo tablets. After finishing the 4 yellow placebo tablets from the second \nblister, start with the next (third) blister.\n\n \n\n\n\n40\n\nIf you want to change the starting day of your period\nIf you take the tablets according to the instructions, then your period will begin during the placebo \ndays. If you have to change this day, reduce the number of placebo days – when you take the yellow \nplacebo tablets – (but never increase them – 4 is the maximum). For example, if you start taking the \nplacebo tablets on Friday, and you want to change this to a Tuesday (3 days earlier) you must start a \nnew blister 3 days earlier than usual. You may not have any bleeding during the shortened period of \nyellow placebo tablet intake. While using the next blister you may have some spotting (drops or flecks \nof blood) or breakthrough bleeding on white active tablet-taking days.\nIf you are not sure what to do, consult your doctor.\n\nIf you have unexpected bleeding\nWith all combined pills, for the first few months, you can have some irregular vaginal bleeding \n(spotting or breakthrough bleeding) between your periods. You may need to use sanitary protection, \nbut keep taking your tablets as usual. Irregular vaginal bleeding usually stops once your body has \nadjusted to the pill (usually after about 3 months). If bleeding continues, becomes heavy or starts \nagain, contact your doctor.\n\nIf you have missed one or more periods\nClinical trials with Zoely have shown that you may occasionally miss your regular monthly period \nafter Day 24.\n If you have taken all the tablets correctly, and you have not vomited or had severe diarrhoea, or \n\nused other medicines, then it is very unlikely that you are pregnant. Keep taking Zoely as usual. \nSee also in section 3 ‘If you vomit or have severe diarrhoea’ or in section 2 ‘Other medicines \nand Zoely’.\n\n If you have not taken all the tablets correctly, or if your expected period does not happen twice \nin a row, you may be pregnant. Contact your doctor immediately. Do not start the next blister of \nZoely until your doctor has checked that you are not pregnant.\n\nIf you stop taking Zoely\nYou can stop taking Zoely at any time. If you do not want to become pregnant, first ask your doctor \nabout other methods of birth control.\nIf you stop taking Zoely because you want to get pregnant, you are recommended to wait until you \nhave had a natural period before trying to conceive. This will help you to determine when the baby \nwill be due.\n\nIf you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.\n\n4. Possible side effects\n\nLike all medicines, this medicine can cause side effects, although not everybody gets them.\nIf you get any side effect, particularly if severe or persistent, or have any change to your health that \nyou think may be due to Zoely, please talk to your doctor.\n\nAn increased risk of blood clots in your veins (venous thromboembolism (VTE)) or blood clots in \nyour arteries (arterial thromboembolism (ATE)) is present for all women taking combined hormonal \ncontraceptives. For more detailed information on the different risks from taking combined hormonal \ncontraceptives, please see section 2, “What you need to know before you use Zoely”.\nThe following side effects have been linked with the use of Zoely:\n\nVery common (may affect more than 1 in 10 people):\n acne\n changes to menstrual periods (e.g. absence or irregularity)\n\nCommon (may affect up to 1 in 10 people):\n decreased interest in sex; depression/depressed mood; mood changes\n headache or migraine\n\n \n\n\n\n41\n\n feeling sick (nausea)\n heavy menstrual periods; breast pain; pelvic pain\n weight gain\n\nUncommon (may affect up to 1 in 100 people):\n increased appetite; fluid retention (oedema)\n hot flush\n swollen abdomen\n increased sweating; hair loss; itching; dry skin; oily skin\n heaviness in limbs\n regular but scanty periods; larger breasts; breast lump; milk production while not pregnant; \n\npremenstrual syndrome; pain during intercourse; dryness in the vagina or vulva; spasm of the \nuterus\n\n irritability\n increased liver enzymes\n\nRare (may affect up to 1 in 1,000 people):\n harmful blood clots in a vein or artery, for example:\n\no in a leg or foot (i.e., DVT)\no in a lung (i.e., PE)\no heart attack\no stroke\no mini-stroke or temporary stroke-like symptoms known as a transient ischaemic attack \n\n(TIA)\no blood clots in the liver, stomach/intestine, kidneys or eye.\n\nThe chance of having a blood clot may be higher if you have any other conditions that increase this \nrisk. (See section 2 for more information on the conditions that increase risk for blood clots and the \nsymptoms of a blood clot.)\n decreased appetite\n increased interest in sex\n disturbance in attention\n dry eye; contact lens intolerance\n dry mouth\n golden brown pigment patches, mostly in the face; excessive hair growth\n vaginal smell; discomfort in the vagina or vulva\n hunger\n disease of the gallbladder\n\nAllergic (hypersensitive) reactions have been reported in users of Zoely, but the frequency cannot be \nestimated from the available data.\n\nFurther information on the possible side effect changes to menstrual periods (e.g. absence or irregular) \nduring the use of Zoely is described in section 3 ‘When and how to take the tablets’, ‘If you have \nunexpected bleeding’ and ‘If you have missed one or more periods’).\n\nReporting of side effects\nIf you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side \neffects not listed in this leaflet.\nYou can also report side effects directly via the national reporting system listed in Appendix V. By \nreporting side effects, you can help provide more information on the safety of this medicine.\n\n5. How to store Zoely\n\nKeep this medicine out of the sight and reach of children.\n\n \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2009/10/WC500004368.pdf\n\n\n42\n\nDo not use this medicine after the expiry date which is stated on the blister and carton after EXP. The \nexpiry date refers to the last day of that month.\n\nThis medicine does not require any special storage conditions.\n\nCombined pills (including Zoely tablets) no longer required should not be disposed via wastewater or \nthe municipal sewage system. The hormonal active ingredients in the tablet may have harmful effects \nif they reach the aquatic environment. Return them to a pharmacy or dispose them in another safe way \naccording to local requirements. These measures will help to protect the environment.\n\n6. Contents of the pack and other information\n\nWhat Zoely contains\n- The active substances are: nomegestrol acetate and estradiol\n\nWhite active film-coated tablets: Each tablet contains 2.5 mg nomegestrol acetate and 1.5 mg \nestradiol (as hemihydrate).\nYellow placebo film-coated tablets: The tablet does not contain active substances.\n\n- The other ingredients are:\nTablet core (white active and yellow placebo film-coated tablets):\nLactose monohydrate (see section 2 ‘Zoely contains lactose’), microcrystalline cellulose (E460), \ncrospovidone (E1201), talc (E553b), magnesium stearate (E572) and colloidal anhydrous silica \nTablet coat (white active film-coated tablets):\nPoly(vinyl alcohol) (E1203), titanium dioxide (E171), macrogol 3350 and talc (E553b)\nTablet coat (yellow placebo film-coated tablets):\nPoly(vinyl alcohol) (E1203), titanium dioxide (E171), macrogol 3350, talc (E553b), iron oxide \nyellow (E172) and iron oxide black (E172)\n\nWhat Zoely looks like and contents of the pack\nThe active film-coated tablets (tablets) are white and round. They are coded ‘ne’ on both sides.\nThe placebo film-coated tablets are yellow and round. They are coded ‘p’ on both sides.\nZoely comes in blisters of 28 film-coated tablets (24 white active film-coated tablets and 4 yellow \nplacebo film-coated tablets) packed in a ply carton. Pack sizes: 28, 84, 168 and 364 film-coated \ntablets.\n\nNot all pack sizes may be marketed.\n\nMarketing Authorisation Holder and Manufacturer\nMarketing Authorisation Holder\nTheramex Ireland Limited\n3rd Floor, Kilmore House,\nPark Lane, Spencer Dock,\nDublin 1\nD01 YE64\nIreland\n\nManufacturer\nDelpharm Lille S.A.S.\nParc d’Activités Roubaix-Est\n22 Rue de Toufflers\nCS 50070\n59452 LYS-LEZ-LANNOY\nFrance\n\nTeva Operations Poland Sp. z o.o.\nul. Mogilska 80\n31-546 Krakow\n\n \n\n\n\n43\n\nPoland\n\nN.V. Organon\nKloosterstraat 6\n5349 AB Oss\nThe Netherlands\n\nMerck Sharp & Dohme B.V.\nWaarderweg 39\n2031 BN Haarlem\nThe Netherlands\n\nThis leaflet was last revised in.\n\nDetailed information on this medicine is available on the European Medicines Agency web site: \nhttp://www.ema.europa.eu.\n\n \n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. PACKAGE LEAFLET"},"Section_1":{"kind":"string","value":"{'Title': '1. what zoely is and what it is used for', 'Section_Content': \"zoely is a contraceptive pill that is used to prevent pregnancy. all 24 white film-coated tablets are active tablets that contain a small amount of two different female hormones. these are nomegestrol acetate (a progestogen) and estradiol (an oestrogen). the 4 yellow tablets are inactive tablets that do not contain hormones and are called placebo tablets. contraceptive pills that contain two different hormones, like zoely, are called 'combined pills'. estradiol, the oestrogen in zoely, is identical to the hormone produced by your ovaries during a menstrual cycle. nomegestrol acetate, the progestogen in zoely, is derived from the hormone progesterone. progesterone is produced by your ovaries during a menstrual cycle.\", 'Entity_Recognition': [{'Text': 'zoely', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 19, 'BeginOffset': 0, 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'Traits': []}, {'Id': 13, 'BeginOffset': 570, 'EndOffset': 589, 'Score': 0.9806028008460999, 'Text': 'nomegestrol acetate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the progestogen in zoely', 'Type': 'TREATMENT', 'BeginOffset': 591, 'EndOffset': 615}, {'Text': 'the hormone progesterone', 'Type': 'TREATMENT', 'BeginOffset': 633, 'EndOffset': 657}, {'Id': 16, 'BeginOffset': 659, 'EndOffset': 671, 'Score': 0.8702578544616699, 'Text': 'progesterone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 692, 'EndOffset': 699, 'Score': 0.6957443952560425, 'Text': 'ovaries', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 18, 'BeginOffset': 709, 'EndOffset': 724, 'Score': 0.4020480513572693, 'Text': 'menstrual cycle', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}]}"},"Section_2":{"kind":"string","value":"{'Title': '2. what you need to know before you use zoely', 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persistent, or have any change to your health that you think may be due to zoely, please talk to your doctor. an increased risk of blood clots in your veins (venous thromboembolism (vte)) or blood clots in your arteries (arterial thromboembolism (ate)) is present for all women taking combined hormonal contraceptives. for more detailed information on the different risks from taking combined hormonal contraceptives, please see section 2, \"what you need to know before you use zoely\". the following side effects have been linked with the use of zoely: very common (may affect more than 1 in 10 people): acne changes to menstrual periods (e.g. absence or irregularity) common (may affect up to 1 in 10 people): decreased interest in sex; depression/depressed mood; mood changes headache or migraine 41 feeling sick (nausea) heavy menstrual periods; breast pain; pelvic pain weight gain uncommon (may affect up to 1 in 100 people): increased appetite; fluid retention (oedema) hot flush swollen abdomen increased sweating; hair loss; itching; dry skin; oily skin heaviness in limbs regular but scanty periods; larger breasts; breast lump; milk production while not pregnant; premenstrual syndrome; pain during intercourse; dryness in the vagina or vulva; spasm of the uterus irritability increased liver enzymes rare (may affect up to 1 in 1,000 people): harmful blood clots in a vein or artery, for example: o in a leg or foot (i.e., dvt) o in a lung (i.e., pe) o heart attack o stroke o mini-stroke or temporary stroke-like symptoms known as a transient ischaemic attack (tia) o blood clots in the liver, stomach/intestine, kidneys or eye. the chance of having a blood clot may be higher if you have any other conditions that increase this risk. (see section 2 for more information on the conditions that increase risk for blood clots and the symptoms of a blood clot.) decreased appetite increased interest in sex disturbance in attention dry eye; contact lens intolerance dry mouth golden brown pigment patches, mostly in the face; excessive hair growth vaginal smell; discomfort in the vagina or vulva hunger disease of the gallbladder allergic (hypersensitive) reactions have been reported in users of zoely, but the frequency cannot be estimated from the available data. further information on the possible side effect changes to menstrual periods (e.g. absence or irregular) during the use of zoely is described in section 3 \\'when and how to take the tablets\\', \\'if you have unexpected bleeding\\' and \\'if you have missed one or more periods\\'). reporting of side effects if you get any side effects talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects, you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'zoely', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 25, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9638739824295044, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6608428359031677}]}, {'Id': 26, 'BeginOffset': 107, 'EndOffset': 118, 'Score': 0.953026533126831, 'Text': 'side effect', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7657597064971924}], 'Attributes': [{'Type': 'ACUITY', 'Score': 0.6739284992218018, 'RelationshipScore': 0.9940265417098999, 'RelationshipType': 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'BeginOffset': 1433, 'EndOffset': 1456}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 1480, 'EndOffset': 1481}, {'Text': '1,000', 'Type': 'NUMBER', 'BeginOffset': 1485, 'EndOffset': 1490}, {'Text': 'harmful blood clots', 'Type': 'PROBLEM', 'BeginOffset': 1500, 'EndOffset': 1519}, {'Id': 14, 'BeginOffset': 1525, 'EndOffset': 1529, 'Score': 0.933472216129303, 'Text': 'vein', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 15, 'BeginOffset': 1533, 'EndOffset': 1539, 'Score': 0.9203516840934753, 'Text': 'artery', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 16, 'BeginOffset': 1561, 'EndOffset': 1564, 'Score': 0.9817546010017395, 'Text': 'leg', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 17, 'BeginOffset': 1568, 'EndOffset': 1572, 'Score': 0.9765470027923584, 'Text': 'foot', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 71, 'BeginOffset': 1580, 'EndOffset': 1583, 'Score': 0.7856085300445557, 'Text': 'dvt', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.5499833822250366}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9817546010017395, 'RelationshipScore': 0.7394967079162598, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 16, 'BeginOffset': 1561, 'EndOffset': 1564, 'Text': 'leg', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9765470027923584, 'RelationshipScore': 0.6195561289787292, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 17, 'BeginOffset': 1568, 'EndOffset': 1572, 'Text': 'foot', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 18, 'BeginOffset': 1592, 'EndOffset': 1596, 'Score': 0.9605830907821655, 'Text': 'lung', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 72, 'BeginOffset': 1604, 'EndOffset': 1606, 'Score': 0.4222763776779175, 'Text': 'pe', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9605830907821655, 'RelationshipScore': 0.4734337627887726, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 18, 'BeginOffset': 1592, 'EndOffset': 1596, 'Text': 'lung', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 73, 'BeginOffset': 1610, 'EndOffset': 1622, 'Score': 0.9432876706123352, 'Text': 'heart attack', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9509862661361694}]}, {'Id': 74, 'BeginOffset': 1625, 'EndOffset': 1631, 'Score': 0.9823057055473328, 'Text': 'stroke', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9628592729568481}]}, {'Id': 75, 'BeginOffset': 1634, 'EndOffset': 1645, 'Score': 0.9543771743774414, 'Text': 'mini-stroke', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8724684715270996}]}, {'Id': 76, 'BeginOffset': 1659, 'EndOffset': 1679, 'Score': 0.7833681106567383, 'Text': 'stroke-like symptoms', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7151503562927246}]}, {'Text': 'a transient ischaemic attack (tia)', 'Type': 'PROBLEM', 'BeginOffset': 1689, 'EndOffset': 1723}, {'Text': 'blood clots in the liver, stomach/intestine, kidneys or eye', 'Type': 'PROBLEM', 'BeginOffset': 1726, 'EndOffset': 1785}, {'Text': 'a blood clot', 'Type': 'PROBLEM', 'BeginOffset': 1808, 'EndOffset': 1820}, {'Text': 'any other conditions', 'Type': 'PROBLEM', 'BeginOffset': 1847, 'EndOffset': 1867}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 1906, 'EndOffset': 1907}, {'Id': 91, 'BeginOffset': 1970, 'EndOffset': 1981, 'Score': 0.9674990773200989, 'Text': 'blood clots', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.4640992283821106}]}, {'Text': 'the symptoms', 'Type': 'PROBLEM', 'BeginOffset': 1986, 'EndOffset': 1998}, {'Text': 'a blood clot', 'Type': 'PROBLEM', 'BeginOffset': 2002, 'EndOffset': 2014}, {'Id': 93, 'BeginOffset': 2017, 'EndOffset': 2035, 'Score': 0.8833324313163757, 'Text': 'decreased appetite', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8968445062637329}]}, {'Id': 94, 'BeginOffset': 2046, 'EndOffset': 2073, 'Score': 0.8733799457550049, 'Text': 'interest in sex disturbance', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6856048703193665}]}, {'Text': 'attention dry eye', 'Type': 'PROBLEM', 'BeginOffset': 2077, 'EndOffset': 2094}, {'Id': 96, 'BeginOffset': 2096, 'EndOffset': 2120, 'Score': 0.7204893231391907, 'Text': 'contact lens intolerance', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8705934286117554}]}, {'Id': 97, 'BeginOffset': 2121, 'EndOffset': 2130, 'Score': 0.36732736229896545, 'Text': 'dry mouth', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7689099311828613}]}, {'Text': 'golden brown pigment patches', 'Type': 'PROBLEM', 'BeginOffset': 2131, 'EndOffset': 2159}, {'Id': 85, 'BeginOffset': 2175, 'EndOffset': 2179, 'Score': 0.9913578033447266, 'Text': 'face', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'excessive hair growth vaginal smell', 'Type': 'PROBLEM', 'BeginOffset': 2181, 'EndOffset': 2216}, {'Text': 'discomfort in the vagina', 'Type': 'PROBLEM', 'BeginOffset': 2218, 'EndOffset': 2242}, {'Text': 'vulva hunger disease', 'Type': 'PROBLEM', 'BeginOffset': 2246, 'EndOffset': 2266}, {'Text': 'the gallbladder allergic (hypersensitive) reactions', 'Type': 'PROBLEM', 'BeginOffset': 2270, 'EndOffset': 2321}, {'Id': 105, 'BeginOffset': 2368, 'EndOffset': 2377, 'Score': 0.3646351099014282, 'Text': 'frequency', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 106, 'BeginOffset': 2459, 'EndOffset': 2478, 'Score': 0.7895448803901672, 'Text': 'side effect changes', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 107, 'BeginOffset': 2482, 'EndOffset': 2499, 'Score': 0.8038774728775024, 'Text': 'menstrual periods', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8744324445724487}]}, {'Text': 'irregular)', 'Type': 'PROBLEM', 'BeginOffset': 2517, 'EndOffset': 2527}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 2576, 'EndOffset': 2577}, {'Text': \"unexpected bleeding'\", 'Type': 'PROBLEM', 'BeginOffset': 2627, 'EndOffset': 2647}, {'Id': 109, 'BeginOffset': 2708, 'EndOffset': 2720, 'Score': 0.9357881546020508, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8145287036895752}]}, {'Id': 110, 'BeginOffset': 2736, 'EndOffset': 2748, 'Score': 0.7736654877662659, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7222959399223328}]}, {'Id': 111, 'BeginOffset': 2818, 'EndOffset': 2830, 'Score': 0.953059732913971, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6494751572608948}]}, {'Id': 112, 'BeginOffset': 2879, 'EndOffset': 2891, 'Score': 0.8601638674736023, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7093625068664551}]}, {'Id': 113, 'BeginOffset': 2945, 'EndOffset': 2956, 'Score': 0.39534085988998413, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.639013946056366}]}, {'Id': 114, 'BeginOffset': 2970, 'EndOffset': 2982, 'Score': 0.9256041646003723, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7618369460105896}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 3039, 'EndOffset': 3052}]}"},"Section_5":{"kind":"string","value":"{'Title': '5. how to store zoely', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister and carton after exp. the expiry date refers to the last day of that month. this medicine does not require any special storage conditions. combined pills (including zoely tablets) no longer required should not be disposed via wastewater or the municipal sewage system. the hormonal active ingredients in the tablet may have harmful effects if they reach the aquatic environment. return them to a pharmacy or dispose them in another safe way according to local requirements. these measures will help to protect the environment.', 'Entity_Recognition': [{'Text': 'zoely', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'combined pills (including zoely tablets', 'Type': 'TREATMENT', 'BeginOffset': 276, 'EndOffset': 315}, {'Text': 'the hormonal active ingredients', 'Type': 'TREATMENT', 'BeginOffset': 406, 'EndOffset': 437}, {'Text': 'these measures', 'Type': 'TREATMENT', 'BeginOffset': 611, 'EndOffset': 625}]}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': \"what zoely contains - the active substances are: nomegestrol acetate and estradiol white active film-coated tablets: each tablet contains 2.5 mg nomegestrol acetate and 1.5 mg estradiol (as hemihydrate). yellow placebo film-coated tablets: the tablet does not contain active substances. - the other ingredients are: tablet core (white active and yellow placebo film-coated tablets): lactose monohydrate (see section 2 'zoely contains lactose'), microcrystalline cellulose (e460), crospovidone (e1201), talc (e553b), magnesium stearate (e572) and colloidal anhydrous silica tablet coat (white active film-coated tablets): poly(vinyl alcohol) (e1203), titanium dioxide (e171), macrogol 3350 and talc (e553b) tablet coat (yellow placebo film-coated tablets): poly(vinyl alcohol) (e1203), titanium dioxide (e171), macrogol 3350, talc (e553b), iron oxide yellow (e172) and iron oxide black (e172) what zoely looks like and contents of the pack the active film-coated tablets (tablets) are white and round. they are coded 'ne' on both sides. the placebo film-coated tablets are yellow and round. they are coded 'p' on both sides. zoely comes in blisters of 28 film-coated tablets (24 white active film-coated tablets and 4 yellow placebo film-coated tablets) packed in a ply carton. pack sizes: 28, 84, 168 and 364 film-coated tablets. not all pack sizes may be marketed.\", 'Entity_Recognition': [{'Text': 'zoely', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 4, 'BeginOffset': 49, 'EndOffset': 68, 'Score': 0.9857524037361145, 'Text': 'nomegestrol acetate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.60157310962677, 'RelationshipScore': 0.967195451259613, 'RelationshipType': 'FORM', 'Id': 6, 'BeginOffset': 96, 'EndOffset': 100, 'Text': 'film', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.4473790228366852, 'RelationshipScore': 0.9590766429901123, 'RelationshipType': 'FORM', 'Id': 7, 'BeginOffset': 101, 'EndOffset': 115, 'Text': 'coated tablets', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'ROUTE_OR_MODE', 'Score': 0.330194354057312, 'RelationshipScore': 0.9712560176849365, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 8, 'BeginOffset': 117, 'EndOffset': 128, 'Text': 'each tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'estradiol white active film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 73, 'EndOffset': 115}, {'Text': '2.5 mg nomegestrol acetate', 'Type': 'TREATMENT', 'BeginOffset': 138, 'EndOffset': 164}, {'Text': '1.5 mg estradiol', 'Type': 'TREATMENT', 'BeginOffset': 169, 'EndOffset': 185}, {'Id': 13, 'BeginOffset': 190, 'EndOffset': 201, 'Score': 0.3320384621620178, 'Text': 'hemihydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'yellow placebo film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 204, 'EndOffset': 238}, {'Text': 'white active and yellow placebo film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 329, 'EndOffset': 380}, {'Text': 'lactose monohydrate', 'Type': 'TREATMENT', 'BeginOffset': 383, 'EndOffset': 402}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 416, 'EndOffset': 417}, {'Id': 18, 'BeginOffset': 445, 'EndOffset': 471, 'Score': 0.9941098690032959, 'Text': 'microcrystalline cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 19, 'BeginOffset': 480, 'EndOffset': 492, 'Score': 0.9925359487533569, 'Text': 'crospovidone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 20, 'BeginOffset': 516, 'EndOffset': 534, 'Score': 0.9947722554206848, 'Text': 'magnesium stearate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'colloidal anhydrous silica tablet coat (white active film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 546, 'EndOffset': 618}, {'Text': 'poly(vinyl alcohol', 'Type': 'TREATMENT', 'BeginOffset': 621, 'EndOffset': 639}, {'Id': 26, 'BeginOffset': 650, 'EndOffset': 666, 'Score': 0.9973969459533691, 'Text': 'titanium dioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 27, 'BeginOffset': 675, 'EndOffset': 688, 'Score': 0.9858148097991943, 'Text': 'macrogol 3350', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.19511118531227112, 'RelationshipScore': 0.9964963793754578, 'RelationshipType': 'STRENGTH', 'Id': 28, 'BeginOffset': 699, 'EndOffset': 705, 'Text': 'e553b)', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.7072492837905884, 'RelationshipScore': 0.9991820454597473, 'RelationshipType': 'FORM', 'Id': 29, 'BeginOffset': 706, 'EndOffset': 712, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'ROUTE_OR_MODE', 'Score': 0.3511063754558563, 'RelationshipScore': 0.9712590575218201, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 32, 'BeginOffset': 756, 'EndOffset': 760, 'Text': 'poly', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'yellow placebo film', 'Type': 'TEST', 'BeginOffset': 719, 'EndOffset': 738}, {'Text': 'poly(vinyl alcohol', 'Type': 'TREATMENT', 'BeginOffset': 756, 'EndOffset': 774}, {'Id': 34, 'BeginOffset': 785, 'EndOffset': 801, 'Score': 0.9972566962242126, 'Text': 'titanium dioxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 35, 'BeginOffset': 810, 'EndOffset': 823, 'Score': 0.9868867993354797, 'Text': 'macrogol 3350', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.2565423250198364, 'RelationshipScore': 0.5023862719535828, 'RelationshipType': 'STRENGTH', 'Id': 36, 'BeginOffset': 831, 'EndOffset': 836, 'Text': 'e553b', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'iron oxide yellow', 'Type': 'TREATMENT', 'BeginOffset': 839, 'EndOffset': 856}, {'Id': 38, 'BeginOffset': 868, 'EndOffset': 884, 'Score': 0.9927268028259277, 'Text': 'iron oxide black', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.8648754954338074, 'RelationshipScore': 0.5189847350120544, 'RelationshipType': 'FORM', 'Id': 40, 'BeginOffset': 971, 'EndOffset': 978, 'Text': 'tablets', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'the active film-coated tablets (tablets', 'Type': 'TREATMENT', 'BeginOffset': 939, 'EndOffset': 978}, {'Id': 1, 'BeginOffset': 1029, 'EndOffset': 1034, 'Score': 0.8893989324569702, 'Text': 'sides', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'the placebo film', 'Type': 'TREATMENT', 'BeginOffset': 1036, 'EndOffset': 1052}, {'Id': 3, 'BeginOffset': 1117, 'EndOffset': 1122, 'Score': 0.9071109294891357, 'Text': 'sides', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': '28 film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 1151, 'EndOffset': 1173}, {'Text': 'white active film-coated tablets', 'Type': 'TREATMENT', 'BeginOffset': 1178, 'EndOffset': 1210}, {'Text': '4 yellow placebo film-coated tablets)', 'Type': 'TREATMENT', 'BeginOffset': 1215, 'EndOffset': 1252}, {'Text': 'a ply carton', 'Type': 'TREATMENT', 'BeginOffset': 1263, 'EndOffset': 1275}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 1289, 'EndOffset': 1291}, {'Text': '84', 'Type': 'NUMBER', 'BeginOffset': 1293, 'EndOffset': 1295}, {'Text': '168', 'Type': 'NUMBER', 'BeginOffset': 1297, 'EndOffset': 1300}, {'Text': '364', 'Type': 'NUMBER', 'BeginOffset': 1305, 'EndOffset': 1308}, {'Text': 'film', 'Type': 'TEST', 'BeginOffset': 1309, 'EndOffset': 1313}]}"}}},{"rowIdx":1054,"cells":{"ID":{"kind":"string","value":"C89FAB3627FDCF11CEF85ABB09623E6A"},"URL":{"kind":"string","value":"https://www.ema.europa.eu/documents/product-information/eklira-genuair-epar-product-information_en.pdf"},"Product_Name":{"kind":"string","value":"Eklira Genuair"},"Full_Content":{"kind":"string","value":"1\n\nANNEX I\n\nSUMMARY OF PRODUCT CHARACTERISTICS\n\n\n\n2\n\nThis medicinal product is subject to additional monitoring. This will allow quick identification of \nnew safety information. Healthcare professionals are asked to report any suspected adverse reactions. \nSee section 4.8 for how to report adverse reactions.\n\n1. NAME OF THE MEDICINAL PRODUCT\n\nEklira Genuair 322 micrograms inhalation powder\n\n2. QUALITATIVE AND QUANTITATIVE COMPOSITION\n\nEach delivered dose (the dose leaving the mouthpiece) contains 375 µg aclidinium bromide equivalent \nto 322 µg of aclidinium. This corresponds to a metered dose of 400 µg aclidinium bromide equivalent \nto 343 µg aclidinium.\n\nExcipients with known effect\nEach delivered dose contains approximately 12 mg lactose (as monohydrate).\n\nFor the full list of excipients, see section 6.1.\n\n3. PHARMACEUTICAL FORM\n\nInhalation powder.\n\nWhite or almost white powder in a white inhaler with an integral dose indicator and a green dosage \nbutton.\n\n4. CLINICAL PARTICULARS\n\n4.1 Therapeutic indications\n\nEklira Genuair is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult \npatients with chronic obstructive pulmonary disease (COPD) (see section 5.1).\n\n4.2 Posology and method of administration\n\nPosology\nThe recommended dose is one inhalation of 322 micrograms aclidinium twice daily.\n\nIf a dose is missed the next dose should be taken as soon as possible. However, if it is nearly time for \nthe next dose, the missed dose should be skipped.\n\nElderly\nNo dose adjustments are required for elderly patients (see section 5.2).\n\nRenal impairment\nNo dose adjustments are required for patients with renal impairment (see section 5.2).\n\nHepatic impairment\nNo dose adjustments are required for patients with hepatic impairment (see section 5.2).\n\nPaediatric population\nThere is no relevant use of Eklira Genuair in children and adolescents (under 18 years of age) for the \nindication of COPD.\n\n\n\n3\n\nMethod of administration\nFor inhalation use.\n\nPatients should be instructed on how to administer the product correctly as the Genuair inhaler may \nwork differently from inhalers the patients may have used previously. It is important to instruct the \npatients to carefully read the Instructions for Use in the Package Leaflet, which is packed together \nwith each inhaler.\n\nFor Instructions for Use, see section 6.6.\n\n4.3 Contraindications\n\nHypersensitivity to aclidinium bromide or to the excipients listed in section 6.1.\n\n4.4 Special warnings and precautions for use\n\nParadoxical bronchospasm:\nAdministration of Eklira Genuair may cause paradoxical bronchospasm. If this occurs, treatment with \nEklira Genuair should be stopped and other treatments considered.\n\nDeterioration of disease:\nAclidinium bromide is a maintenance bronchodilator and should not be used for the relief of acute \nepisodes of bronchospasm, i.e. as a rescue therapy. In the event of a change in COPD intensity while \nthe patient is being treated with aclidinium bromide so that the patient considers additional rescue \nmedication is required, a re-evaluation of the patient and the patients’ treatment regimen should be \nconducted.\n\nCardiovascular effects:\nEklira Genuair should be used with caution in patients who had a myocardial infarction during the \nprevious 6 months, unstable angina, newly diagnosed arrhythmia within the previous 3 months, or \nhospitalisation within the previous 12 months for heart failure functional classes III and IV as per the \n“New York Heart Association”. Experience in patients with cardiovascular comorbidities in clinical \ntrials is limited (see section 5.1). These conditions may be affected by the anticholinergic mechanism \nof action.\n\nAnticholinergic activity:\nDry mouth, which has been observed with anticholinergic treatment, may in the long term be \nassociated with dental caries.\n\nConsistent with its anticholinergic activity, aclidinium bromide should be used with caution in patients \nwith symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle glaucoma \n(even though direct contact of the product with the eyes is very unlikely).\n\nExcipients:\nThis medicinal product contains lactose. Patients with rare hereditary problems of galactose \nintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal \nproduct.\n\n4.5 Interaction with other medicinal products and other forms of interaction\n\nCo-administration of aclidinium bromide with other anticholinergic-containing medicinal products has \nnot been studied and is not recommended.\n\nAlthough no formal in vivo drug interaction studies have been performed, inhaled aclidinium bromide \nhas been used concomitantly with other COPD medicinal products including sympathomimetic \nbronchodilators, methylxanthines, and oral and inhaled steroids without clinical evidence of drug \ninteractions.\n\n\n\n4\n\nIn vitro studies have shown that aclidinium bromide or the metabolites of aclidinium bromide at the \ntherapeutic dose are not expected to cause interactions with active substances that are substrates of \nP-glycoprotein (P-gp), or active substances metabolised by cytochrome P450 (CYP450) enzymes and \nesterases (see section 5.2).\n\n4.6 Fertility, pregnancy and lactation\n\nPregnancy\nThere are no data available on the use of aclidinium bromide in pregnant women.\n\nStudies in animals have shown foetotoxicity only at dose levels much higher than the maximum \nhuman exposure to aclidinium bromide (see section 5.3). Aclidinium bromide should only be used \nduring pregnancy if the expected benefits outweigh the potential risks.\n\nBreast-feeding\nIt is unknown whether aclidinium bromide/metabolites are excreted in human milk. Animal studies \nhave shown excretion of small amounts of aclidinium bromide/metabolites into milk. A risk to \nnewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding \nor to discontinue/abstain from Eklira Genuair therapy taking into account the benefit of breast-feeding \nfor the child and the benefit of therapy for the woman.\n\nFertility\nStudies in rats have shown slight reductions in fertility only at dose levels much higher than the \nmaximum human exposure to aclidinium bromide (see section 5.3). It is considered unlikely that \naclidinium bromide administered at the recommended dose will affect fertility in humans.\n\n4.7 Effects on ability to drive and use machines\n\nAclidinium bromide may have minor influence on the ability to drive and use machines. The \noccurrence of headache, dizziness or blurred vision following administration of aclidinium bromide \n(see section 4.8) may influence the ability to drive or to use machinery.\n\n4.8 Undesirable effects \n\nSummary of the safety profile\nThe most frequently reported adverse reactions with Eklira Genuair were headache (6.6%) and\nnasopharyngitis (5.5%).\n\nTabulated summary of adverse reactions\nThe frequencies assigned to the undesirable effects listed below are based on crude incidence rates of \nadverse reactions (i.e. events attributed to Eklira Genuair) observed with Eklira Genuair 322 µg (636 \npatients) in the pooled analysis of one 6-month and two 3-month randomised, placebo-controlled \nclinical trials.\n\nA placebo-controlled trial in 1791 patients with moderate to very severe COPD treated with Eklira \nGenuair up to 36 months did not identify other adverse reactions. \n\nThe frequency of adverse reactions is defined using the following convention: very common (≥1/10); \ncommon (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare \n(<1/10,000) and not known (cannot be estimated from the available data).\n\nSystem organ class Preferred term Frequency\nInfections and infestations Sinusitis Common\n\nNasopharyngitis Common\nImmune system disorders Hypersensitivity Rare\n\nAngioedema Not known\n\n\n\n5\n\nAnaphylactic reaction Not known\nNervous system disorders Headache Common\n\nDizziness Uncommon\nEye disorders Blurred vision Uncommon\nCardiac disorders Tachycardia Uncommon\n\nPalpitations Uncommon\nRespiratory, thoracic and \nmediastinal disorders\n\nCough Common\nDysphonia Uncommon\n\nGastrointestinal disorders Diarrhoea Common\nNausea Common\n\nDry mouth Uncommon\nStomatitis Uncommon\n\nSkin and subcutaneous tissue \ndisorders\n\nRash Uncommon\nPruritus Uncommon\n\nRenal and urinary disorders Urinary retention Uncommon\n\nReporting of suspected adverse reactions\nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V.\n\n4.9 Overdose\n\nHigh doses of aclidinium bromide may lead to anticholinergic signs and symptoms.\nHowever, single inhaled doses up to 6,000 µg aclidinium bromide have been administered to healthy \nsubjects without systemic anticholinergic adverse reactions. Additionally, no clinically relevant \nadverse reactions were observed following 7-day twice daily dosing of up to 800 µg aclidinium \nbromide in healthy subjects.\n\nAcute intoxication by inadvertent medicinal product ingestion of aclidinium bromide is unlikely, due \nto its low oral bioavailability and the breath-actuated dosing mechanism of the Genuair inhaler.\n\n5. PHARMACOLOGICAL PROPERTIES\n\n5.1 Pharmacodynamic properties\n\nPharmacotherapeutic group: Drugs for obstructive airway diseases, anticholinergics; ATC Code: \nR03BB05.\n\nMechanism of action\nAclidinium bromide is a competitive, selective muscarinic receptor antagonist (also known as an \nanticholinergic), with a longer residence time at the M3 receptors than the M2 receptors. M3 receptors \nmediate contraction of airway smooth muscle. Inhaled aclidinium bromide acts locally in the lungs to \nantagonise M3 receptors of airway smooth muscle and induce bronchodilation. Nonclinical in vitro and \nin vivo studies showed rapid, dose-dependent and long-lasting inhibition by aclidinium of \nacetylcholine-induced bronchoconstriction. Aclidinium bromide is quickly broken down in plasma, the \nlevel of systemic anticholinergic side effects is therefore low.\n\nPharmacodynamic effects\nClinical efficacy studies showed that Eklira Genuair provided clinically meaningful improvements in \nlung function (as measured by the forced expiratory volume in 1 second [FEV1]) over 12 hours\nfollowing morning and evening administration, which were evident within 30 minutes of the first dose \n(increases from baseline of 124-133 mL). Maximal bronchodilation was achieved within 1-3 hours \nafter dosing with mean peak improvements in FEV1 relative to baseline of 227-268 mL at steady-state.\n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc?_sm_au_=iWHNfPk6pL272dJN\n\n\n6\n\nCardiac electrophysiology\nNo effects on QT interval (corrected using either the Fridericia or Bazett method or individually-\ncorrected) were observed when aclidinium bromide (200 µg or 800 µg) was administered once daily \nfor 3 days to healthy subjects in a thorough QT study.\n\nIn addition, no clinically significant effects of Eklira Genuair on cardiac rhythm were observed on \n24-hour Holter monitoring after 3 months treatment of 336 patients (of whom 164 received Eklira \nGenuair 322 µg twice daily).\n\nClinical efficacy and safety\nThe Eklira Genuair Phase III clinical development programme included 269 patients treated with \nEklira Genuair 322 µg twice daily in one 6-month randomised, placebo-controlled study and \n190 patients treated with Eklira Genuair 322 µg twice daily in one 3-month randomised, placebo-\ncontrolled study. Efficacy was assessed by measures of lung function and symptomatic outcomes such \nas breathlessness, disease-specific health status, use of rescue medication and occurrence of \nexacerbations. In the long-term safety studies, Eklira Genuair was associated with bronchodilatory \nefficacy when administered over a 1-year treatment period.\n\nBronchodilation\nIn the 6-month study, patients receiving Eklira Genuair 322 µg twice daily experienced a clinically \nmeaningful improvement in their lung function (as measured by FEV1). Maximal bronchodilatory\neffects were evident from day one and were maintained over the 6-month treatment period. After \n6 months treatment, the mean improvement in morning pre-dose (trough) FEV1 compared to placebo \nwas 128 mL (95% CI=85-170; p<0.0001).\nSimilar observations were made with Eklira Genuair in the 3 month study.\n\nDisease-Specific Health Status and Symptomatic Benefits\nEklira Genuair provided clinically meaningful improvements in breathlessness (assessed using the \nTransition Dyspnoea Index [TDI]) and disease-specific health status (assessed using the St. George’s \nRespiratory Questionnaire [SGRQ]). The Table below shows symptom relief obtained after 6 months \ntreatment with Eklira Genuair.\n\nVariable\nTreatment Improvement over \n\nplacebo\np-value\n\nEklira Genuair Placebo\n\nTDI\nPercentage of Patients who \nachieved MCIDa\n\n56.9 45.5\n1.68-foldc increase \n\nin likelihood\n0.004\n\nMean Change from baseline 1.9 0.9 1.0 unit <0.001\n\nSGRQ\n\nPercentage of Patients who \nachieved MCIDb\n\n57.3 41.0\n1.87-foldc increase \n\nin likelihood\n<0.001\n\nMean Change from baseline -7.4 -2.8 - 4.6 units <0.0001\n\na Minimum clinically important difference (MCID) of at least 1 unit change in TDI.\nb MCID of at least - 4 units change in SGRQ.\nc Odds ratio, increase in the likelihood of achieving the MCID compared to placebo.\n\nPatients treated with Eklira Genuair required less rescue medication than patients treated with placebo \n(a reduction of 0.95 puffs per day at 6 months [p=0.005]). Eklira Genuair also improved daily \nsymptoms of COPD (dyspnoea, cough and sputum production) and night-time and early morning \nsymptoms.\n\nPooled efficacy analysis of the 6-month and 3-month placebo controlled studies demonstrated a \nstatistically significant reduction in the rate of moderate to severe exacerbations (requiring treatment \nwith antibiotics or corticosteroids or resulting in hospitalisations) with aclidinium 322 µg twice daily \ncompared to placebo (rate per patient per year: 0.31 vs 0.44 respectively; p=0.0149).\n\n\n\n7\n\nLong Term Safety and Efficacy Trial up to 3 years\nThe effect of aclidinium bromide on the occurrence of major adverse cardiovascular events (MACE) \nwas assessed in a randomised, double-blind, placebo-controlled, parallel-group study in 3630 adult \npatients between 40 and 91 years of age with moderate to very severe COPD, treated for up to \n36 months. 58.7% were male and 90.7% were Caucasian, with a mean postbronchodilator FEV1 of \n47.9% of predicted value and a mean CAT (COPD Assessment Test) of 20.7. All patients had a \nhistory of cardiovascular or cerebrovascular disease and/or significant cardiovascular risk factors. \n59.8% of patients had at least one COPD exacerbation within the past 12 months from the screening \nvisit. Approximately 48% of enrolled patients had a prior history of at least 1 documented previous \ncardiovascular event; cerebrovascular disease (13.1%), coronary artery disease (35.4%), peripheral \nvascular disease or history of claudication (13.6%). \n\nThe study had an event-driven design and was terminated once sufficient MACE events for the \nprimary safety analysis were observed. Patients discontinued treatment if they experienced a MACE \nevent and entered into the post-treatment follow-up period during the study. 70.7% of patients \ncompleted the study per investigator assessment. The median time on-treatment in the Eklira Genuair \nand placebo groups was 1.1 and 1 year, respectively. The median time on-study in the Eklira Genuair \nand placebo groups was approximately 1.4 and 1.3 years, respectively.\n\nThe primary safety endpoint was the time to first occurrence of MACE, defined as any of the \nfollowing adjudicated events: cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal \nischemic stroke. The frequency of patients with at least one MACE was 3.85% vs. 4.23% patients in \nthe aclidinium and placebo groups, respectively. Eklira Genuair did not increase the MACE risk in \npatients with COPD compared to placebo when added to current background therapy (hazard ratio \n(HR) 0.89; 95% CI: 0.64, 1.23). The upper bound of the confidence interval excluded a pre-defined\nrisk margin of 1.8.\n\nThe rate of moderate or severe COPD exacerbations per patient per year during the first year of \ntreatment was evaluated as the primary efficacy endpoint in the study. Patients treated with Eklira \nGenuair showed a statistically significant reduction of 22% compared to placebo (rate ratio [RR] 0.78; \n95% CI 0.68 to 0.89; p<0.001). In addition, Eklira Genuair showed a statistically significant reduction \nof 35% in the rate of hospitalisations due to COPD exacerbations while on-treatment during the first \nyear compared with placebo (RR 0.65; 95% CI 0.48 to 0.89; p=0.006).\n\nThe Eklira Genuair group showed a statistically significant delay in the time to first moderate or \nsevere exacerbation while on-treatment compared to the placebo group. Patients in the aclidinium \nbromide group had a 18% relative reduction of the risk of an exacerbation (HR 0.82; 95% CI [0.73, \n0.92], p<0.001).\n\nExercise tolerance\nIn a 3-week crossover, randomised, placebo-controlled clinical study Eklira Genuair was associated \nwith a statistically significant improvement in exercise endurance time in comparison to placebo of 58 \nseconds (95% CI=9-108; p=0.021; pre-treatment value: 486 seconds). Eklira Genuair statistically \nsignificantly reduced lung hyperinflation at rest (functional residual capacity [FRC]=0.197 L [95% \nCI=0.321, 0.072; p=0.002]; residual volume [RV]=0.238 L [95% CI=0.396, 0.079; p=0.004]) and also \nimproved trough inspiratory capacity (by 0.078 L; 95% CI=0.01, 0.145; p=0.025) and reduced \ndyspnoea during exercise (Borg scale) (by 0.63 Borg units; 95% CI=1.11, 0.14; p=0.012).\n\nPaediatric population\nThe European Medicines Agency has waived the obligation to submit the results of studies with Eklira \nGenuair in all subsets of the paediatric population in COPD (see section 4.2 for information on \npaediatric use).\n\n\n\n8\n\n5.2 Pharmacokinetic properties\n\nAbsorption\nAclidinium bromide is rapidly absorbed from the lung, achieving maximum plasma concentrations \nwithin 5 minutes of inhalation in healthy subjects, and normally within the first 15 minutes in COPD \npatients. The fraction of the inhaled dose that reaches the systemic circulation as unchanged \naclidinium is very low at less than 5%.\n\nSteady state peak plasma concentrations achieved after dry powder inhalation by COPD patients of \n400 µg aclidinium bromide were approximately 224 pg/mL. Steady-state plasma levels were attained \nwithin seven days of twice daily dosing.\n\nDistribution\nWhole lung deposition of inhaled aclidinium bromide via the Genuair inhaler averaged approximately \n30% of the metered dose.\n\nThe plasma protein binding of aclidinium bromide determined in vitro most likely corresponded to the \nprotein binding of the metabolites due to the rapid hydrolysis of aclidinium bromide in plasma; plasma \nprotein binding was 87% for the carboxylic acid metabolite and 15% for the alcohol metabolite. The \nmain plasma protein that binds aclidinium bromide is albumin.\n\nBiotransformation\nAclidinium bromide is rapidly and extensively hydrolysed to its pharmacologically inactive alcohol-\nand carboxylic acid-derivatives. The hydrolysis occurs both chemically (non-enzymatically) and \nenzymatically by esterases, butyrylcholinesterase being the main human esterase involved in the \nhydrolysis. Plasma levels of the acid metabolite are approximately 100-fold greater than those of the \nalcohol metabolite and the unchanged active substance following inhalation.\n\nThe low absolute bioavailability of inhaled aclidinium bromide (<5%) is because aclidinium bromide \nundergoes extensive systemic and pre-systemic hydrolysis whether deposited in the lung or \nswallowed.\n\nBiotransformation via CYP450 enzymes plays a minor role in the total metabolic clearance of\naclidinium bromide.\n\nIn vitro studies have shown that aclidinium bromide at the therapeutic dose or its metabolites do not \ninhibit or induce any of the cytochrome P450 (CYP450) enzymes and do not inhibit esterases \n(carboxylesterase, acetylcholinesterase and butyrylcholinesterase). In vitro studies have shown that \naclidinium bromide or the metabolites of aclidinium bromide are not substrates or inhibitors of \nP-glycoprotein.\n\nElimination\nThe terminal elimination half-life and effective half-life of aclidinium bromide are approximately 14 \nhours and 10 hours, respectively, following inhalation of twice daily 400 µg doses in COPD patients.\n\nFollowing intravenous administration of 400 µg radiolabelled aclidinium bromide to healthy subjects, \napproximately 1% of the dose was excreted as unchanged aclidinium bromide in the urine. Up to 65% \nof the dose was eliminated as metabolites in the urine and up to 33% as metabolites in the faeces.\n\nFollowing inhalation of 200 µg and 400 µg of aclidinium bromide by healthy subjects or COPD \npatients, the urinary excretion of unchanged aclidinium was very low at about 0.1% of the \nadministered dose, indicating that renal clearance plays a minor role in the total aclidinium clearance \nfrom plasma.\n\nLinearity/non-linearity\n\n\n\n9\n\nAclidinium bromide demonstrated kinetic linearity and a time-independent pharmacokinetic behaviour \nin the therapeutic range.\n\nSpecial populations\nElderly patients\nThe pharmacokinetic properties of aclidinium bromide in patients with moderate to severe COPD \nappear to be similar in patients aged 40–59 years and in patients aged ≥70 years. Therefore, no dose \nadjustment is required for elderly COPD patients.\n\nHepatically-impaired patients\nNo studies have been performed on hepatically-impaired patients. As aclidinium bromide is \nmetabolised mainly by chemical and enzymatic cleavage in the plasma, hepatic dysfunction is very \nunlikely to alter its systemic exposure. No dose adjustment is required for hepatically-impaired COPD \npatients.\n\nRenally-impaired patients\nNo significant pharmacokinetic differences were observed between subjects with normal renal \nfunction and subjects with renal impairment. Therefore, no dose adjustment and no additional \nmonitoring are required for renally-impaired COPD patients.\n\nRace\nFollowing repeated inhalations, the systemic exposure of aclidinium bromide has been observed to be\nsimilar in Japanese and Caucasian patients.\n\nPharmacokinetic/pharmacodynamic relationship\nBecause aclidinium bromide acts locally in the lungs and is quickly broken down in plasma there is no \ndirect relationship between pharmacokinetics and pharmacodynamics.\n\n5.3 Preclinical safety data\n\nNonclinical data reveal no special hazard for humans based on conventional studies of safety \npharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to \nreproduction and development.\n\nEffects in nonclinical studies with respect to cardiovascular parameters (increased heart rates in dogs), \nreproductive toxicity (foetotoxic effects), and fertility (slight decreases in conception rate, number of \ncorpora lutea, and pre- and post-implantation losses) were observed only at exposures considered \nsufficiently in excess of the maximum human exposure indicating little relevance to clinical use.\n\nThe low toxicity observed in nonclinical toxicity studies is in part due to rapid metabolism of \naclidinium bromide in plasma and the lack of significant pharmacological activity of the major \nmetabolites. The safety margins for human systemic exposure with 400 µg twice daily over the no \nobserved adverse effect levels in these studies ranged from 7- to 73-fold.\n\n6. PHARMACEUTICAL PARTICULARS\n\n6.1 List of excipients\n\nLactose monohydrate.\n\n6.2 Incompatibilities\n\nNot applicable.\n\n6.3 Shelf life\n\n\n\n10\n\n3 years.\n\nTo be used within 90 days of opening the pouch.\n\n6.4 Special precautions for storage\n\nKeep the inhaler inside the pouch until the administration period starts.\n\n6.5 Nature and contents of container\n\nThe inhaler device is a multicomponent device made of polycarbonate, acrylonitrile-butadiene-styrene, \npolyoxymethylene, polyester-butylene-terephthalate, polypropylene, polystyrene and stainless steel. It \nis white-coloured with an integral dose indicator and a green dosage button. The mouthpiece is \ncovered with a removable green protective cap. The inhaler is supplied in a plastic laminate pouch, \nplaced in a cardboard carton.\n\nCarton containing 1 inhaler with 30 doses.\nCarton containing 1 inhaler with 60 doses.\nCarton containing 3 inhalers each with 60 doses.\nNot all pack sizes may be marketed.\n\n6.6 Special precautions for disposal and other handling\n\nAny unused medicinal product or waste material should be disposed of in accordance with local \nrequirements.\n\nInstructions for Use\n\nGetting Started\n\nRead these Instructions for Use before you start using the medicine.\n\nBecome familiar with the parts of your Genuair inhaler.\n\nFigure A\n\nBefore use:\n\na) Before first use, tear open the sealed bag and remove the inhaler. Throw away the bag.\nb) Do not press the green button until you are ready to take a dose.\nc) Pull off the cap by lightly squeezing the arrows marked on each side (Figure B).\n\nControl window\nRed = confirms correct inhalation\n\nGreen button\n\nDose\nindicator\n\nMouthpiece\n\nProtective \nCap\n\nControl window\nGreen = inhaler ready to use\n\n\n\n11\n\nSTEP 1: Prepare your dose\n\n1.1 Look in the opening of the mouthpiece and make sure nothing is blocking it (Figure C).\n\n1.2 Look at the control window (should be red, Figure C).\n\nFigure C\n\n1.3 Hold the inhaler horizontally with the mouthpiece facing you and the green button on top \n\n(Figure D).\n\n Figure D\n\n1.4 Press the green button all the way down to load your dose (Figure E).\n\nWhen you press the button all the way down, the control window changes from red to green.\n\nMake sure the green button is on top. Do not tilt.\n\n1.5 Release the green button (Figure F).\n\nMake sure you release the button so the inhaler can work correctly.\n\nFigure B\n\nSqueeze here \nand pull\n\nRED\n\nCheck mouthpiece\nopening\n\n\n\n12\n\nFigure E Figure F\n\nStop and Check:\n\n1.6 Make sure the control window is now green (Figure G).\n\nYour medicine is ready to be inhaled.\n\nGo to ‘STEP 2: Inhale your medicine’.\n\n Figure G\n\nWhat to do if the control window is still red after pressing the button (Figure H).\n\n Figure H\n\nThe dose is not prepared. Go back to ‘STEP 1 Prepare your dose’ and repeat steps 1.1 to 1.6.\n\nSTEP 2: Inhale your medicine\n\nRead steps 2.1 to 2.7 fully before use. Do not tilt.\n\n2.1 Hold the inhaler away from your mouth, and breathe out completely. Never breathe out into\n\nthe inhaler (Figure I).\n\nGREEN\n\n\n\n13\n\n Figure I\n\n2.2 Hold your head upright, put the mouthpiece between your lips, and close your lips\n\ntightly around it (Figure J).\n\nDo not hold the green button down while inhaling.\n\nFigure J\n\n2.3 Take a strong, deep breath through your mouth. Keep breathing in for as long as possible.\n\nA ‘click’ will let you know that you are inhaling correctly. Keep breathing in as long as possible \nafter you hear the ‘click’. Some patients may not hear the ‘click’. Use the control window to ensure \nyou have inhaled correctly.\n\n2.4 Take the inhaler out of your mouth.\n\n2.5 Hold your breath for as long as possible.\n\n2.6 Slowly breathe out away from the inhaler.\n\nSome patients may experience a grainy sensation in their mouth, or a slightly sweet or bitter taste. Do \n\nnot take an extra dose even if you do not taste or feel anything after inhaling.\n\nStop and Check:\n\n2.7 Make sure the control window is now red (Figure K). This means you have inhaled your \n\nmedicine correctly.\n\n\n\n14\n\nFigure K\n\nWhat to do if the control window is still green after inhalation (Figure L).\n\nFigure L\n\nThis means you have not inhaled your medicine correctly. Go back to ‘STEP 2 Inhale your medicine’\n\nand repeat steps 2.1 to 2.7.\n\nIf the control window still does not change to red, you may have forgotten to release the green button\nbefore inhaling, or you may not have inhaled strongly enough. If this happens, try again. Make sure you\nhave released the green button, and you have breathed out completely. Then take a strong, deep breath\nthrough the mouthpiece.\nPlease contact your doctor if the control window is still green after repeated attempts.\n\nPush the protective cap back onto the mouthpiece after each use (Figure M), to prevent contamination \nof the inhaler with dust or other materials. You should discard your inhaler if you lose the cap.\n\nAdditional information\n\nWhat should you do if you accidently prepare a dose?\n\nFigure M\n\nRED\n\n\n\n15\n\nStore your inhaler with the protective cap in place until it is time to inhale your medicine, then remove \n\nthe cap and start at Step 1.6.\n\nHow does the dose indicator work?\n\n The dose indicator shows the total number of doses left in the inhaler (Figure N).\n On first use, every inhaler contains at least 60 doses, or at least 30 doses, depending on the pack \n\nsize.\n Each time you load a dose by pressing the green button, the dose indicator moves by a small \n\namount towards the next number (50, 40, 30, 20, 10, or 0).\n\nWhen should you get a new inhaler?\n\nYou should get a new inhaler:\n If your inhaler appears to be damaged or if you lose the cap, or\n When a red band appears in the dose indicator, this means you are nearing your last dose \n\n(Figure N), or\n If your inhaler is empty (Figure O).\n\n Figure N\n\nHow do you know that your inhaler is empty?\n\nWhen the green button will not return to its full upper position and is locked in a middle position, you \nhave reached the last dose (Figure O). Even though the green button is locked, your last dose may still \nbe inhaled. After that, the inhaler cannot be used again and you should start using a new inhaler.\n\nHow should you clean the inhaler?\n\nFigure O\n\nLocked\n\nDose\nindicator\n\nRed band\n\nDose indicator moves slowly from 60 to\n0: 60, 50, 40, 30, 20, 10, 0.\n\n\n\n16\n\nNEVER use water to clean the inhaler, as this may damage your medicine.\n\nIf you wish to clean your inhaler, just wipe the outside of the mouthpiece with a dry tissue or paper \ntowel.\n\n7. MARKETING AUTHORISATION HOLDER\n\nAstraZeneca AB\nSE-151 85 Södertälje\nSweden\n\n8. MARKETING AUTHORISATION NUMBER(S) \n\nEU/1/12/778/001\nEU/1/12/778/002\nEU/1/12/778/003\n\n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION\n\nDate of first authorisation: 20 July 2012\nDate of last renewal: 20 April 2017\n\n10. DATE OF REVISION OF THE TEXT\n\nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency http://www.ema.europa.eu\n\nhttp://www.ema.europa.eu/\n\n\n17\n\nANNEX II\n\nA. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE\n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \nAUTHORISATION\n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \nEFFECTIVE USE OF THE MEDICINAL PRODUCT\n\n\n\n18\n\nA. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE\n\nName and address of the manufacturer(s) responsible for batch release\n\nIndustrias Farmacéuticas Almirall, S.A.\nCtra. Nacional II, Km. 593\n08740 Sant Andreu de la Barca\nBarcelona\nSpain\n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\nMedicinal product subject to medical prescription.\n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \nAUTHORISATION\n\nPharmacovigilance system\nThe MAH must ensure that the system of pharmacovigilance presented in Module 1.8.1. of the \nMarketing Authorisation is in place and functioning before and whilst the medicinal product is on the \nmarket.\n\nRisk Management Plan (RMP)\nThe MAH shall perform the pharmacovigilance activities detailed in the Pharmacovigilance Plan, as \nagreed in the Risk Management Plan presented in Module 1.8.2. of the Marketing Authorisation and \nany subsequent updates of the RMP agreed by the Committee for Medicinal Products for Human Use \n(CHMP).\n\nAs per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the \nupdated RMP should be submitted at the same time as the next Periodic Safety Update Report \n(PSUR).\n\nIn addition, an updated RMP should be submitted\n When new information is received that may impact on the current Safety Specification, \n\nPharmacovigilance Plan or risk minimisation activities\n Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being \n\nreached\n At the request of the European Medicines Agency.\n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n\n Obligation to conduct post-authorisation measures\n\nThe MAH shall complete, within the stated timeframe, the below measures:\n\nDescription Due date\n\nSubmission of the results of the agreed post-authorisation safety study (PASS) \nfor aclidinium bromide to evaluate the overall mortality and the proposed \ncardiovascular safety endpoints (with an additional endpoint of cardiac \narrhythmia) among patients with COPD using aclidinium, according to a \nprotocol agreed by the PRAC. \n\n2023\n\n\n\n19\n\nANNEX III\n\nLABELLING AND PACKAGE LEAFLET\n\n\n\n20\n\nA. LABELLING\n\n\n\n21\n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING\n\nOUTER CARTON\n\n1. NAME OF THE MEDICINAL PRODUCT\n\nEklira Genuair 322 micrograms inhalation powder\naclidinium (aclidinium bromide)\n\n2. STATEMENT OF ACTIVE SUBSTANCE(S)\n\nEach delivered dose contains 375 micrograms aclidinium bromide equivalent to 322 micrograms of \naclidinium.\n\n3. LIST OF EXCIPIENTS\n\nAlso contains: Lactose\n\n4. PHARMACEUTICAL FORM AND CONTENTS\n\n1 inhaler containing 30 doses\n1 inhaler containing 60 doses\n3 inhalers each containing 60 doses\n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION\n\nRead the package leaflet before use\nInhalation use\n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \nOF THE SIGHT AND REACH OF CHILDREN\n\nKeep out of the sight and reach of children\n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY\n\n8. EXPIRY DATE\n\nEXP\nTo be used within 90 days of opening the pouch\n\n9. SPECIAL STORAGE CONDITIONS\n\nKeep the Genuair inhaler inside the pouch until the administration period starts.\n\n\n\n22\n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE\n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER\n\nAstraZeneca AB\nSE-151 85 Södertälje\nSweden\n\nAstraZeneca (AstraZeneca logo)\n\n12. MARKETING AUTHORISATION NUMBER(S) \n\nEU/1/12/778/001 30 doses\nEU/1/12/778/002 60 doses\nEU/1/12/778/003 3 inhalers each containing 60 doses\n\n13. BATCH NUMBER\n\nLot\n\n14. GENERAL CLASSIFICATION FOR SUPPLY\n\n15. INSTRUCTIONS ON USE\n\n16. INFORMATION IN BRAILLE\n\neklira genuair\n\n17. UNIQUE IDENTIFIER – 2D BARCODE\n\n2D barcode carrying the unique identifier included.\n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA\n\nPC\nSN\nNN\n\n\n\n23\n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS\n\nInhaler label\n\n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION\n\nEklira Genuair 322 mcg inhalation powder\naclidinium (aclidinium bromide)\nInhalation use\n\n2. METHOD OF ADMINISTRATION\n\n3. EXPIRY DATE\n\nEXP\nTo be used within 90 days of opening the pouch.\n\n4. BATCH NUMBER\n\nLot\n\n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT\n\n30 doses\n60 doses\n\n6. OTHER\n\nAstraZeneca (AstraZeneca logo)\n\n\n\n24\n\nB. PACKAGE LEAFLET\n\n\n\n25\n\nPackage leaflet: Information for the patient\n\nEklira Genuair 322 micrograms inhalation powder\nAclidinium (aclidinium bromide)\n\nThis medicine is subject to additional monitoring. This will allow quick identification of new \nsafety information. You can help by reporting any side effects you may get. See the end of section 4 \nfor how to report side effects.\n\nRead all of this leaflet carefully before you start using this medicine because it contains \nimportant information for you.\n- Keep this leaflet. You may need to read it again.\n- If you have any further questions, ask your doctor, pharmacist or nurse.\n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours.\n- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible \n\nside effects not listed in this leaflet. See section 4.\n\nWhat is in this leaflet:\n1. What Eklira Genuair is and what it is used for\n2. What you need to know before you use Eklira Genuair\n3. How to use Eklira Genuair\n4. Possible side effects\n5. How to store Eklira Genuair\n6. Contents of the pack and other information\n\nInstructions for Use\n\n1. What Eklira Genuair is and what it is used for\n\nWhat Eklira Genuair is\nThe active ingredient of Eklira Genuair is aclidinium bromide, which belongs to a group of medicines \ncalled bronchodilators. Bronchodilators relax airways and help keep bronchioles open. Eklira Genuair \nis a dry powder inhaler that uses your breath to deliver the medicine directly into your lungs. This\nmakes it easier for chronic obstructive pulmonary disease (COPD) patients to breathe.\n\nWhat Eklira Genuair is used for\nEklira Genuair is indicated to help open the airways and relieve symptoms of COPD, a serious, long-\nterm lung disease characterised by breathing difficulties. Regular use of Eklira Genuair can help you \nwhen you have ongoing shortness of breath related to your disease to help you minimise the effects of \nthe disease on your everyday life and reduce the number of flare-ups (the worsening of your COPD \nsymptoms for several days).\n\n2. What you need to know before you use Eklira Genuair\n\nDo not use Eklira Genuair\n- if you are allergic to aclidinium bromide or any of the other ingredients of this medicine (listed in \n\nsection 6).\n\nWarnings and precautions\nTalk to your doctor, pharmacist or nurse before using Eklira Genuair:\n- if you have had heart problems recently.\n- if you see halos around lights or coloured images (glaucoma).\n- if you have an enlarged prostate, problems passing urine, or a blockage in your bladder.\n\n\n\n26\n\nEklira Genuair is indicated for maintenance treatment and should not be used to treat a sudden attack \nof breathlessness or wheezing. If your COPD symptoms (breathlessness, wheezing, cough) do not \nimprove or get worse you should contact your doctor for advice as soon as possible.\n\nDry mouth, which has been observed with medicines like Eklira Genuair, may after using your \nmedicine for a long time, be associated with tooth decay. Therefore, please remember to pay attention \nto oral hygiene.\n\nStop taking Eklira Genuair and seek medical help immediately:\n- if you get tightness of the chest, coughing, wheezing or breathlessness immediately after using \n\nthe medicine. These may be signs of a condition called bronchospasm.\n\nChildren and adolescents\nEklira Genuair is not for use in children or adolescents below 18 years of age.\n\nOther medicines and Eklira Genuair\nTell your doctor or pharmacist if you are taking, have recently taken or might take any other \nmedicines.\n\nInform your doctor if you have been or are using similar medicines for breathing problems, such as\nmedicines containing tiotropium, ipratropium. Ask your doctor or pharmacist if you are not sure. The \nuse of Eklira Genuair with these medicines is not recommended.\n\nPregnancy and breast-feeding\nIf you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask\nyour doctor or pharmacist for advice before taking this medicine. You should not use Eklira Genuair if \nyou are pregnant or are breast-feeding unless your doctor tells you so.\n\nDriving and using machines\nEklira Genuair may have minor influence on the ability to drive and use machines. This medicine may \ncause headache, dizziness or blurred vision. If you are affected by any of these side effects do not \ndrive or use machinery until the headache has cleared, the feeling of dizziness has passed and your \nvision has returned to normal.\n\nEklira Genuair contains lactose\nIf you have been told by your doctor that you have an intolerance to some sugars, contact your doctor \nbefore taking this medicinal product.\n\n3. How to use Eklira Genuair\n\nAlways use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor \nor pharmacist if you are not sure.\n\nThe recommended dose is one inhalation twice a day in the morning and evening.\nThe effects of Eklira Genuair last for 12 hours; therefore, you should try to use your Eklira Genuair \ninhaler at the same time every morning and evening. This ensures that there is always enough \nmedicine in your body to help you breathe more easily throughout the day and night. It will also help \nyou to remember to use it.\n\nThe recommended dose can be used for elderly patients and for patients with kidney or liver problems. \nNo dose adjustments are necessary.\n\nCOPD is a long-term disease; therefore, it is recommended that Eklira Genuair is used every day, \ntwice a day and not only when breathing problems or other symptoms of COPD are experienced.\n\nRoute of administration\n\n\n\n27\n\nThe medicine is for inhalation use.\n\nRefer to the Instructions for Use for instructions on how to use the Genuair inhaler. If you are not sure \nof how to use Eklira Genuair, contact your doctor or pharmacist.\n\nYou can use Eklira Genuair any time before or after food or drink.\n\nIf you use more Eklira Genuair than you should\nIf you think you may have used more Eklira Genuair than you should, contact your doctor or \npharmacist.\n\nIf you forget to use Eklira Genuair\nIf you forget a dose of Eklira Genuair, inhale the dose as soon as you remember. However, if it is \nnearly time for your next dose, skip the missed dose.\nDo not take a double dose to make up for a forgotten dose.\n\nIf you stop using Eklira Genuair\nThis medicine is for long-term use. If you want to stop treatment, first talk to your doctor, as your \nsymptoms may worsen.\n\nIf you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.\n\n4. Possible side effects\n\nLike all medicines, this medicine can cause side effects, although not everybody gets them.\n\nAllergic reactions may rarely occur (may affect up to 1 in 1,000 people). Stop using the medicine and \ncontact your doctor immediately if you develop swelling of your face, throat, lips or tongue (with or \nwithout difficulty breathing or swallowing), dizziness or fainting, faster heart rate or if you get raised \nseverely itchy bumps on your skin (hives) as these may be symptoms of an allergic reaction.\n\nThe following side effects may occur whilst using Eklira Genuair:\nCommon: may affect up to 1 in 10 people\n- Headache\n- Inflammation of the sinuses (sinusitis)\n- Common cold (nasopharyngitis)\n- Cough\n- Diarrhoea\n- Nausea\n\nUncommon: may affect up to 1 in 100 people\n- Dizziness\n- Dry mouth\n- Inflammation of the mouth (stomatitis)\n- Hoarseness (dysphonia)\n- Faster heart beat (tachycardia)\n- Sensation of heart beating (palpitations) \n- Difficulty passing urine (urinary retention)\n- Blurred vision\n- Rash\n- Itching of the skin\n\nReporting of side effects\nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \neffects not listed in this leaflet. You can also report side effects directly via the national reporting \n\n\n\n28\n\nsystem listed in Appendix V. By reporting side effects you can help provide more information on the \nsafety of this medicine.\n\n5. How to store Eklira Genuair\n\nKeep this medicine out of the sight and reach of children.\n\nDo not use this medicine after the expiry date which is stated on the inhaler label and carton after \n“EXP”. The expiry date refers to the last day of that month.\n\nKeep the inhaler inside the pouch until the administration period starts.\n\nTo be used within 90 days of opening the pouch.\n\nDo not use the Eklira Genuair if you notice that the pack is damaged or shows signs of tampering.\n\nAfter you have taken the last dose, the inhaler has to be disposed of. Do not throw away any medicines \nvia wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer \nuse. These measures will help protect the environment.\n\n6. Contents of the pack and other information\n\nWhat Eklira Genuair contains\n- The active substance is aclidinium bromide. Each delivered dose contains 375 micrograms\n\naclidinium bromide equivalent to 322 micrograms of aclidinium.\n- The other ingredient is lactose monohydrate (refer to Section 2 “Eklira Genuair contains \n\nlactose”).\n\nWhat Eklira Genuair looks like and contents of the pack\nEklira Genuair is a white or almost white powder.\nThe Genuair inhaler device is white coloured with an integral dose indicator and a green dosage \nbutton. The mouthpiece is covered with a removable green protective cap. It is supplied in a plastic \npouch.\n\nPack sizes supplied:\nCarton containing 1 inhaler with 30 doses.\nCarton containing 1 inhaler with 60 doses.\nCarton containing 3 inhalers each with 60 doses.\n\nNot all pack sizes may be marketed.\n\nMarketing Authorisation Holder\nAstraZeneca AB\nSE-151 85 Södertälje\nSweden\n\nManufacturer\nIndustrias Farmacéuticas Almirall, S.A.\nCtra. Nacional II, Km. 593\n08740 Sant Andreu de la Barca, Barcelona\nSpain\n\nFor any information about this medicine, please contact the local representative of the Marketing \nAuthorisation Holder:\n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc?_sm_au_=iWHNfPk6pL272dJN\n\n\n29\n\nBelgië/Belgique/Belgien\nAstraZeneca S.A./N.V.\nTel: +32 2 370 48 11\n\nLietuva\nUAB AstraZeneca Lietuva\nTel: +370 5 2660550\n\nБългария\nАстраЗенека България ЕООД\nТел.: +359 (2) 44 55 000\n\nLuxembourg/Luxemburg\nAstraZeneca S.A./N.V.\nTél/Tel: +32 2 370 48 11\n\nČeská republika\nAstraZeneca Czech Republic s.r.o. \nTel: +420 222 807 111\n\nMagyarország\nAstraZeneca Kft.\nTel.: +36 1 883 6500\n\nDanmark\nAstraZeneca A/S \nTlf: +45 43 66 64 62\n\nMalta\nAssociated Drug Co. Ltd\nTel: +356 2277 8000\n\nDeutschland\nAstraZeneca GmbH \nTel: +49 41 03 7080\n\nNederland\nAstraZeneca BV \nTel: +31 79 363 2222\n\nEesti\nAstraZeneca\nTel: +372 6549 600\n\nNorge\nAstraZeneca AS \nTlf: +47 21 00 64 00\n\nΕλλάδα\nAstraZeneca A.E. \nΤηλ: +30 2 106871500\n\nÖsterreich\nAstraZeneca Österreich GmbH \nTel: +43 1 711 31 0\n\nEspaña\nAstraZeneca Farmacéutica Spain, S.A. \nTel: +34 91 301 91 00\n\nPolska\nAstraZeneca Pharma Poland Sp. z o.o.\nTel.: +48 22 245 73 00\n\nFrance\nAstraZeneca\nTél: +33 1 41 29 40 00\n\nPortugal\nAstraZeneca Produtos Farmacêuticos, Lda.\nTel: +351 21 434 61 00\n\nHrvatska\nAstraZeneca d.o.o.\nTel: +385 1 4628 000\n\nRomânia\nAstraZeneca Pharma SRL\nTel: +40 21 317 60 41\n\nIreland\nA. Menarini Pharmaceuticals Ireland Ltd \nTel: +353 1 284 6744\n\nSlovenija\nAstraZeneca UK Limited\nTel: +386 1 51 35 600\n\nÍsland\nVistor hf.\nSími: +354 535 70 00\n\nSlovenská republika\nAstraZeneca AB, o.z. \nTel: +421 2 5737 7777\n\nItalia\nAstraZeneca S.p.A. \nTel: +39 02 9801 1\n\nSuomi/Finland\nAstraZeneca Oy \nPuh/Tel: +358 10 23 010\n\nΚύπρος\nΑλέκτωρ Φαρµακευτική Λτδ \nΤηλ: +357 22490305\n\nSverige\nAstraZeneca AB \nTel: +46 8 553 26 000\n\n\n\n30\n\nLatvija\nSIA AstraZeneca Latvija\nTel: +371 67377100\n\nUnited Kingdom\nAstraZeneca UK Ltd \nTel: +44 1582 836 836\n\nThis leaflet was last revised in <{month YYYY}>.\n\nDetailed information on this medicine is available on the European Medicines Agency web site: \nhttp://www.ema.europa.eu/.\n\nhttp://www.ema.europa.eu/\n\n\n31\n\nInstructions for Use\n\nThis section contains information on how to use your Genuair inhaler. It is important that you read this \ninformation as the Genuair may work differently from inhalers you have used previously. If you have \nany questions about how to use your inhaler, please ask your doctor, pharmacist or nurse for \nassistance.\n\nThe Instructions for Use is divided into the following sections:\n\n- Getting started\n- Step 1: Prepare your dose\n- Step 2: Inhale your medicine\n- Additional information\n\nGetting Started\n\nRead these Instructions for Use before you start using the medicine.\n\nBecome familiar with the parts of your Genuair inhaler.\n\nFigure A\n\nBefore use:\n\na) Before first use, tear open the sealed bag and remove the inhaler. Throw away the bag.\nb) Do not press the green button until you are ready to take a dose.\nc) Pull off the cap by lightly squeezing the arrows marked on each side (Figure B).\n\nControl window\nRed = confirms correct inhalation\n\nGreen button\n\nDose \nindicator\n\nMouthpiece\n\nProtective \nCap\n\nControl window\nGreen = inhaler ready to use\n\n\n\n32\n\nFigure B\n\nSTEP 1: Prepare your dose\n\n1.1 Look in the opening of the mouthpiece and make sure nothing is blocking it (Figure C).\n\n1.2 Look at the control window (should be red, Figure C).\n\nFigure C\n\n1.3 Hold the inhaler horizontally with the mouthpiece facing you and the green button on top \n\n(Figure D).\n\n Figure D\n\n1.4 Press the green button all the way down to load your dose (Figure E).\n\nWhen you press the button all the way down, the control window changes from red to green.\n\nMake sure the green button is on top. Do not tilt.\n\n1.5 Release the green button (Figure F).\n\nMake sure you release the button so the inhaler can work correctly.\n\nSqueeze here \nand pull\n\nRED\n\nCheck mouthpiece\nopening\n\n\n\n33\n\nFigure E Figure F\n\nStop and Check:\n\n1.6 Make sure the control window is now green (Figure G).\n\nYour medicine is ready to be inhaled.\n\nGo to ‘STEP 2: Inhale your medicine’.\n\nFigure G\n\nWhat to do if the control window is still red after pressing the button (Figure H).\n\nFigure H\n\nThe dose is not prepared. Go back to ‘STEP 1 Prepare your dose’ and repeat steps 1.1 to 1.6.\n\nSTEP 2: Inhale your medicine\n\nRead steps 2.1 to 2.7 fully before use. Do not tilt.\n\nGREEN\n\n\n\n34\n\n2.1 Hold the inhaler away from your mouth, and breathe out completely. Never breathe out into\nthe inhaler (Figure I).\n\nFigure I\n\n2.2 Hold your head upright, put the mouthpiece between your lips, and close your lips\ntightly around it (Figure J).\n\nDo not hold the green button down while inhaling.\n\n2.3 Take a strong, deep breath through your mouth. Keep breathing in for as long as possible.\n\nA ‘click’ will let you know that you are inhaling correctly. Keep breathing in as long as possible \nafter you hear the ‘click’. Some patients may not hear the ‘click’. Use the control window to ensure \nyou have inhaled correctly.\n\n2.4 Take the inhaler out of your mouth.\n\n2.5 Hold your breath for as long as possible.\n\n2.6 Slowly breathe out away from the inhaler.\n\nSome patients may experience a grainy sensation in their mouth, or a slightly sweet or bitter taste. Do \nnot take an extra dose even if you do not taste or feel anything after inhaling.\n\nStop and Check:\n\n2.7 Make sure the control window is now red (Figure K). This means you have inhaled your \n\nmedicine correctly.\n\nFigure J\n\n\n\n35\n\nFigure K\n\nWhat to do if the control window is still green after inhalation (Figure L).\n\nFigure L\n\nThis means you have not inhaled your medicine correctly. Go back to ‘STEP 2 Inhale your medicine’\n\nand repeat steps 2.1 to 2.7.\n\nIf the control window still does not change to red, you may have forgotten to release the green button\nbefore inhaling, or you may not have inhaled strongly enough. If this happens, try again. Make sure you\nhave released the green button, and you have breathed out completely. Then take a strong, deep breath\nthrough the mouthpiece.\n\nPlease contact your doctor if the control window is still green after repeated attempts.\n\nPush the protective cap back onto the mouthpiece after each use (Figure M), to prevent contamination \nof the inhaler with dust or other materials. You should discard your inhaler if you lose the cap.\n\nAdditional information\n\nWhat should you do if you accidently prepare a dose?\n\nStore your inhaler with the protective cap in place until it is time to inhale your medicine, then remove \n\nthe cap and start at Step 1.6.\n\nHow does the dose indicator work?\n\nFigure M\n\nRED\n\n\n\n36\n\n The dose indicator shows the total number of doses left in the inhaler (Figure N).\n On first use, every inhaler contains at least 60 doses, or at least 30 doses, depending on the pack\n\nsize.\n Each time you load a dose by pressing the green button, the dose indicator moves by a small \n\namount towards the next number (50, 40, 30, 20, 10, or 0).\n\nWhen should you get a new inhaler?\n\nYou should get a new inhaler:\n\n If your inhaler appears to be damaged or if you lose the cap, or\n When a red band appears in the dose indicator, this means you are nearing your last dose \n\n(Figure N), or\n If your inhaler is empty (Figure O).\n\nFigure N\n\nHow do you know that your inhaler is empty?\n\nWhen the green button will not return to its full upper position and is locked in a middle position, you \nhave reached the last dose (Figure O). Even though the green button is locked, your last dose may still \nbe inhaled. After that, the inhaler cannot be used again and you should start using a new inhaler.\n\nHow should you clean the inhaler?\n\nFigure O\n\nLocked\n\nDose indicator moves slowly from 60 to\n0: 60, 50, 40, 30, 20, 10, 0.\n\nDose\nindicator\n\nRed band\n\n\n\n37\n\nNEVER use water to clean the inhaler, as this may damage your medicine.\n\nIf you wish to clean your inhaler, just wipe the outside of the mouthpiece with a dry tissue or paper \ntowel.\n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. PACKAGE LEAFLET"},"Section_1":{"kind":"string","value":"{'Title': '1. what eklira genuair is and what it is used for', 'Section_Content': 'what eklira genuair is the active ingredient of eklira genuair is aclidinium bromide, which belongs to a group of medicines called bronchodilators. bronchodilators relax airways and help keep bronchioles open. eklira genuair is a dry powder inhaler that uses your breath to deliver the medicine directly into your lungs. this makes it easier for chronic obstructive pulmonary disease (copd) patients to breathe. what eklira genuair is used for eklira genuair is indicated to help open the airways and relieve symptoms of copd, a serious, long- term lung disease characterised by breathing difficulties. regular use of eklira genuair can help you when you have ongoing shortness of breath related to your disease to help you minimise the effects of the disease on your everyday life and reduce the number of flare-ups (the worsening of your copd symptoms for several days).', 'Entity_Recognition': [{'Text': 'eklira genuair', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 2, 'BeginOffset': 48, 'EndOffset': 62, 'Score': 0.4634452164173126, 'Text': 'eklira genuair', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 3, 'BeginOffset': 66, 'EndOffset': 84, 'Score': 0.9800098538398743, 'Text': 'aclidinium bromide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 114, 'EndOffset': 123}, {'Id': 4, 'BeginOffset': 131, 'EndOffset': 146, 'Score': 0.6538960337638855, 'Text': 'bronchodilators', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'bronchodilators relax', 'Type': 'TREATMENT', 'BeginOffset': 148, 'EndOffset': 169}, {'Text': 'a dry powder inhaler', 'Type': 'TREATMENT', 'BeginOffset': 228, 'EndOffset': 248}, {'Text': 'your breath', 'Type': 'PROBLEM', 'BeginOffset': 259, 'EndOffset': 270}, {'Text': 'the 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symptoms', 'Type': 'PROBLEM', 'BeginOffset': 835, 'EndOffset': 853}]}"},"Section_2":{"kind":"string","value":"{'Title': '2. what you need to know before you use eklira genuair', 'Section_Content': 'do not use eklira genuair - if you are allergic to aclidinium bromide or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor, pharmacist or nurse before using eklira genuair: - if you have had heart problems recently. - if you see halos around lights or coloured images (glaucoma). - if you have an enlarged prostate, problems passing urine, or a blockage in your bladder. eklira genuair is indicated for maintenance treatment and should not be used to treat a sudden attack of breathlessness or wheezing. if your copd symptoms (breathlessness, wheezing, cough) do not improve or get worse you should contact your doctor for advice as soon as possible. dry mouth, which has been observed with medicines like eklira genuair, may after using your medicine for a long time, be associated with tooth decay. therefore, please remember to pay attention to oral hygiene. stop taking eklira genuair and seek medical help immediately: - if you get tightness of the chest, coughing, wheezing or breathlessness immediately after using the medicine. these may be signs of a condition called bronchospasm. children and adolescents eklira genuair is not for use in children or adolescents below 18 years of age. other medicines and eklira genuair tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. inform your doctor if you have been or are using similar medicines for breathing problems, such as medicines containing tiotropium, ipratropium. ask your doctor or pharmacist if you are not sure. the use of eklira genuair with these medicines is not recommended. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. you should not use eklira genuair if you are pregnant or are breast-feeding unless your doctor tells you so. driving and using machines eklira genuair may have minor influence on the ability to drive and use machines. this medicine may cause headache, dizziness or blurred vision. if you are affected by any of these side effects do not drive or use machinery until the headache has cleared, the feeling of dizziness has passed and your vision has returned to normal. eklira genuair contains lactose if you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.', 'Entity_Recognition': [{'Text': 'eklira genuair', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 7, 'BeginOffset': 11, 'EndOffset': 25, 'Score': 0.3066582977771759, 'Text': 'eklira genuair', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 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'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9311988353729248}]}, {'Id': 45, 'BeginOffset': 2176, 'EndOffset': 2188, 'Score': 0.8068587779998779, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6525753140449524}]}, {'Text': 'the headache', 'Type': 'PROBLEM', 'BeginOffset': 2225, 'EndOffset': 2237}, {'Id': 47, 'BeginOffset': 2266, 'EndOffset': 2275, 'Score': 0.9542899131774902, 'Text': 'dizziness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.917593240737915}]}, {'Id': 48, 'BeginOffset': 2413, 'EndOffset': 2439, 'Score': 0.5150169730186462, 'Text': 'intolerance to some sugars', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5615535378456116}]}, {'Text': 'this medicinal product', 'Type': 'TREATMENT', 'BeginOffset': 2475, 'EndOffset': 2497}]}"},"Section_3":{"kind":"string","value":"{'Title': '3. how to use eklira genuair', 'Section_Content': 'always use this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the recommended dose is one inhalation twice a day in the morning and evening. the effects of eklira genuair last for 12 hours; therefore, you should try to use your eklira genuair inhaler at the same time every morning and evening. this ensures that there is always enough medicine in your body to help you breathe more easily throughout the day and night. it will also help you to remember to use it. the recommended dose can be used for elderly patients and for patients with kidney or liver problems. no dose adjustments are necessary. copd is a long-term disease; therefore, it is recommended that eklira genuair is used every day, twice a day and not only when breathing problems or other symptoms of copd are experienced. route of administration 27 the medicine is for inhalation use. refer to the instructions for use for instructions on how to use the genuair inhaler. if you are not sure of how to use eklira genuair, contact your doctor or pharmacist. you can use eklira genuair any time before or after food or drink. if you use more eklira genuair than you should if you think you may have used more eklira genuair than you should, contact your doctor or pharmacist. if you forget to use eklira genuair if you forget a dose of eklira genuair, inhale the dose as soon as you remember. however, if it is nearly time for your next dose, skip the missed dose. do not take a double dose to make up for a forgotten dose. if you stop using eklira genuair this medicine is for long-term use. if you want to stop treatment, first talk to your doctor, as your symptoms may worsen. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.', 'Entity_Recognition': [{'Text': 'eklira genuair', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 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effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. allergic reactions may rarely occur (may affect up to 1 in 1,000 people). stop using the medicine and contact your doctor immediately if you develop swelling of your face, throat, lips or tongue (with or without difficulty breathing or swallowing), dizziness or fainting, faster heart rate or if you get raised severely itchy bumps on your skin (hives) as these may be symptoms of an allergic reaction. the following side effects may occur whilst using eklira genuair: common: may affect up to 1 in 10 people - headache - inflammation of the sinuses (sinusitis) - common cold (nasopharyngitis) - cough - diarrhoea - nausea uncommon: may affect up to 1 in 100 people - dizziness - dry mouth - inflammation of the mouth (stomatitis) - hoarseness (dysphonia) - faster heart beat (tachycardia) - sensation of heart beating (palpitations) - difficulty passing urine (urinary retention) - blurred vision - rash - itching of the skin reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting 28 system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': None}"},"Section_5":{"kind":"string","value":"{'Title': '5. how to store eklira genuair', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the inhaler label and carton after \"exp\". the expiry date refers to the last day of that month. keep the inhaler inside the pouch until the administration period starts. to be used within 90 days of opening the pouch. do not use the eklira genuair if you notice that the pack is damaged or shows signs of tampering. after you have taken the last dose, the inhaler has to be disposed of. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information instructions for use', 'Section_Content': 'what eklira genuair contains - the active substance is aclidinium bromide. each delivered dose contains 375 micrograms aclidinium bromide equivalent to 322 micrograms of aclidinium. - the other ingredient is lactose monohydrate (refer to section 2 \"eklira genuair contains lactose\"). what eklira genuair looks like and contents of the pack eklira genuair is a white or almost white powder. the genuair inhaler device is white coloured with an integral dose indicator and a green dosage button. the mouthpiece is covered with a removable green protective cap. it is supplied in a plastic pouch. pack sizes supplied: carton containing 1 inhaler with 30 doses. carton containing 1 inhaler with 60 doses. carton containing 3 inhalers each with 60 doses. not all pack sizes may be marketed.', 'Entity_Recognition': None}"}}},{"rowIdx":1055,"cells":{"ID":{"kind":"string","value":"528B762D4619412DFD587388A74F39C1"},"URL":{"kind":"string","value":"https://www.ema.europa.eu/documents/product-information/refixia-epar-product-information_en.pdf"},"Product_Name":{"kind":"string","value":"Refixia"},"Full_Content":{"kind":"string","value":"1 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX I \n \n\nSUMMARY OF PRODUCT CHARACTERISTICS \n\n\n\n2 \n\nThis medicinal product is subject to additional monitoring. This will allow quick identification of \nnew safety information. Healthcare professionals are asked to report any suspected adverse reactions. \nSee section 4.8 for how to report adverse reactions. \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nRefixia 500 IU powder and solvent for solution for injection \nRefixia 1000 IU powder and solvent for solution for injection \nRefixia 2000 IU powder and solvent for solution for injection \n \n \n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \nRefixia 500 IU powder and solvent for solution for injection \nEach vial contains nominally 500 IU nonacog beta pegol*. \nAfter reconstitution, 1 ml of Refixia contains approximately 125 IU nonacog beta pegol. \n \nRefixia 1000 IU powder and solvent for solution for injection \nEach vial contains nominally 1000 IU nonacog beta pegol*. \nAfter reconstitution, 1 ml of Refixia contains approximately 250 IU nonacog beta pegol. \n \nRefixia 2000 IU powder and solvent for solution for injection \nEach vial contains nominally 2000 IU nonacog beta pegol*. \nAfter reconstitution, 1 ml of Refixia contains approximately 500 IU nonacog beta pegol. \n \n*recombinant human factor IX, produced in Chinese Hamster Ovary (CHO) cells by recombinant \nDNA technology, covalently conjugated to a 40 kDa polyethylene-glycol (PEG). \n \nThe potency (International Units) is determined using the European Pharmacopeia one-stage clotting \ntest. The specific activity of Refixia is approximately 152 IU/mg protein. \n \nRefixia is a purified recombinant human factor IX (rFIX) with a 40 kDa polyethylene-glycol (PEG) \nselectively attached to specific N-linked glycans in the rFIX activation peptide. Upon activation of \nRefixia, the activation peptide including the 40 kDa polyethylene-glycol moiety is cleaved off, leaving \nthe native activated factor IX molecule. The primary amino acid sequence of the rFIX in Refixia is \nidentical to the Ala148 allelic form of human plasma-derived factor IX. No additives of human or \nanimal origin are used in the cell culture, purification, conjugation, or formulation of Refixia. \n \nExcipient with known effect \nLess than 1 mmol sodium (23 mg) per vial. \n \nFor the full list of excipients, see section 6.1. \n \n \n3. PHARMACEUTICAL FORM \n \nPowder and solvent for solution for injection. \n \nThe powder is white to off-white. \n \nThe solvent is clear and colourless. \n \npH: 6.4. \n \nOsmolality: 272 mOsmol/kg. \n \n\n\n\n3 \n\n \n4. CLINICAL PARTICULARS \n \n4.1 Therapeutic indications \n \nTreatment and prophylaxis of bleeding in patients 12 years and above with haemophilia B (congenital \nfactor IX deficiency). \n \n4.2 Posology and method of administration \n \nTreatment should be under the supervision of a physician experienced in the treatment of haemophilia. \n \nPreviously untreated patients \nThe safety and efficacy of Refixia in previously untreated patients have not yet been established. \n \nTreatment monitoring \nRoutine monitoring of factor IX activity levels for the purpose of dose adjustment is not necessary. In \nthe clinical trial programme, dose adjustment was not performed. Mean steady state factor IX trough \nlevels above 15% were observed for all age groups, see section 5.2 for details. \n \nDue to the interference of polyethylene glycol (PEG) in the one-stage clotting assay with various aPTT \nreagents, it is recommended to use a chromogenic assay (e.g. Rox Factor IX or Biophen) when \nmonitoring is needed. If a chromogenic assay is not available, it is recommended to use a one-stage \nclotting assay with an aPTT reagent (e.g. Cephascreen) qualified for use with Refixia. For modified \nlong-acting factor products it is known that the one-stage clotting assay results are highly dependent \non the aPTT reagent and reference standard used. For Refixia some reagents will cause \nunderestimation (30–50%), while most silica containing reagents will cause severe overestimation of \nthe factor IX activity (more than 400%). Therefore, silica based reagents should be avoided. Use of a \nreference laboratory is recommended when a chromogenic assay or a qualified one-stage clotting \nassay is not available locally. \n \nPosology \nThe number of units of factor IX administered is expressed in International Units (IU), which are \nrelated to the current WHO standard for factor IX products. Factor IX activity in plasma is expressed \neither as a percentage (relative to normal human plasma) or in International Units (relative to an \nInternational Standard for factor IX in plasma). \n \nProphylaxis \n40 IU/kg body weight once weekly. \nAdjustments of doses and administration intervals may be considered based on achieved FIX levels \nand individual bleeding tendency. The trough levels achieved with the weekly 40 IU/kg dosing \nregimen are summarised in section 5.2. \n \nPatients on prophylaxis who forget a dose are advised to take their dose upon discovery and thereafter \ncontinue with the usual once weekly dosing schedule. A double dose should be avoided. \n \nOn-demand treatment \nDose and duration of the substitution therapy depend on the location and severity of the bleeding, see \nTable 1 for dosing guidance in bleeding episodes. \n \nTable 1 Treatment of bleeding episodes with Refixia \n\nDegree of \nhaemorrhage \n\nRecommended \ndose IU/kg of \nRefixia \n\nDosing recommendations \n\n\n\n4 \n\nEarly \nhaemarthrosis, \nmuscle bleeding or \noral bleeding. \n \nMore extensive \nhaemarthrosis, \nmuscle bleeding or \nhaematoma. \n\n40 A single dose is recommended. \n\nSevere or life \nthreatening \nhaemorrhages. \n\n80 Additional doses of 40 IU/kg can be \ngiven. \n\n \nSurgery \nThe dose level and dosing intervals for surgery depend on the procedure and local practice. General \nrecommendations are provided in Table 2. \n \nTable 2 Treatment in surgery with Refixia \n\nType of surgical \nprocedure \n\nRecommended \ndose IU/kg body \nweight \n\nDosing recommendations \n\nMinor surgery \nincluding tooth \nextraction. \n\n40 Additional doses can be given if needed. \n\nMajor surgery. 80 Pre-operative dose. \n\n40 Consider two repeated doses of 40 IU/kg \n(in 1–3 day intervals) within the first \nweek after surgery. \n \nDue to the long half-life of Refixia, the \nfrequency of dosing in the post-surgical \nperiod may be extended to once weekly \nafter the first week until bleeding stops \nand healing is achieved. \n\n \nPaediatric population \nThe dose recommendations in adolescents (12–18 years) are the same as for adults: 40 IU/kg body \nweight. The long-term safety of Refixia in children below 12 years has not yet been established. \n \nMethod of administration \nIntravenous use. \n \nRefixia is administered by intravenous bolus injection over several minutes after reconstitution of the \npowder for injection with the histidine solvent. The rate of administration should be determined by the \npatient’s comfort level up to a maximum injection rate of 4 ml/min. \n \nFor instructions on reconstitution of the medicinal product before administration, see section 6.6. \n \nIn case of self-administration or administration by caregiver appropriate training is needed. \n \n4.3 Contraindications \n\n\n\n5 \n\n \nHypersensitivity to the active substance or to any of the excipients listed in section 6.1. \n \nKnown allergic reaction to hamster protein. \n \n4.4 Special warnings and precautions for use \n \nHypersensitivity \nAllergic type hypersensitivity reactions are possible with Refixia. The product contains traces of \nhamster proteins. If symptoms of hypersensitivity occur, patients should be advised to discontinue use \nof the medicinal product immediately and contact their physician. Patients should be informed of the \nearly signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, \nwheezing, hypotension, and anaphylaxis. \n \nIn case of shock, standard medical treatment for shock should be implemented. \n \nInhibitors \nAfter repeated treatment with human coagulation factor IX (rDNA) products, patients should be \nmonitored for the development of neutralising antibodies (inhibitors) that should be quantified in \nBethesda Units (BU) using appropriate biological testing. \n \nThere have been reports in the literature showing a correlation between the occurrence of a factor IX \ninhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated \nfor the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an \nincreased risk of anaphylaxis with subsequent challenge with factor IX. \n \nBecause of the risk of allergic reactions with factor IX products, the initial administrations of factor IX \nshould, according to the treating physician’s judgement, be performed under medical observation \nwhere proper medical care for allergic reactions could be provided. \n \nIn case of residual FIX activity levels, there is a risk of interference when performing the Nijmegen \nmodified Bethesda assay for inhibitor testing. Therefore a pre-heating step or a wash-out is \nrecommended in order to ensure detection of low-titre inhibitors. \n \nThromboembolism \nBecause of the potential risk of thrombotic complications, clinical surveillance for early signs of \nthrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when \nadministering this product to patients with liver disease, to patients post-operatively, to new-born \ninfants, or to patients at risk of thrombotic phenomena or DIC. In each of these situations, the benefit \nof treatment with Refixia should be weighed against the risk of these complications. \n \nCardiovascular event \nIn patients with existing cardiovascular risk factors, substitution therapy with FIX may increase the \ncardiovascular risk. \n \nCatheter-related complications \nIf a central venous access device (CVAD) is required, risk of CVAD-related complications including \nlocal infections, bacteraemia and catheter site thrombosis should be considered. \n \nPaediatric population \nRefixia is not indicated for use in children (below 12 years). The listed warnings and precautions apply \nboth to adults and adolescents (12–18 years). \n \nSodium content \nThis medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. it is essentially \n“sodium-free”. \n \n\n\n\n6 \n\nRecord of use \nIt is strongly recommended that every time that Refixia is administered to a patient, the name and \nbatch number of the product are recorded in order to maintain a link between the patient and the batch \nof the medicinal product. \n \n4.5 Interaction with other medicinal products and other forms of interaction \n \nNo interactions of human coagulation factor IX (rDNA) products with other medicinal products have \nbeen reported. \n \n4.6 Fertility, pregnancy and lactation \n \nAnimal reproduction studies have not been conducted with factor IX. Based on the rare occurrence of \nhaemophilia B in women, experience regarding the use of factor IX during pregnancy and \nbreastfeeding is not available. Therefore, factor IX should be used during pregnancy and lactation only \nif clearly indicated. \n \n4.7 Effects on ability to drive and use machines \n \nRefixia has no influence on the ability to drive and use machines. \n \n4.8 Undesirable effects \n \nSummary of the safety profile \nHypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the \ninfusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, \nrestlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed \nrarely with recombinant factor IX products and may in some cases progress to severe anaphylaxis \n(including shock). In some cases, these reactions have progressed to severe anaphylaxis, and they have \noccurred in close temporal association with development of factor IX inhibitors (see also section 4.4). \nNephrotic syndrome has been reported following attempted immune tolerance induction in \nhaemophilia B patients with factor IX inhibitors and a history of allergic reaction. \n \nVery rarely development of antibodies to hamster protein with related hypersensitivity reactions has \nbeen observed. \n \nPatients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. If such \ninhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it \nis recommended that a specialised haemophilia centre is contacted. \n \nThere is a potential risk of thromboembolic episodes following the administration of factor IX \nproducts, with a higher risk for low purity preparations. The use of low purity factor IX products has \nbeen associated with instances of myocardial infarction, disseminated intravascular coagulation, \nvenous thrombosis and pulmonary embolism. The use of high purity factor IX products like Refixia is \nrarely associated with such adverse reactions. \n \nTabulated list of adverse reactions \nThe table presented below is according to the MedDRA system organ classification (SOC and \nPreferred Term Level). \n \nFrequencies have been evaluated according to the following convention: very common (≥ 1/10); \ncommon (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very \nrare (< 1/10,000), not known (cannot be estimated from the available data). \nWithin each frequency grouping, adverse reactions are presented in order of decreasing seriousness. \n \nA total of 115 previously treated male patients with moderate or severe haemophilia B have been \nexposed to Refixia for a total of 170 patient years in the completed clinical trials. \n\n\n\n7 \n\n \nTable 3 Frequency of adverse reactions in clinical trials \n\nSystem Organ Class Adverse reaction Frequency \n\nImmune system disorders Hypersensitivity \nAnaphylaxis \nInhibitors \n\nUncommon \nUnknown \nUnknown \n\nCardiac disorders Palpitations Uncommon \n\nGastrointestinal disorders Nausea Common \n\nSkin and subcutaneous tissue \ndisorders \n\nPruritus* Common \n\nGeneral disorders and \nadministration site conditions \n\nFatigue \nHot flush \nInjection site reactions** \n\nCommon \nUncommon \nCommon \n\n*Pruritus includes the terms pruritus and ear pruritus \n**Injection site reactions include injection site pain, infusion site pain, injection site swelling, injection site erythema and \ninjection site rash. \n \nDescription of selected adverse reactions \nIn an ongoing trial in previously untreated patients, anaphylaxis has occurred in close temporal \nassociation with development of factor IX inhibitors following treatment with Refixia. There are \ninsufficient data to provide information on inhibitor incidence in previously untreated patients. \n \nPaediatric population \nRefixia is indicated for patients 12 years and above. No difference in the safety profile of Refixia was \nobserved between previously treated adolescent (12–18 years) and adult patients. \n \nReporting of suspected adverse reactions \nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V. \n \n4.9 Overdose \n \nOverdoses up to 169 IU/kg have been reported in clinical trials. No symptoms associated with \noverdoses have been reported. \n \n \n5. PHARMACOLOGICAL PROPERTIES \n \n5.1 Pharmacodynamic properties \n \nPharmacotherapeutic group: antihaemorrhagics, blood coagulation factor IX, ATC code: B02BD04. \n \nMechanism of action \nRefixia is a purified recombinant human factor IX (rFIX) with a 40 kDa polyethylene-glycol (PEG) \nconjugated to the protein. The average molecular weight of Refixia is approximately 98 kDa and the \nmolecular weight of the protein moiety alone is 56 kDa. Upon activation of Refixia, the activation \npeptide including the 40 kDa polyethylene-glycol moiety is cleaved off, leaving the native activated \nfactor IX molecule. \n \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n8 \n\nFactor IX is a single chain glycoprotein. It is a vitamin-K dependent coagulation factor and it is \nsynthesised in the liver. Factor IX is activated by factor XIa and by factor VII/tissue factor complex. \nActivated factor IX, in combination with activated factor VIII, activates factor X. Activated factor X \nconverts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is \nformed. Haemophilia B is a sex-linked hereditary disorder of blood coagulation due to decreased \nlevels of factor IX and results in profuse bleeding into joints, muscles, or internal organs, either \nspontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels \nof factor IX are increased, thereby enabling a temporary correction of the factor deficiency and \ncorrection of the bleeding tendencies. \n \nClinical efficacy \nThe completed clinical trial programme included one phase 1 trial and four phase 3 multicentre, non-\ncontrolled trials. \n \nProphylaxis \nFifty-four of the patients across all age-groups were treated with a weekly prophylactic dose of \n40 IU/kg where 23 (43%) of these patients had no bleeding episodes. \n \nPivotal trial \nThe pivotal trial included 74 adolescent (13–17 years) and adult (18–65 years) previously treated \npatients. The trial included one open-label on-demand arm with treatment for approximately 28 weeks \nand two prophylaxis treatment arms with single-blind randomisation to either 10 IU/kg or 40 IU/kg \nonce-weekly for approximately 52 weeks. When comparing the 10 IU/kg and 40 IU/kg treatments, the \nannualised bleeding rate for patients in the 40 IU/kg arm was found to be 49% lower than the bleeding \nrate (95% CI: 5%;73%) for patients in the 10 IU/kg arm (p<0.05). \n \nThe median (IQR) overall annual bleeding rate (ABR) in patients (13–65 years) treated with a \nprophylactic dose of 40 IU/kg once weekly was 1.04 (0.00; 4.01) whereas the traumatic ABR was 0.00 \n(0.00; 2.05), joint ABR was 0.97 (0.00; 2.07) and spontaneous ABR was 0.00 (0.00; 0.99). \nOf note, ABR is not comparable between different factor concentrates and between different clinical \nstudies. \n \nIn this pivotal trial in adolescent and adult patients, there were 70 breakthrough bleeding episodes for \n16 out of 29 patients in the 40 IU/kg prophylaxis arm. The overall success rate for treatment of \nbreakthrough bleeds was 97.1% (67 out of 69 evaluated bleeds). A total of 69 (98.6%) of the 70 \nbleeding episodes were treated with one injection. Bleeding episodes were treated with Refixia at \n40 IU/kg for mild or moderate bleeds. \n \nIn 29 adult and adolescent patients treated, 13 patients with 20 target joints were treated for one year \nwith a weekly prophylactic dose of 40 IU/kg. Eighteen out of these 20 joints (90%) were no longer \nconsidered target joints at the end of the trial. \n \nOn-demand treatment \nIn the pivotal trial there was a non-randomised arm where 15 patients were treated in an on-demand \nregimen with 40 IU/kg for mild or moderate bleeds and 80 IU/kg for severe bleeds. The overall \nsuccess rate (defined as excellent or good) for treatment of bleeds was 95% with 98% of the bleeds \ntreated with one or two injections. \n \nPaediatric population \nThe use of Refixia in children below 12 years is not indicated (see section 4.2 for information on \npaediatric use). \n \nA trial including 25 paediatric previously treated patients (ages 0–12 years) who received a \nprophylactic dose 40 IU/kg once weekly was performed. \nIn children aged 0–12 years, the median (IQR) annualised bleeding rate was 1.0 (0.00; 2.06) and the \nspontaneous bleeding rate was 0.00 (0.00; 0.00). \n \n\n\n\n9 \n\nFor treatment of bleeds in paediatrics, the overall success rate (defined as excellent or good) was 93% \n(39 out of 42 bleeds), where 36 (86 %) of the bleeds were resolved with 1 injection, and 5 (12%) of the \nbleeds were resolved with 2 injections of Refixia. \n \nThe European Medicines Agency has deferred the completion of the study with Refixia in previously \nuntreated patients (see section 4.2 for information on paediatric use). \n \nOverall haemostatic efficacy \nBleeding episodes were treated with Refixia at 40 IU/kg for mild or moderate bleeds or 80 IU/kg for \nsevere bleeds, where one bleed was evaluated as severe. An overall assessment of haemostatic efficacy \nwas performed by the patient or caretaker (for home treatment) or study site investigator (for treatment \nunder health care professional supervision) using a 4-point scale of excellent, good, moderate, or poor. \nThe overall success rate (defined as excellent or good) for treatment of bleeds was 93% (551 out of \n591). Of the 597 treated bleeds observed in 79 (75%) of the 105 patients, 521 (87%) of the bleeds were \nresolved with 1 injection and 60 (10%) of the bleeds were resolved with 2 injections of Refixia. \n \nThe success rate and dose needed for treatment of the bleeding episodes were independent of the \nlocalisation of the bleed. The success rate for treatment of bleeding episodes was also independent of \nwhether the bleed was traumatic or spontaneous of nature. \n \nSurgery \nThree trials of which one trial was a dedicated surgery trial included in total 15 major and 26 minor \nsurgery procedures (patients aged 13 to 56 years). Haemostatic effect of Refixia during surgery was \nconfirmed with a success rate of 100% in the 15 major surgeries in the trials. All evaluated minor \nsurgeries were performed successfully. \n \nIn a dedicated surgery trial, the efficacy analysis included 13 major surgical procedures performed in \n13 previously treated adult and adolescent patients. The procedures included 9 orthopaedic, 1 \ngastrointestinal, and 3 surgeries in the oral cavity. The patients received 1 pre-operative injection of \n80 IU/kg on the day of surgery, and post-operatively, injections of 40 IU/kg. A pre-operative dose of \n80 IU/kg Refixia was effective and no patients required additional doses on the day of surgery. In the \npost-surgery period Day 1 to 6 and Day 7 to 13, the median number of additional 40 IU/kg doses \nadministered was 2.0 and 1.5, respectively. The mean total consumption of Refixia during and after \nsurgery was 241 IU/kg (range: 81–460 IU/kg). \n \n5.2 Pharmacokinetic properties \n \nRefixia has a prolonged half-life compared to unmodified factor IX. All pharmacokinetic studies with \nRefixia were conducted in previously treated patients with haemophilia B (factor IX ≤2%). The \nanalysis of plasma samples was conducted using the one-stage clotting assay. \n \nSteady state pharmacokinetic parameters for adolescents and adults are shown in Table 4 \n \nTable 4 Steady state pharmacokinetic parameters of Refixia (40 IU/kg) in adolescents and \n\nadults (geometric mean (CV%)) \nPK Parameter 13–17 years \n\nN=3 \n≥18 years \nN=6 \n\nHalf-life (t1/2) (hours) 103 (14) 115 (10) \n\nIncremental Recovery (IR) (IU/ml per \nIU/kg) \n\n0.018 (28) 0.019 (20) \n\nArea under the curve (AUC)0-168h \n(IU*hours/ml) \n\n91 (22) 93 (15) \n\nClearance (CL) (ml/hour/kg) 0.4 (17) 0.4 (11) \n\nMean residence time (MRT) (hours) 144 (15) 158 (10) \n\n\n\n10 \n\nVolume of distribution (Vss) (ml/kg) 61 (31) 66 (12) \n\nFactor IX activity 168 h post dosing \n(IU/ml) \n\n0.29 (19) 0.32 (17) \n\nClearance = body weight adjusted clearance; Incremental recovery = incremental recovery 30 min post dosing, Volume of \ndistribution = body weight adjusted volume of distribution at steady state. CV = coefficient of variation. \n \nAll patients assessed in the steady state pharmacokinetic session had factor IX activity levels above \n0.24 IU/ml at 168 hours post dosing with a weekly dose of 40 IU/kg. \n \nSingle-dose pharmacokinetic parameters of Refixia are listed by age in Table 5. The use of Refixia in \nchildren below 12 years is not indicated. \n \nTable 5 Single-dose pharmacokinetic parameters of Refixia (40 IU/kg) by age (geometric \n\nmean (CV%)) \n\nPK Parameter 0–6 years \nN=12 \n\n7–12 years \nN=13 \n\n13–17 years \nN=3 \n\n≥18 years \nN=6 \n\nHalf-life (t1/2) \n(hours) \n\n70 (16) 76 (26) 89 (24) 83 (23) \n\nIncremental \nRecovery (IR) \n(IU/ml per IU/kg) \n\n0.015 (7) 0.016 (16) 0.020 (15) 0.023 (11) \n\nArea under the \ncurve (AUC)inf \n(IU*hours/ml) \n\n46 (14) 56 (19) 80 (35) 91 (16) \n\nClearance CL \n(ml/hour/kg) \n\n0.8 (13) 0.6 (22) 0.5 (30) 0.4 (15) \n\nMean residence \ntime (MRT) \n(hours) \n\n95 (15) 105 (24) 124 (24) 116 (22) \n\nVolume of \ndistribution (Vss) \n(ml/kg) \n\n72 (15) 68 (22) 59 (8) 47 (16) \n\nFactor IX activity \n168 h post dosing \n(IU/ml) \n\n0.08 (16) 0.11 (19) 0.15 (60) 0.17 (31) \n\nClearance = body weight adjusted clearance; Incremental recovery = incremental recovery 30 min post dosing, Volume of \ndistribution = body weight adjusted volume of distribution at steady state. CV = coefficient of variation. \n \nAs expected, body weight adjusted clearance in paediatric and adolescent patients was higher \ncompared to adults. No dose adjustment was required for paediatric or adolescent patients in clinical \ntrials. \n \nThe mean trough levels at steady state are presented in Table 6; based on all pre-dose measurements \ntaken every 8 weeks at steady state for all patients on once weekly dosing of 40 IU/kg. The use of \nRefixia in children below 12 years is not indicated. \n \nTable 6 Mean of trough levels* of Refixia (40 IU/kg) at steady state \n\n 0–6 years 7–12 years 13–17 years 18–65 years \n\n\n\n11 \n\nN=12 N=13 N=9 N=20 \n\nEstimated mean \nfactor IX trough \nlevels IU/ml \n(95% CI) \n\n0.15 \n(0.13;0.18) \n\n0.19 \n(0.16;0.22) \n\n0.24 \n(0.20;0.28) \n\n0.29 \n(0.26;0.33) \n\n* Factor IX trough levels = factor IX activity measured prior to next weekly dose (5 to 10 days post dosing) at steady state. \n \nPharmacokinetics were investigated in 16 adult and adolescent patients of which 6 were normal weight \n(BMI 18.5–24.9 kg/m2) and 10 were overweight (BMI 25–29.9 kg/m2). There were no apparent \ndifferences in the pharmacokinetic profiles between normal weight and overweight patients. \n \n5.3 Preclinical safety data \n \nIn a repeat dose toxicity study in monkeys, mild and transient body tremors were seen 3 hours post \ndosing and abated within 1 hour. These body tremors were seen at doses of Refixia (3,750 IU/kg), \nwhich were more than 90 times higher than the recommended dose for humans (40 IU/kg). No \nmechanism behind the tremors was identified. Tremors have not been reported in the clinical trials. \n \nNon-clinical data reveal no concern for humans based on conventional safety pharmacology and \nrepeated dose toxicity studies in rats and monkeys. \n \nIn repeat dose toxicity studies in rats and monkeys, 40 kDa polyethylene-glycol (PEG) was detected \nby immunohistochemical staining in epithelial cells of choroid plexus in the brain. This finding was \nnot associated with tissue damage or abnormal clinical signs. \n \nIn distribution and excretion studies in mice and rats, the 40 kDa polyethylene-glycol (PEG) moiety of \nRefixia was shown to be widely distributed to and eliminated from organs, and excreted via plasma in \nurine (44–56%) and faeces (28–50%). Based on modelled data using observed terminal half-lives (15–\n49 days) in rat tissue distribution studies, the 40 kDa polyethylene-glycol (PEG) moiety will reach \nsteady state levels in all human tissues within 1–2 years of treatment. \n \nLong-term studies in animals to evaluate the carcinogenic potential of Refixia, or studies to determine \nthe effects of Refixia on genotoxicity, fertility, development, or reproduction have not been performed. \n \n \n6. PHARMACEUTICAL PARTICULARS \n \n6.1 List of excipients \n \nPowder \nSodium chloride \nHistidine \nSucrose \nPolysorbate 80 \nMannitol \nSodium hydroxide (for pH adjustment) \nHydrochloric acid (for pH adjustment) \n \nSolvent \nHistidine \nWater for injections \nSodium hydroxide (for pH adjustment) \nHydrochloric acid (for pH adjustment) \n \n6.2 Incompatibilities \n\n\n\n12 \n\n \nIn the absence of compatibility studies, this medicine must not be mixed with other medicinal products \nor reconstituted with infusion solutions other than the provided histidine solvent. \n \n6.3 Shelf life \n \nUnopened \n2 years. During the shelf life Refixia may be stored up to 30°C for a single period not exceeding \n6 months. Once the product has been taken out of the refrigerator the product must not be returned to \nthe refrigerator. Please record the beginning of storage at room temperature on the product carton. \n \nAfter reconstitution \n \nChemical and physical in-use stability have been demonstrated for 24 hours stored in a refrigerator \n(2°C – 8°C) and 4 hours stored at room temperature (≤ 30°C). \n \nFrom a microbiological point of view, the reconstituted product should be used immediately. If not \nused immediately, in-use storage times and conditions prior to use are the responsibility of the users \nand would normally not be recommended for longer than 4 hours stored at room temperature (≤ 30°C) \nor 24 hours in a refrigerator (2°C – 8°C), unless reconstitution has taken place under controlled and \nvalidated aseptic conditions. \n \n6.4 Special precautions for storage \n \nStore in a refrigerator (2°C – 8°C). Do not freeze. \nStore in the original package in order to protect from light. \nFor storage at room temperature and storage conditions after reconstitution of the medicinal product, \nsee section 6.3. \n \n6.5 Nature and contents of container \n \nEach pack contains: \n– 1 glass vial (type I) with powder and chlorobutyl rubber stopper \n– 1 sterile vial adapter for reconstitution \n– 1 pre-filled syringe of 4 ml histidine solvent with backstop (polypropylene), a rubber plunger \n\n(bromobutyl) and a tip cap with a stopper (bromobutyl) \n– 1 plunger rod (polypropylene). \n \nPack size of 1. \n \n6.6 Special precautions for disposal and other handling \n \nRefixia is to be administered intravenously after reconstitution of the powder with the solvent supplied \nin the syringe. After reconstitution the solution appears as a clear and colourless liquid free of visible \nparticles. Reconstituted medicinal product should be inspected visually for particulate matter and \ndiscoloration prior to administration. Do not use solutions that are cloudy or have deposits. \n \nFor instructions on reconstitution of the medicinal product before administration, see the package \nleaflet. \n \nThe rate of administration should be determined by the patient’s comfort level up to a maximum \ninjection rate of 4 ml/min. \n \nAn infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads and plasters will also \nbe needed. These devices are not included in the Refixia package. \n \nAlways use an aseptic technique. \n\n\n\n13 \n\n \nDisposal \nAfter injection, safely dispose of the syringe with the infusion set and the vial with the vial adapter. \nAny unused medicinal product or waste material should be disposed of in accordance with local \nrequirements. \n \n \n7. MARKETING AUTHORISATION HOLDER \n \nNovo Nordisk A/S \nNovo Allé \nDK-2880 Bagsværd \nDenmark \n \n \n8. MARKETING AUTHORISATION NUMBERS \n \nEU/1/17/1193/001 \nEU/1/17/1193/002 \nEU/1/17/1193/003 \n \n \n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n \n \n10. DATE OF REVISION OF THE TEXT \n \nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency http://www.ema.europa.eu. \n \n\nhttp://www.ema.europa.eu/\n\n\n14 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX II \n \n\nA. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND \nMANUFACTURER RESPONSIBLE FOR BATCH RELEASE \n\n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n\n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n \n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n\n \n\n\n\n15 \n\nA. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND \nMANUFACTURER RESPONSIBLE FOR BATCH RELEASE \n\n \nName and address of the manufacturers of the biological active substance \n \nNovo Nordisk A/S \nBrennum Park 25K \nDK-3400 Hillerød \nDenmark \n \nNovo Nordisk A/S \nHagedornsvej 1 \nDK-2820 Gentofte \nDenmark \n \nName and address of the manufacturer responsible for batch release \n \nNovo Nordisk A/S \nNovo Alle \nDK-2880 Bagsværd \nDenmark \n \n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n \nMedicinal product subject to restricted medical prescription (see Annex I: Summary of Product \nCharacteristics, section 4.2). \n \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n \n• Periodic safety update reports \n \nThe requirements for submission of periodic safety update reports for this medicinal product are set \nout in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive \n2001/83/EC and any subsequent updates published on the European medicines web-portal. \nThe marketing authorisation holder shall submit the first periodic safety update report for this \nproduct within 6 months following authorisation. \n \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n \n• Risk Management Plan (RMP) \n \nThe MAH shall perform the required pharmacovigilance activities and interventions detailed in the \nagreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent \nupdates of the RMP. \nAn updated RMP should be submitted: \n\n• At the request of the European Medicines Agency; \n• Whenever the risk management system is modified, especially as the result of new \n\ninformation being received that may lead to a significant change to the benefit/risk profile \nor as the result of an important (pharmacovigilance or risk minimisation) milestone being \nreached. \n\n \n• Obligation to conduct post-authorisation measures \n\n\n\n16 \n\n \nThe MAH shall complete, within the stated timeframe, the below measures: \n \nDescription Due date \nNon-interventional post-authorisation safety study (PASS): In order to investigate \nthe potential effects of PEG accumulation in the choroid plexus of the brain and \nother tissues/organs, the MAH should conduct and submit the results of a non-\ninterventional post-authorisation safety study deriving from a registry of \nHaemophilia patients according to an agreed protocol. \n\nSubmission of \nstudy results: \nQ2-2028 \n\n \n\n\n\n17 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX III \n \n\nLABELLING AND PACKAGE LEAFLET \n\n\n\n18 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nA. LABELLING \n\n\n\n19 \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCarton \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nRefixia 500 IU powder and solvent for solution for injection \n \nnonacog beta pegol \n(recombinant coagulation factor IX) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE \n \nPowder: 500 IU nonacog beta pegol (approx. 125 IU/ml after reconstitution), \n \n \n3. LIST OF EXCIPIENTS \n \nPowder: \nsodium chloride, histidine, sucrose, polysorbate 80, mannitol, sodium hydroxide, hydrochloric acid \n \nSolvent: Histidine, water for injections, sodium hydroxide, hydrochloric acid \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nPowder and solvent for solution for injection \n \nPack contains: 1 powder vial, 4 ml solvent in a pre-filled syringe, 1 plunger rod and 1 vial adapter \n \n \n5. METHOD AND ROUTE OF ADMINISTRATION \n \nRead the package leaflet before use \n \nIntravenous use, after reconstitution \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children \n \n \n7. OTHER SPECIAL WARNINGS, IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n\n\n\n20 \n\n \nStore in a refrigerator. Do not freeze \nCan be stored at room temperature (up to 30°C) for a single period up to 6 months. Must not be \nreturned to refrigerator after storage at room temperature \n \nDate removed from refrigerator: ____________ \n \nStore in the original package to protect from light \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nNovo Nordisk A/S \nNovo Allé \nDK-2880 Bagsværd \nDenmark \n \n \n12. MARKETING AUTHORISATION NUMBER \n \nEU/1/17/1193/001 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nRefixia 500 IU \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: \nSN: \nNN: \n\n\n\n21 \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVial \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION \n \nRefixia 500 IU powder for solution for injection \n \nnonacog beta pegol \n \nIV \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n500 IU \n \n \n6. OTHER \n \nNovo Nordisk A/S\n\n\n\n22 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCarton \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nRefixia 1000 IU powder and solvent for solution for injection \n \nnonacog beta pegol \n(recombinant coagulation factor IX) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE \n \nPowder: 1000 IU nonacog beta pegol (approx. 250 IU/ml after reconstitution), \n \n \n3. LIST OF EXCIPIENTS \n \nPowder: \nsodium chloride, histidine, sucrose, polysorbate 80, mannitol, sodium hydroxide, hydrochloric acid \n \nSolvent: Histidine, water for injections, sodium hydroxide, hydrochloric acid \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nPowder and solvent for solution for injection \n \nPack contains: 1 powder vial, 4 ml solvent in a pre-filled syringe, 1 plunger rod and 1 vial adapter \n \n \n5. METHOD AND ROUTE OF ADMINISTRATION \n \nRead the package leaflet before use \n \nIntravenous use, after reconstitution \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children \n \n \n7. OTHER SPECIAL WARNINGS, IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n\n\n\n23 \n\n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. Do not freeze \nCan be stored at room temperature (up to 30°C) for a single period up to 6 months. Must not be \nreturned to refrigerator after storage at room temperature \n \nDate removed from refrigerator: ____________ \n \nStore in the original package to protect from light \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nNovo Nordisk A/S \nNovo Allé \nDK-2880 Bagsværd \nDenmark \n \n \n12. MARKETING AUTHORISATION NUMBER \n \nEU/1/17/1193/002 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nRefixia 1000 IU \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: \nSN: \nNN: \n\n\n\n24 \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVial \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION \n \nRefixia 1000 IU powder for solution for injection \n \nnonacog beta pegol \n \nIV \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n1000 IU \n \n \n6. OTHER \n \nNovo Nordisk A/S \n\n\n\n25 \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCarton \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nRefixia 2000 IU powder and solvent for solution for injection \n \nnonacog beta pegol \n(recombinant coagulation factor IX) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE \n \nPowder: 2000 IU nonacog beta pegol (approx. 500 IU/ml after reconstitution), \n \n \n3. LIST OF EXCIPIENTS \n \nPowder: \nsodium chloride, histidine, sucrose, polysorbate 80, mannitol, sodium hydroxide, hydrochloric acid \n \nSolvent: Histidine, water for injections, sodium hydroxide, hydrochloric acid \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nPowder and solvent for solution for injection \n \nPack contains: 1 powder vial, 4 ml solvent in a pre-filled syringe, 1 plunger rod and 1 vial adapter \n \n \n5. METHOD AND ROUTE OF ADMINISTRATION \n \nRead the package leaflet before use \n \nIntravenous use, after reconstitution \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children \n \n \n7. OTHER SPECIAL WARNINGS, IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n\n\n\n26 \n\n \nStore in a refrigerator. Do not freeze \nCan be stored at room temperature (up to 30°C) for a single period up to 6 months. Must not be \nreturned to refrigerator after storage at room temperature \n \nDate removed from refrigerator: ____________ \n \nStore in the original package to protect from light \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nNovo Nordisk A/S \nNovo Allé \nDK-2880 Bagsværd \nDenmark \n \n \n12. MARKETING AUTHORISATION NUMBER \n \nEU/1/17/1193/003 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nRefixia 2000 IU \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: \nSN: \nNN: \n \n\n\n\n27 \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVial \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION \n \nRefixia 2000 IU powder for solution for injection \n \nnonacog beta pegol \n \nIV \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n2000 IU \n \n \n6. OTHER \n \nNovo Nordisk A/S \n\n\n\n28 \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nPre-filled syringe \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION \n \nSolvent for Refixia \n \nHistidine solution \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n4 ml \n \n \n6. OTHER \n \nNovo Nordisk A/S \n\n\n\n29 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nB. PACKAGE LEAFLET \n\n\n\n30 \n\nPackage leaflet: Information for the user \n \n\nRefixia 500 IU powder and solvent for solution for injection \nRefixia 1000 IU powder and solvent for solution for injection \nRefixia 2000 IU powder and solvent for solution for injection \n\nnonacog beta pegol \n \n\nThis medicine is subject to additional monitoring. This will allow quick identification of new \nsafety information. You can help by reporting any side effects you may get. See the end of section 4 \nfor how to report side effects. \n \nRead all of this leaflet carefully before you start using this medicine because it contains \nimportant information for you. \n• Keep this leaflet. You may need to read it again. \n• If you have any further questions, ask your doctor. \n• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n• If you get any side effects, talk to your doctor. This includes any possible side effects not listed \n\nin this leaflet. See section 4. \n \nWhat is in this leaflet \n \n1. What Refixia is and what it is used for \n2. What you need to know before you use Refixia \n3. How to use Refixia \n4. Possible side effects \n5. How to store Refixia \n6. Contents of the pack and other information \n \n \n1. What Refixia is and what it is used for \n \nWhat Refixia is \nRefixia contains the active substance nonacog beta pegol and is a long-acting recombinant coagulation \nfactor IX product. Factor IX is a protein naturally found in the blood that helps to stop bleeding. \n \nWhat Refixia is used for \nRefixia is used to treat and prevent bleeding in patients 12 years and above with haemophilia B \n(inborn factor IX deficiency). \n \nIn patients with haemophilia B, factor IX is missing or does not work properly. Refixia replaces this \nfaulty or missing factor IX and helps blood to form clots at the site of bleeding. When you bleed, \nRefixia is activated in the blood to form factor IX. \n \n \n2. What you need to know before you use Refixia \n \nDo not use Refixia: \n• if you are allergic to the active substance or any of the other ingredients of this medicine (listed \n\nin section 6). \n• if you are allergic to hamster proteins. \n \nIf you are not sure if either of the above applies to you, talk to your doctor before using this medicine. \n \nWarnings and precautions \n \n \n\n\n\n31 \n\nAllergic reactions and development of inhibitors \nThere is a rare risk that you may experience a sudden and severe allergic reaction (e.g. anaphylactic \nreaction) to Refixia. Stop the injection and contact your doctor or an emergency unit immediately if \nyou have signs of an allergic reaction such as rash, hives, weals, itching on large areas of skin, redness \nand/or swelling of lips, tongue, face or hands, difficulty in swallowing or breathing, shortness of \nbreath, wheezing, tightness of the chest, pale and cold skin, fast heartbeat, and/or dizziness. \n \nYour doctor may need to treat you promptly for these reactions. Your doctor may also do a blood test \nto check if you have developed factor IX inhibitors (neutralising antibodies) against your medicine, as \ninhibitors may develop together with allergic reactions. If you have such antibodies, you may be at an \nincreased risk of sudden and severe allergic reactions (e.g. anaphylactic reaction) during future \ntreatment with factor IX. \n \nBecause of the risk of allergic reactions with factor IX, your initial treatment with Refixia should be \ngiven in a medical clinic or in the presence of health care professionals where proper medical care for \nallergic reactions can be provided if needed. \n \nTalk to your doctor immediately if your bleeding does not stop as expected or if you have to \nsignificantly increase your usage of Refixia in order to stop a bleed. Your doctor will do a blood test to \ncheck if you have developed inhibitors (neutralising antibodies) against Refixia. The risk for \ndeveloping inhibitors is highest if you have not been treated with factor IX medicines before i.e. for \nsmall children. \n \nBlood clots \nTell your doctor, if any of the following apply to you as there is an increased risk of blood clots during \ntreatment with Refixia: \n• you have recently had surgery \n• you suffer from other serious illness e.g. liver disease, heart disease, or cancer \n• you have risk factors for heart disease e.g high blood pressure, obesity, or smoking. \n \nKidney disorder (nephrotic syndrome) \nThere is a rare risk of developing a specific kidney disorder called “nephrotic syndrome” following \nhigh doses of factor IX in haemophilia B patients with factor IX inhibitors and a history of allergic \nreactions. \n \nCatheter-related problems \nIf you have a central venous access device (CVAD), you may develop infections or blood clots at the \nsite of the catheter. \n \nOther medicines and Refixia \nTell your doctor if you are taking, have recently taken or might take any other medicines. \n \nPregnancy and breast-feeding \nIf you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask \nyour doctor for advice before using Refixia. \n \nDriving and using machines \nRefixia has no influence on the ability to drive and use machines. \n \nRefixia contains sodium \nThis medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. it is essentially “sodium-free”. \n \n \n3. How to use Refixia \n \n\n\n\n32 \n\nTreatment with Refixia will be started by a doctor who is experienced in the care of patients with \nhaemophilia B. Always use this medicine exactly as your doctor has told you. Check with your doctor \nif you are not sure about how to use Refixia. \n \nYour doctor will calculate your dose for you. The dose will depend on your weight and what the \nmedicine is being used for. \n \nPrevention of bleeding \nThe dose of Refixia is 40 international units (IU) per kg of body weight. This is given as one injection \nevery week. Your doctor may choose another dose or how often the injections should be given, based \non your need. \n \nTreatment of bleeding \nThe dose of Refixia is 40 international units (IU) per kg of body weight. Depending on the location \nand the severity of bleeding you may need a higher dose (80 IU per kg) or extra injections. Discuss \nwith your doctor the dose and number of injections you need. \n \nUse in children and adolescents \nRefixia can be used only in adolescents (12 years and above). The dose in adolescents is also \ncalculated according to body weight and is the same dose as for adults. \n \nHow Refixia is given \nRefixia is given as an injection into a vein. See “Instructions on how to use Refixia” for more \ninformation. \n \nIf you use more Refixia than you should \nIf you use more Refixia than you should, contact your doctor. \n \nIf you have to significantly increase your usage of Refixia to stop a bleed, talk to your doctor \nimmediately. For further information, see section 2 “Allergic reactions and development of inhibitors”. \n \nIf you forget to use Refixia \nIf you forget a dose, inject the missed dose as soon as you remember. Do not inject a double dose to \nmake up for a forgotten dose. If you are in doubt contact your doctor. \n \nIf you stop using Refixia \nIf you stop using Refixia you may no longer be protected against bleeding or a current bleed may not \nstop. Do not stop using Refixia without talking to your doctor. \n \nIf you have any further questions on the use of this medicine, ask your doctor. \n \n \n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. \n \nAllergic reactions are possible with this medicine. \nIf sudden and severe allergic reactions (e.g. anaphylactic reactions) occur, the injection must be \nstopped immediately. You must contact your doctor or an emergency unit immediately if you have \nearly signs of an allergic reaction such as: \n• difficulty in swallowing or breathing \n• shortness of breath or wheezing \n• chest tightness \n• redness and/or swelling of the lips, tongue, face or hands \n• rash, hives, weals or itching \n• pale and cold skin, fast heartbeat, and/or dizziness (low blood pressure). \n \n\n\n\n33 \n\nThe following side effects have been observed with Refixia: \n \nCommon side effects (may affect up to 1 in 10 people) \n• itching (pruritus) \n• skin reactions at the site of injection \n• feeling sick (nausea) \n• feeling very tired. \n \nUncommon side effects (may affect up to 1 in 100 people) \n• allergic reactions (hypersensitivity). This may become severe and could be life-threatening \n\n(anaphylactic reactions) \n• heart palpitations \n• hot flush. \n \nSide effects with unknown frequency (frequency cannot be estimated from the available data) \n• neutralising antibodies (inhibitors). \n \nReporting of side effects \nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \neffects not listed in this leaflet. You can also report side effects directly via the national reporting \nsystem listed in Appendix V. By reporting side effects you can help provide more information on the \nsafety of this medicine. \n \n \n5. How to store Refixia \n \nKeep this medicine out of the sight and reach of children. \n \nDo not use Refixia after the expiry date which is stated after “EXP” on the carton and on the vial and \nthe pre-filled syringe labels. The expiry date refers to the last day of that month. \n \nStore in a refrigerator (2°C – 8°C). Do not freeze. Store in the original package in order to protect \nfrom light. \n \nRefixia may be taken out of the refrigerator for a maximum period of 6 months and stored at room \ntemperature (up to 30°C). Please record on the carton the date Refixia is removed from the refrigerator \nand placed at room temperature. This new expiry date should never exceed the one initially mentioned \non the outer carton. If the medicine has not been used before the new expiry date, it should be disposed \nof. After storage at room temperature the medicine must not be put back in the refrigerator. \n \nUse the injection immediately after reconstitution. If it cannot be used immediately, use within \n24 hours if stored in a refrigerator at 2°C – 8°C or within 4 hours if stored out of the refrigerator at a \nmaximum temperature of 30°C. \n \nThe powder in the vial appears as a white to off-white powder. Do not use the powder if the colour has \nchanged. \n \nThe reconstituted solution will be clear and colourless. Do not use the reconstituted solution if you \nnotice any particles or discolouration. \n \nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \nthrow away medicines you no longer use. These measures will help protect the environment. \n \n \n6. Contents of the pack and other information \n \nWhat Refixia contains \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n34 \n\n• The active substance is nonacog beta pegol (pegylated human coagulation factor IX (rDNA)). \nEach vial of Refixia contains nominally 500 IU, 1000 IU or 2000 IU nonacog beta pegol \ncorresponding to approximately 125 IU/ml, 250 IU/ml or 500 IU/ml respectively after \nreconstitution with histidine solvent. \n\n• The other ingredients in the powder are sodium chloride, histidine, sucrose, polysorbate 80, \nmannitol, sodium hydroxide and hydrochloric acid. \n\n• The ingredients in the sterilised solvent are histidine, water for injections, sodium hydroxide and \nhydrochloric acid. \n\n \nWhat Refixia looks like and contents of the pack \n• Refixia is provided as a powder and solvent for solution for injection (500 IU, 1000 IU or \n\n2000 IU powder in a vial and 4 ml solvent in a pre-filled syringe, a plunger rod with a vial \nadapter – pack size of 1). \n\n• The powder is white to off-white and the solvent is clear and colourless. \n \nMarketing Authorisation Holder and Manufacturer \n \nNovo Nordisk A/S \nNovo Allé \nDK-2880 Bagsværd, Denmark \n \n \nThis leaflet was last revised in \n \n \nOther sources of information \n \nDetailed information on this medicine is available on the European Medicines Agency web site: \nhttp://www.ema.europa.eu. \n\nhttp://www.ema.europa.eu/\n\n\n35 \n\n \n\nInstructions on how to use Refixia \n \nRead these instructions carefully before using Refixia. \n \nRefixia is supplied as a powder. Before injection it must be reconstituted with the solvent supplied in \nthe syringe. The solvent is a histidine solution. The reconstituted product must be injected into your \nvein (intravenous (IV) injection). The equipment in this package is designed to reconstitute and inject \nRefixia. \n \nYou will also need an infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads and \nplasters. These items are not included in the Refixia package. \n \nDo not use the equipment without proper training from your doctor or nurse. \n \nAlways wash your hands and ensure that the area around you is clean. \n \nWhen you prepare and inject medicine directly into the veins, it is important to use a clean and germ \nfree (aseptic) technique. Incorrect technique can introduce germs that can infect the blood. \n \nDo not open the equipment until you are ready to use it. \n \nDo not use the equipment if it has been dropped, or if it is damaged. Use a new package instead. \n \nDo not use the equipment if it has expired. Use a new package instead. The expiry date is printed on \nthe outer carton, on the vial, on the vial adapter, and on the pre-filled syringe. \n \nDo not use the equipment if you suspect it is contaminated. Use a new package instead. \n \nDo not dispose of any of the items until after you have injected the reconstituted solution. \n \nThe equipment is for single use only. \n\nContents \nThe package contains: \n• 1 vial with Refixia powder \n• 1 vial adapter \n• 1 pre-filled syringe with solvent \n• 1 plunger rod (placed under the syringe) \n \n \n\n\n\n36 \n\n \n\nVial with Refixia powder \n\nPlastic cap \nRubber stopper \n\n(under plastic cap) \n\nOverview \n\n \n \n\nVial adapter \n\nProtective cap \n\nSpike \n(under protective paper) \n\nProtective \npaper \n\n \n \n\nPre-filled syringe with solvent \n\nSyringe tip \n(under syringe cap) Scale \n\nPlunger \n\nSyringe cap \n\n \n \n\n\n\n37 \n\n \n\nPlunger rod \n\nThread Wide top \nend \n\n \n\n1. Prepare the vial and the syringe \n \n• Take out the number of Refixia packages \n\nyou need. \n \n\n• Check the expiry date. \n \n\n• Check the name, strength and colour of \nthe package, to make sure it contains the \ncorrect product. \n\n \n• Wash your hands and dry them properly \n\nusing a clean towel or air dry. \n \n\n• Take the vial, the vial adapter and the pre-\nfilled syringe out of the carton. Leave the \nplunger rod untouched in the carton. \n\n \n• Bring the vial and the pre-filled syringe \n\nto room temperature. You can do this by \nholding them in your hands until they feel \nas warm as your hands. \n\n \n• Do not use any other way to warm the \n\nvial and pre-filled syringe. \n\n A \n\n \n\n• Remove the plastic cap from the vial. If \nthe plastic cap is loose or missing, do not \nuse the vial. \n\n \n• Wipe the rubber stopper with a sterile \n\nalcohol swab and allow it to air dry for a \nfew seconds before use to ensure that it is \nas germ free as possible. \n\n \n• Do not touch the rubber stopper with \n\nyour fingers as this can transfer germs. \n\n B \n\n \n \n\n\n\n38 \n\n2. Attach the vial adapter \n \n• Remove the protective paper from the \n\nvial adapter. \n \n\nIf the protective paper is not fully sealed \nor if it is broken, do not use the vial \nadapter. \n \nDo not take the vial adapter out of the \nprotective cap with your fingers. \nIf you touch the spike on the vial adapter, \ngerms from your fingers can be transferred. \n\n C \n\n \n\n• Place the vial on a flat and solid surface. \n \n• Turn over the protective cap, and snap \n\nthe vial adapter onto the vial. \n \n\nOnce attached, do not remove the vial \nadapter from the vial. \n\n D \n\n \n \n\n• Lightly squeeze the protective cap with \nyour thumb and index finger as shown. \n\n \nRemove the protective cap from the vial \nadapter. \n \nDo not lift the vial adapter from the vial \nwhen removing the protective cap. \n\n E \n\n \n\n3. Attach the plunger rod and the syringe \n \n• Grasp the plunger rod by the wide top end \n\nand take it out of the carton. Do not touch \nthe sides or the thread of the plunger \nrod. If you touch the sides or the thread, \ngerms from your fingers can be transferred. \n\n \n• Immediately connect the plunger rod to \n\nthe syringe by turning it clockwise into the \nplunger inside the pre-filled syringe until \nresistance is felt. \n\n \n\n F \n\n \n\n• Remove the syringe cap from the \npre-filled syringe by bending it down until \nthe perforation breaks. \n\n \n• Do not touch the syringe tip under the \n\nsyringe cap. If you touch the syringe tip, \ngerms from your fingers can be transferred. \n\n \nIf the syringe cap is loose or missing, do \n\n G \n\n \n\n\n\n39 \n\nnot use the pre-filled syringe. \n\n• Screw the pre-filled syringe securely onto \nthe vial adapter until resistance is felt. \n\n H \n\n \n\n4. Reconstitute the powder with the solvent \n \n• Hold the pre-filled syringe slightly tilted \n\nwith the vial pointing downwards. \n \n• Push the plunger rod to inject all the \n\nsolvent into the vial. \n\n I \n\n \n\n• Keep the plunger rod pressed down and \nswirl the vial gently until all the powder is \ndissolved. \n\n \nDo not shake the vial as this will cause \nfoaming. \n\n \n• Check the reconstituted solution. It must \n\nbe clear and colourless and no particles \nshould be visible. If you notice particles \nor discolouration, do not use it. Use a \nnew package instead. \n\n J \n\n \n\nRefixia is recommended to be used immediately after it has been reconstituted. This is because if \nleft, the medicine may no longer be sterile and could cause infections. \n \nIf you cannot use the reconstituted Refixia solution immediately, it should be used within 4 hours \nwhen stored at room temperature (up to 30°C) and within 24 hours when stored in a refrigerator \n(2°C – 8°C). Store the reconstituted product in the vial. \n \nDo not freeze reconstituted Refixia solution or store it in syringes. \n \nKeep reconstituted Refixia solution out of direct light. \n \n\n \nIf your dose requires more than one vial, repeat steps A to J with additional vials, vial adapters and \npre-filled syringes until you have reached your required dose. \n\n\n\n40 \n\n• Keep the plunger rod pushed completely \nin. \n\n \n• Turn the syringe with the vial upside \n\ndown. \n \n\n• Stop pushing the plunger rod and let it \nmove back on its own while the \nreconstituted solution fills the syringe. \n\n \n• Pull the plunger rod slightly downwards \n\nto draw the reconstituted solution into the \nsyringe. \n\n \n• In case you only need part of the entire \n\nvial, use the scale on the syringe to see \nhow much reconstituted solution you \nwithdraw, as instructed by your doctor \nor nurse. \n\n \nIf, at any point, there is air in the syringe, \ninject the air back into the vial. \n\n \n• While holding the vial upside down, tap \n\nthe syringe gently to let any air bubbles \nrise to the top. \n\n \n• Push the plunger rod slowly until all air \n\nbubbles are gone. \n\n K \n\n \n\n• Unscrew the vial adapter with the vial. \n \n• Do not touch the syringe tip. If you touch \n\nthe syringe tip, germs from your fingers \ncan be transferred. \n\n L \n\n \n\n5. Inject the reconstituted solution \n \nRefixia is now ready to inject into your vein. \n• Inject the reconstituted solution as instructed by your doctor or nurse. \n• Inject slowly over 1 to 3 minutes. \n• Do not mix Refixia with any other intravenous infusions or medications. \n \nInjecting Refixia via needleless connectors for intravenous (IV) catheters \n \nCaution: The pre-filled syringe is made of glass and is designed to be compatible with standard luer-\nlock connections. Some needleless connectors with an internal spike are incompatible with the \npre-filled syringe. This incompatibility may prevent administration of the drug and/or result in damage \nto the needleless connector. \n \nInjecting the solution via a central venous access device (CVAD) such as a central venous catheter or \na subcutaneous port: \n• Use a clean and germ free (aseptic) technique. Follow the instructions for proper use for your \n\nconnector and CVAD in consultation with your doctor or nurse. \n\n\n\n41 \n\n• Injecting into a CVAD may require using a sterile 10 ml plastic syringe for withdrawal of the \nreconstituted solution. This should be done right after step J. \n\n• If the CVAD line needs to be flushed before or after Refixia injection, use sodium chloride \n9 mg/ml solution for injection. \n\nDisposal \n \n• After injection, safely dispose of all \n\nunused Refixia solution, the syringe with \nthe infusion set, the vial with the vial \nadapter and other waste materials as \ninstructed by your pharmacist. \n\n \nDo not throw it out with the ordinary \nhousehold waste. \n\n M \n\n \n\nDo not disassemble the equipment before disposal. \n \nDo not reuse the equipment. \n\n \n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION \n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. PACKAGE LEAFLET"},"Section_1":{"kind":"string","value":"{'Title': '1. what refixia is and what it is used for', 'Section_Content': 'what refixia is refixia contains the active substance nonacog beta pegol and is a long-acting recombinant coagulation factor ix product. factor ix is a protein naturally found in the blood that helps to stop bleeding. what refixia is used for refixia is used to treat and prevent bleeding in patients 12 years and above with haemophilia b (inborn factor ix deficiency). in patients with haemophilia b, factor ix is missing or does not work properly. refixia replaces this faulty or missing factor ix and helps blood to form clots at the site of bleeding. when you bleed, refixia is activated in the blood to form factor ix.', 'Entity_Recognition': [{'Text': 'refixia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'refixia', 'Type': 'PROBLEM', 'BeginOffset': 16, 'EndOffset': 23}, {'Text': 'the active substance nonacog beta pegol', 'Type': 'TREATMENT', 'BeginOffset': 33, 'EndOffset': 72}, {'Text': 'a long-acting recombinant coagulation factor ix product', 'Type': 'TREATMENT', 'BeginOffset': 80, 'EndOffset': 135}, {'Text': 'factor ix', 'Type': 'PROBLEM', 'BeginOffset': 137, 'EndOffset': 146}, {'Text': 'a protein naturally', 'Type': 'PROBLEM', 'BeginOffset': 150, 'EndOffset': 169}, {'Text': 'the blood', 'Type': 'PROBLEM', 'BeginOffset': 179, 'EndOffset': 188}, {'Id': 1, 'BeginOffset': 208, 'EndOffset': 216, 'Score': 0.6613272428512573, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'refixia', 'Type': 'TREATMENT', 'BeginOffset': 243, 'EndOffset': 250}, {'Id': 2, 'BeginOffset': 280, 'EndOffset': 288, 'Score': 0.9881094098091125, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6549317240715027}]}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 301, 'EndOffset': 303}, {'Text': 'haemophilia b (inborn factor ix deficiency', 'Type': 'PROBLEM', 'BeginOffset': 325, 'EndOffset': 367}, {'Id': 5, 'BeginOffset': 387, 'EndOffset': 398, 'Score': 0.6948233842849731, 'Text': 'haemophilia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.5652453303337097}]}, {'Id': 6, 'BeginOffset': 402, 'EndOffset': 422, 'Score': 0.8082478642463684, 'Text': 'factor ix is missing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.470569372177124}]}, {'Text': 'this faulty', 'Type': 'PROBLEM', 'BeginOffset': 467, 'EndOffset': 478}, {'Text': 'missing factor ix', 'Type': 'PROBLEM', 'BeginOffset': 482, 'EndOffset': 499}, {'Id': 7, 'BeginOffset': 524, 'EndOffset': 529, 'Score': 0.6403788328170776, 'Text': 'clots', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 545, 'EndOffset': 553, 'Score': 0.9661247134208679, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.46187978982925415}]}, {'Text': 'you bleed', 'Type': 'PROBLEM', 'BeginOffset': 560, 'EndOffset': 569}, {'Text': 'refixia', 'Type': 'PROBLEM', 'BeginOffset': 571, 'EndOffset': 578}]}"},"Section_2":{"kind":"string","value":"{'Title': '2. what you need to know before you use refixia', 'Section_Content': 'do not use refixia: if you are allergic to the active substance or any of the other ingredients of this medicine (listed in section 6). if you are allergic to hamster proteins. if you are not sure if either of the above applies to you, talk to your doctor before using this medicine. warnings and precautions 31 allergic reactions and development of inhibitors there is a rare risk that you may experience a sudden and severe allergic reaction (e.g. anaphylactic reaction) to refixia. stop the injection and contact your doctor or an emergency unit immediately if you have signs of an allergic reaction such as rash, hives, weals, itching on large areas of skin, redness and/or swelling of lips, tongue, face or hands, difficulty in swallowing or breathing, shortness of breath, wheezing, tightness of the chest, pale and cold skin, fast heartbeat, and/or dizziness. your doctor may need to treat you promptly for these reactions. your doctor may also do a blood test to check if you have developed factor ix inhibitors (neutralising antibodies) against your medicine, as inhibitors may develop together with allergic reactions. if you have such antibodies, you may be at an increased risk of sudden and severe allergic reactions (e.g. anaphylactic reaction) during future treatment with factor ix. because of the risk of allergic reactions with factor ix, your initial treatment with refixia should be given in a medical clinic or in the presence of health care professionals where proper medical care for allergic reactions can be provided if needed. talk to your doctor immediately if your bleeding does not stop as expected or if you have to significantly increase your usage of refixia in order to stop a bleed. your doctor will do a blood test to check if you have developed inhibitors (neutralising antibodies) against refixia. the risk for developing inhibitors is highest if you have not been treated with factor ix medicines before i.e. for small children. blood clots tell your doctor, if any of the following apply to you as there is an increased risk of blood clots during treatment with refixia: you have recently had surgery you suffer from other serious illness e.g. liver disease, heart disease, or cancer you have risk factors for heart disease e.g high blood pressure, obesity, or smoking. kidney disorder (nephrotic syndrome) there is a rare risk of developing a specific kidney disorder called \"nephrotic syndrome\" following high doses of factor ix in haemophilia b patients with factor ix inhibitors and a history of allergic reactions. catheter-related problems if you have a central venous access device (cvad), you may develop infections or blood clots at the site of the catheter. other medicines and refixia tell your doctor if you are taking, have recently taken or might take any other medicines. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using refixia. driving and using machines refixia has no influence on the ability to drive and use machines. refixia contains sodium this medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. it is essentially \"sodium-free\".', 'Entity_Recognition': [{'Text': 'refixia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 31, 'EndOffset': 39}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 99, 'EndOffset': 112}, {'Id': 7, 'BeginOffset': 147, 'EndOffset': 175, 'Score': 0.43315285444259644, 'Text': 'allergic to hamster proteins', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5490298271179199}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 269, 'EndOffset': 282}, {'Text': '31', 'Type': 'NUMBER', 'BeginOffset': 309, 'EndOffset': 311}, {'Id': 8, 'BeginOffset': 312, 'EndOffset': 330, 'Score': 0.8144558668136597, 'Text': 'allergic reactions', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4401457607746124}, {'Name': 'DIAGNOSIS', 'Score': 0.6084556579589844}]}, {'Text': 'inhibitors', 'Type': 'TREATMENT', 'BeginOffset': 350, 'EndOffset': 360}, {'Text': 'a sudden and severe allergic reaction', 'Type': 'PROBLEM', 'BeginOffset': 406, 'EndOffset': 443}, {'Id': 10, 'BeginOffset': 450, 'EndOffset': 471, 'Score': 0.9736200571060181, 'Text': 'anaphylactic reaction', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7912070155143738}]}, {'Text': 'an allergic reaction', 'Type': 'PROBLEM', 'BeginOffset': 582, 'EndOffset': 602}, {'Id': 12, 'BeginOffset': 611, 'EndOffset': 615, 'Score': 0.9992033839225769, 'Text': 'rash', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.863627016544342}]}, {'Id': 13, 'BeginOffset': 617, 'EndOffset': 622, 'Score': 0.9983525276184082, 'Text': 'hives', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8166745901107788}]}, {'Id': 14, 'BeginOffset': 624, 'EndOffset': 629, 'Score': 0.9375274777412415, 'Text': 'weals', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9287054538726807}]}, {'Id': 15, 'BeginOffset': 631, 'EndOffset': 638, 'Score': 0.9968968629837036, 'Text': 'itching', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9508659839630127}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9949899315834045, 'RelationshipScore': 0.9980320334434509, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 0, 'BeginOffset': 657, 'EndOffset': 661, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9988961219787598, 'RelationshipScore': 0.6127389073371887, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 4, 'BeginOffset': 712, 'EndOffset': 717, 'Text': 'hands', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'large areas of skin', 'Type': 'PROBLEM', 'BeginOffset': 642, 'EndOffset': 661}, {'Id': 16, 'BeginOffset': 663, 'EndOffset': 670, 'Score': 0.987949013710022, 'Text': 'redness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9538441300392151}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9949899315834045, 'RelationshipScore': 0.6433677673339844, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 0, 'BeginOffset': 657, 'EndOffset': 661, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9991523027420044, 'RelationshipScore': 0.9878607392311096, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 1, 'BeginOffset': 690, 'EndOffset': 694, 'Text': 'lips', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9974867105484009, 'RelationshipScore': 0.9410630464553833, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 2, 'BeginOffset': 696, 'EndOffset': 702, 'Text': 'tongue', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9980729818344116, 'RelationshipScore': 0.9741078615188599, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 3, 'BeginOffset': 704, 'EndOffset': 708, 'Text': 'face', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9988961219787598, 'RelationshipScore': 0.9684992432594299, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 4, 'BeginOffset': 712, 'EndOffset': 717, 'Text': 'hands', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'swelling of lips, tongue, face or hands', 'Type': 'PROBLEM', 'BeginOffset': 678, 'EndOffset': 717}, {'Id': 18, 'BeginOffset': 719, 'EndOffset': 756, 'Score': 0.9288513660430908, 'Text': 'difficulty in swallowing or breathing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9708302021026611}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9974867105484009, 'RelationshipScore': 0.5857904553413391, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 2, 'BeginOffset': 696, 'EndOffset': 702, 'Text': 'tongue', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9980729818344116, 'RelationshipScore': 0.5110937356948853, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 3, 'BeginOffset': 704, 'EndOffset': 708, 'Text': 'face', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 19, 'BeginOffset': 758, 'EndOffset': 777, 'Score': 0.9975161552429199, 'Text': 'shortness of breath', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9763699173927307}]}, {'Id': 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depend on your weight and what the medicine is being used for. prevention of bleeding the dose of refixia is 40 international units (iu) per kg of body weight. this is given as one injection every week. your doctor may choose another dose or how often the injections should be given, based on your need. treatment of bleeding the dose of refixia is 40 international units (iu) per kg of body weight. depending on the location and the severity of bleeding you may need a higher dose (80 iu per kg) or extra injections. discuss with your doctor the dose and number of injections you need. use in children and adolescents refixia can be used only in adolescents (12 years and above). the dose in adolescents is also calculated according to body weight and is the same dose as for adults. how refixia is given refixia is given as an injection into a vein. see \"instructions on how to use refixia\" for more information. if you use more refixia than you should if you use more refixia than you should, contact your doctor. if you have to significantly increase your usage of refixia to stop a bleed, talk to your doctor immediately. for further information, see section 2 \"allergic reactions and development of inhibitors\". if you forget to use refixia if you forget a dose, inject the missed dose as soon as you remember. do not inject a double dose to make up for a forgotten dose. if you are in doubt contact your doctor. if you stop using refixia if you stop using refixia you may no longer be protected against bleeding or a current bleed may not stop. do not stop using refixia without talking to your doctor. if you have any further questions on the use of this medicine, ask your doctor.', 'Entity_Recognition': [{'Text': 'refixia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 9}, {'Text': 'refixia', 'Type': 'TREATMENT', 'BeginOffset': 15, 'EndOffset': 22}, {'Text': 'haemophilia b.', 'Type': 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site of injection feeling sick (nausea) feeling very tired. uncommon side effects (may affect up to 1 in 100 people) allergic reactions (hypersensitivity). this may become severe and could be life-threatening (anaphylactic reactions) heart palpitations hot flush. side effects with unknown frequency (frequency cannot be estimated from the available data) neutralising antibodies (inhibitors). reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'refixia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 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0.997859537601471, 'Text': 'face', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'hands rash', 'Type': 'PROBLEM', 'BeginOffset': 522, 'EndOffset': 532}, {'Id': 22, 'BeginOffset': 534, 'EndOffset': 539, 'Score': 0.9977309107780457, 'Text': 'hives', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9756220579147339}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9994565844535828, 'RelationshipScore': 0.797775387763977, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 1, 'BeginOffset': 500, 'EndOffset': 504, 'Text': 'lips', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9976256489753723, 'RelationshipScore': 0.849545955657959, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 2, 'BeginOffset': 506, 'EndOffset': 512, 'Text': 'tongue', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.997859537601471, 'RelationshipScore': 0.737737774848938, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 3, 'BeginOffset': 514, 'EndOffset': 518, 'Text': 'face', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 23, 'BeginOffset': 541, 'EndOffset': 546, 'Score': 0.9332918524742126, 'Text': 'weals', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9607797265052795}]}, {'Text': 'itching pale', 'Type': 'PROBLEM', 'BeginOffset': 550, 'EndOffset': 562}, {'Id': 26, 'BeginOffset': 567, 'EndOffset': 576, 'Score': 0.783514678478241, 'Text': 'cold skin', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9197863340377808}]}, {'Id': 27, 'BeginOffset': 578, 'EndOffset': 592, 'Score': 0.930304229259491, 'Text': 'fast heartbeat', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9757444858551025}]}, {'Id': 28, 'BeginOffset': 601, 'EndOffset': 610, 'Score': 0.9986568689346313, 'Text': 'dizziness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9765921235084534}]}, {'Text': 'low blood pressure)', 'Type': 'PROBLEM', 'BeginOffset': 612, 'EndOffset': 631}, {'Id': 30, 'BeginOffset': 647, 'EndOffset': 659, 'Score': 0.8893066048622131, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.871610701084137}]}, {'Text': 'common side effects', 'Type': 'PROBLEM', 'BeginOffset': 693, 'EndOffset': 712}, {'Id': 32, 'BeginOffset': 718, 'EndOffset': 724, 'Score': 0.2281019687652588, 'Text': 'affect', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 731, 'EndOffset': 732}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 736, 'EndOffset': 738}, {'Text': 'itching (pruritus)', 'Type': 'PROBLEM', 'BeginOffset': 747, 'EndOffset': 765}, {'Id': 35, 'BeginOffset': 766, 'EndOffset': 780, 'Score': 0.8258066177368164, 'Text': 'skin reactions', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.887345552444458}]}, {'Id': 36, 'BeginOffset': 806, 'EndOffset': 818, 'Score': 0.6885064840316772, 'Text': 'feeling sick', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9151033759117126}]}, {'Id': 37, 'BeginOffset': 820, 'EndOffset': 826, 'Score': 0.9975693821907043, 'Text': 'nausea', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9343103170394897}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9577648043632507, 'RelationshipScore': 0.6139464378356934, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 6, 'BeginOffset': 766, 'EndOffset': 770, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'very tired', 'Type': 'PROBLEM', 'BeginOffset': 836, 'EndOffset': 846}, {'Text': 'uncommon side effects', 'Type': 'PROBLEM', 'BeginOffset': 848, 'EndOffset': 869}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 888, 'EndOffset': 889}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 893, 'EndOffset': 896}, {'Id': 40, 'BeginOffset': 905, 'EndOffset': 923, 'Score': 0.8600614070892334, 'Text': 'allergic reactions', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6481819748878479}]}, {'Id': 41, 'BeginOffset': 925, 'EndOffset': 941, 'Score': 0.9724323749542236, 'Text': 'hypersensitivity', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.4090667963027954}]}, {'Id': 42, 'BeginOffset': 998, 'EndOffset': 1020, 'Score': 0.9315484762191772, 'Text': 'anaphylactic reactions', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7138749361038208}, {'Name': 'DIAGNOSIS', 'Score': 0.4376230239868164}]}, {'Text': 'heart palpitations hot flush', 'Type': 'PROBLEM', 'BeginOffset': 1022, 'EndOffset': 1050}, {'Id': 45, 'BeginOffset': 1052, 'EndOffset': 1064, 'Score': 0.9222471714019775, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7637165784835815}]}, {'Id': 46, 'BeginOffset': 1078, 'EndOffset': 1087, 'Score': 0.48504921793937683, 'Text': 'frequency', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 47, 'BeginOffset': 1089, 'EndOffset': 1098, 'Score': 0.6194992065429688, 'Text': 'frequency', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4102398157119751}]}, {'Text': 'neutralising antibodies (inhibitors', 'Type': 'TREATMENT', 'BeginOffset': 1144, 'EndOffset': 1179}, {'Id': 48, 'BeginOffset': 1195, 'EndOffset': 1207, 'Score': 0.9334115386009216, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7726871967315674}]}, {'Id': 49, 'BeginOffset': 1223, 'EndOffset': 1235, 'Score': 0.9182136654853821, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7610309720039368}]}, {'Id': 50, 'BeginOffset': 1306, 'EndOffset': 1318, 'Score': 0.9519163966178894, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6538662314414978}]}, {'Id': 51, 'BeginOffset': 1367, 'EndOffset': 1379, 'Score': 0.8601099848747253, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7099798917770386}]}, {'Id': 52, 'BeginOffset': 1433, 'EndOffset': 1444, 'Score': 0.36894774436950684, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.626948356628418}]}, {'Id': 53, 'BeginOffset': 1458, 'EndOffset': 1470, 'Score': 0.8550413250923157, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7452174425125122}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1526, 'EndOffset': 1539}]}"},"Section_5":{"kind":"string","value":"{'Title': '5. how to store refixia', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use refixia after the expiry date which is stated after \"exp\" on the carton and on the vial and the pre-filled syringe labels. the expiry date refers to the last day of that month. store in a refrigerator (2 8). do not freeze. store in the original package in order to protect from light. refixia may be taken out of the refrigerator for a maximum period of 6 months and stored at room temperature (up to 30). please record on the carton the date refixia is removed from the refrigerator and placed at room temperature. this new expiry date should never exceed the one initially mentioned on the outer carton. if the medicine has not been used before the new expiry date, it should be disposed of. after storage at room temperature the medicine must not be put back in the refrigerator. use the injection immediately after reconstitution. if it cannot be used immediately, use within 24 hours if stored in a refrigerator at 2 8 or within 4 hours if stored out of the refrigerator at a maximum temperature of 30. the powder in the vial appears as a white to off-white powder. do not use the powder if the colour has changed. the reconstituted solution will be clear and colourless. do not use the reconstituted solution if you notice any particles or discolouration. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'refixia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 272, 'EndOffset': 273}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 274, 'EndOffset': 275}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 424, 'EndOffset': 425}, {'Text': '30.', 'Type': 'NUMBER', 'BeginOffset': 471, 'EndOffset': 474}, {'Text': 'the injection', 'Type': 'TREATMENT', 'BeginOffset': 857, 'EndOffset': 870}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 950, 'EndOffset': 952}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 990, 'EndOffset': 991}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 992, 'EndOffset': 993}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 1004, 'EndOffset': 1005}, {'Text': 'a maximum temperature', 'Type': 'TEST', 'BeginOffset': 1049, 'EndOffset': 1070}, {'Text': '30.', 'Type': 'NUMBER', 'BeginOffset': 1074, 'EndOffset': 1077}, {'Text': 'the powder in the vial', 'Type': 'TREATMENT', 'BeginOffset': 1078, 'EndOffset': 1100}, {'Text': 'white powder', 'Type': 'TREATMENT', 'BeginOffset': 1127, 'EndOffset': 1139}, {'Text': 'the powder', 'Type': 'TREATMENT', 'BeginOffset': 1152, 'EndOffset': 1162}, {'Text': 'the reconstituted solution', 'Type': 'TREATMENT', 'BeginOffset': 1190, 'EndOffset': 1216}, {'Text': 'the reconstituted solution', 'Type': 'TREATMENT', 'BeginOffset': 1258, 'EndOffset': 1284}, {'Text': 'discolouration', 'Type': 'PROBLEM', 'BeginOffset': 1316, 'EndOffset': 1330}]}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': 'what refixia contains 34 the active substance is nonacog beta pegol (pegylated human coagulation factor ix (rdna)). each vial of refixia contains nominally 500 iu, 1000 iu or 2000 iu nonacog beta pegol corresponding to approximately 125 iu/ml, 250 iu/ml or 500 iu/ml respectively after reconstitution with histidine solvent. the other ingredients in the powder are sodium chloride, histidine, sucrose, polysorbate 80, mannitol, sodium hydroxide and hydrochloric acid. the ingredients in the sterilised solvent are histidine, water for injections, sodium hydroxide and hydrochloric acid. what refixia looks like and contents of the pack refixia is provided as a powder and solvent for solution for injection (500 iu, 1000 iu or 2000 iu powder in a vial and 4 ml solvent in a pre-filled syringe, a plunger rod with a vial adapter pack size of 1). the powder is white to off-white and the solvent is clear and colourless.', 'Entity_Recognition': [{'Text': 'refixia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': '34', 'Type': 'NUMBER', 'BeginOffset': 22, 'EndOffset': 24}, {'Text': 'nonacog beta pegol (pegylated human coagulation factor ix', 'Type': 'TREATMENT', 'BeginOffset': 49, 'EndOffset': 106}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 156, 'EndOffset': 159}, {'Text': '1000', 'Type': 'NUMBER', 'BeginOffset': 164, 'EndOffset': 168}, {'Text': '2000', 'Type': 'NUMBER', 'BeginOffset': 175, 'EndOffset': 179}, {'Text': 'nonacog beta pegol', 'Type': 'TREATMENT', 'BeginOffset': 183, 'EndOffset': 201}, {'Text': '125', 'Type': 'NUMBER', 'BeginOffset': 233, 'EndOffset': 236}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 244, 'EndOffset': 247}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 257, 'EndOffset': 260}, {'Id': 5, 'BeginOffset': 306, 'EndOffset': 323, 'Score': 0.34893694519996643, 'Text': 'histidine solvent', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 365, 'EndOffset': 380, 'Score': 0.9813015460968018, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 382, 'EndOffset': 391, 'Score': 0.9215745329856873, 'Text': 'histidine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 393, 'EndOffset': 400, 'Score': 0.7138574123382568, 'Text': 'sucrose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 402, 'EndOffset': 416, 'Score': 0.6599057912826538, 'Text': 'polysorbate 80', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 418, 'EndOffset': 426, 'Score': 0.9205037951469421, 'Text': 'mannitol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 428, 'EndOffset': 444, 'Score': 0.9984684586524963, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 449, 'EndOffset': 466, 'Score': 0.9953880906105042, 'Text': 'hydrochloric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 514, 'EndOffset': 523, 'Score': 0.5334805846214294, 'Text': 'histidine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.6046119928359985, 'RelationshipScore': 0.9995589852333069, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 14, 'BeginOffset': 535, 'EndOffset': 545, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 535, 'EndOffset': 545}, {'Id': 15, 'BeginOffset': 547, 'EndOffset': 563, 'Score': 0.9990899562835693, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.6046119928359985, 'RelationshipScore': 0.5915699005126953, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 14, 'BeginOffset': 535, 'EndOffset': 545, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 16, 'BeginOffset': 568, 'EndOffset': 585, 'Score': 0.9951306581497192, 'Text': 'hydrochloric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.6918653249740601, 'RelationshipScore': 0.7129587531089783, 'RelationshipType': 'DOSAGE', 'Id': 18, 'BeginOffset': 716, 'EndOffset': 723, 'Text': '1000 iu', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'the pack refixia', 'Type': 'TREATMENT', 'BeginOffset': 627, 'EndOffset': 643}, {'Text': 'a powder and solvent for solution', 'Type': 'TREATMENT', 'BeginOffset': 659, 'EndOffset': 692}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 708, 'EndOffset': 711}, {'Text': '1000', 'Type': 'NUMBER', 'BeginOffset': 716, 'EndOffset': 720}, {'Text': '2000', 'Type': 'NUMBER', 'BeginOffset': 727, 'EndOffset': 731}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 756, 'EndOffset': 757}, {'Text': 'a pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 772, 'EndOffset': 792}, {'Text': 'a plunger rod', 'Type': 'TREATMENT', 'BeginOffset': 794, 'EndOffset': 807}, {'Text': 'a vial adapter pack size', 'Type': 'TREATMENT', 'BeginOffset': 813, 'EndOffset': 837}, {'Text': 'the powder', 'Type': 'TREATMENT', 'BeginOffset': 845, 'EndOffset': 855}]}"}}},{"rowIdx":1056,"cells":{"ID":{"kind":"string","value":"24F22F9DA3FA2ED775EDC64E4696201A"},"URL":{"kind":"string","value":"https://www.ema.europa.eu/documents/product-information/pelmeg-epar-product-information_en.pdf"},"Product_Name":{"kind":"string","value":"Pelmeg"},"Full_Content":{"kind":"string","value":"1 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX I \n \n\nSUMMARY OF PRODUCT CHARACTERISTICS \n \n \n\n\n\n2 \n\n This medicinal product is subject to additional monitoring. This will allow quick identification of \nnew safety information. Healthcare professionals are asked to report any suspected adverse \nreactions. See section 4.8 for how to report adverse reactions. \n\n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nPelmeg 6 mg solution for injection in pre-filled syringe \n \n \n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \nEach pre-filled syringe contains 6 mg of pegfilgrastim* in 0.6 mL solution for injection. The \nconcentration is 10 mg/mL based on protein only**. \n \n*Produced in Escherichia coli cells by recombinant DNA technology followed by conjugation with \npolyethylene glycol (PEG). \n \n** The concentration is 20 mg/mL if the PEG moiety is included. \nThe potency of this product should not be compared to the potency of another pegylated or \nnonpegylated protein of the same therapeutic class. For more information, see section 5.1 \n \nExcipient with known effect \n \nEach pre-filled syringe contains 30 mg sorbitol (E420). \n \nFor the full list of excipients, see section 6.1. \n \n \n3. PHARMACEUTICAL FORM \n \nSolution for injection \nClear, colourless solution for injection. \n \n \n4. CLINICAL PARTICULARS \n \n4.1 Therapeutic indications \n \nReduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients \ntreated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia \nand myelodysplastic syndromes). \n \n4.2 Posology and method of administration \n \nPelmeg therapy should be initiated and supervised by physicians experienced in oncology and/or \nhaematology. \n \nPosology \n \nOne 6 mg dose (a single pre-filled syringe) of Pelmeg is recommended for each chemotherapy cycle, \ngiven at least 24 hours after cytotoxic chemotherapy. \n \n\n\n\n3 \n\nSpecial populations \n \nPaediatric population \n \nThe safety and efficacy of pegfilgrastim in children has not yet been established. Currently available \ndata are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made. \n \nPatients with renal impairment \n \nNo dose change is recommended in patients with renal impairment, including those with end stage \nrenal disease. \n \nMethod of administration \n \nPelmeg is injected subcutaneously. The injections should be given into the thigh, abdomen or upper \narm. For instructions on handling of the medicinal product before administration, see section 6.6. \n \n4.3 Contraindications \n \nHypersensitivity to the active substance or to any of the excipients listed in section 6.1. \n \n4.4 Special warnings and precautions for use \n \nTraceability \n \nIn order to improve the traceability of biologic medicinal products, the tradename and the batch \nnumber of the administered product should be clearly recorded in the patient file. \n \nLimited clinical data suggest a comparable effect on time to recovery of severe neutropenia for \npegfilgrastim to filgrastim in patients with de novo acute myeloid leukaemia (AML) (see section 5.1). \nHowever, the long-term effects of Pelmeg have not been established in AML; therefore, it should be \nused with caution in this patient population. \n \nGranulocyte-colony stimulating factor can promote growth of myeloid cells in vitro and similar effects \nmay be seen on some non-myeloid cells in vitro. \n \nThe safety and efficacy of Pelmeg have not been investigated in patients with myelodysplastic \nsyndrome, chronic myelogenous leukaemia, and in patients with secondary AML; therefore, it should \nnot be used in such patients. Particular care should be taken to distinguish the diagnosis of blast \ntransformation of chronic myeloid leukaemia from AML. \n \nThe safety and efficacy of Pelmeg administration in de novo AML patients aged < 55 years with \ncytogenetics t (15;17) have not been established. \n \nThe safety and efficacy of Pelmeg have not been investigated in patients receiving high dose \nchemotherapy. This medicinal product should not be used to increase the dose of cytotoxic \nchemotherapy beyond established dosage regimens. \n \nPulmonary adverse events \n \nPulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSF \nadministration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher \nrisk (see section 4.8). The onset of pulmonary signs such as cough, fever, and dyspnoea in association \nwith radiological signs of pulmonary infiltrates, and deterioration in pulmonary function along with \nincreased neutrophil count may be preliminary signs of Acute Respiratory Distress Syndrome \n(ARDS). In such circumstances Pelmeg should be discontinued at the discretion of the physician and \nthe appropriate treatment given (see section 4.8). \n\n\n\n4 \n\n \nGlomerulonephritis \n \nGlomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, \nevents of glomerulonephritis resolved after dose reduction or withdrawal of filgrastim and \npegfilgrastim. Urinalysis monitoring is recommended. \n \nCapillary leak syndrome \n \nCapillary leak syndrome has been reported after granulocyte-colony stimulating factor administration \nand is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients \nwho develop symptoms of capillary leak syndrome should be closely monitored and receive standard \nsymptomatic treatment, which may include a need for intensive care (see section 4.8). \n \nSplenomegaly and splenic rupture \n \nGenerally asymptomatic cases of splenomegaly and cases of splenic rupture, including some fatal \ncases, have been reported following administration of pegfilgrastim (see section 4.8). Therefore, \nspleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of \nsplenic rupture should be considered in patients reporting left upper abdominal pain or shoulder tip \npain. \n \nThrombocytopenia and anaemia \n \nTreatment with pegfilgrastim alone does not preclude thrombocytopenia and anaemia because full \ndose myelosuppressive chemotherapy is maintained on the prescribed schedule. Regular monitoring of \nplatelet count and haematocrit is recommended. Special care should be taken when administering \nsingle or combination chemotherapeutic agents which are known to cause severe thrombocytopenia. \n \nSickle cell anaemia \n \nSickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell trait or \nsickle cell disease (see section 4.8). Therefore, physicians should use caution when prescribing Pelmeg \nin patients with sickle cell trait or sickle cell disease, should monitor appropriate clinical parameters \nand laboratory status and be attentive to the possible association of this medicinal product with splenic \nenlargement and vaso-occlusive crisis. \n \nLeukocytosis \n \nWhite blood cell (WBC) counts of 100 × 109/L or greater have been observed in less than 1 % of \npatients receiving pegfilgrastim therapy. No adverse events directly attributable to this degree of \nleukocytosis have been reported. Such elevation in white blood cells is transient, typically seen 24 to \n48 hours after administration and is consistent with the pharmacodynamic effects of this medicinal \nproduct. Consistent with the clinical effects and the potential for leukocytosis, a WBC count should be \nperformed at regular intervals during therapy. If leukocyte counts exceed 50 × 109/L after the expected \nnadir, this medicinal product should be discontinued immediately. \n \nHypersensitivity \n \nHypersensitivity, including anaphylactic reactions, occurring on initial or subsequent treatment have \nbeen reported in patients treated with pegfilgrastim. Permanently discontinue Pelmeg in patients with \nclinically significant hypersensitivity. Do not administer Pelmeg to patients with a history of \nhypersensitivity to pegfilgrastim or filgrastim. If a serious allergic reaction occurs, appropriate therapy \nshould be administered, with close patient follow-up over several days. \n \n\n\n\n5 \n\nStevens-Johnson syndrome \n \nStevens-Johnson syndrome (SJS), which can be life-threatening or fatal, has been reported rarely in \nassociation with pegfilgrastim treatment. If the patient has developed SJS with the use of \npegfilgrastim, treatment with pegfilgrastim must not be restarted in this patient at any time. \n\n \nImmunogenicity \n \nAs with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of \nantibodies against pegfilgrastim is generally low. Binding antibodies do occur as expected with all \nbiologics; however, they have not been associated with neutralising activity at present. \n \nAortitis \n \nAortitis has been reported after G-CSF administration in healthy subjects and in cancer patients. The \nsymptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory \nmarkers (e.g. C-reactive protein and white blood cell count). In most cases aortitis was diagnosed by \nCT scan and generally resolved after withdrawal of G-CSF (see section 4.8). \n \n \n \n \nOther warnings \n \nThe safety and efficacy of Pelmeg for the mobilisation of blood progenitor cells in patients or healthy \ndonors has not been adequately evaluated. \nIncreased haematopoietic activity of the bone marrow in response to growth factor therapy has been \nassociated with transient positive bone imaging findings. This should be considered when interpreting \nbone-imaging results. \n \nThis medicinal product contains 30 mg sorbitol in each pre-filed syringe which is equivalent to \n50 mg / mL. The additive effect of concomitantly administered products containing sorbitol (or \nfructose) and dietary intake of sorbitol (or fructose) should be taken into account. \n. \nThis medicinal product contains less than 1 mmol (23 mg) sodium per 6 mg dose, that is to say \nessentially ‘sodium-free’. \n \n4.5 Interaction with other medicinal products and other forms of interaction \n \nDue to the potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy‚ Pelmeg \nshould be administered at least 24 hours after administration of cytotoxic chemotherapy. In clinical \ntrials, pegfilgrastim has been safely administered 14 days before chemotherapy. Concomitant use of \nPelmeg with any chemotherapy agent has not been evaluated in patients. In animal models \nconcomitant administration of pegfilgrastim and 5-fluorouracil (5-FU) or other antimetabolites has \nbeen shown to potentiate myelosuppression. \n \nPossible interactions with other haematopoietic growth factors and cytokines have not been \nspecifically investigated in clinical trials. \n \nThe potential for interaction with lithium, which also promotes the release of neutrophils, has not been \nspecifically investigated. There is no evidence that such an interaction would be harmful. \n \nThe safety and efficacy of Pelmeg have not been evaluated in patients receiving chemotherapy \nassociated with delayed myelosuppression e.g., nitrosoureas. \n \n\n\n\n6 \n\nSpecific interaction or metabolism studies have not been performed, however, clinical trials have not \nindicated an interaction of pegfilgrastim with any other medicinal products. \n \n4.6 Fertility, pregnancy and lactation \n \nPregnancy \n \nThere are no or limited amount of data from the use of pegfilgrastim in pregnant women. Studies in \nanimals have shown reproductive toxicity (see section 5.3). Pelmeg is not recommended during \npregnancy and in women of childbearing potential not using contraception. \n \nBreast-feeding \n \nThere is insufficient information on the excretion of pegfilgrastim / metabolites in human milk a risk \nto the newborns/infants cannot be excluded. A decision must be made whether to discontinue \nbreast-feeding or to discontinue/abstain from Pelmeg therapy taking into account the benefit of \nbreast-feeding for the child and the benefit of therapy for the woman. \n \nFertility \n \nPegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative \nweekly doses approximately 6 to 9 times higher than the recommended human dose (based on body \nsurface area) (see section 5.3). \n \n4.7 Effects on ability to drive and use machines \n \nPelmeg has no or negligible influence on the ability to drive and use machines. \n \n4.8 Undesirable effects \n \nSummary of the safety profile \n \nThe most frequently reported adverse reactions were bone pain (very common [≥ 1/10]) and \nmusculoskeletal pain (common). Bone pain was generally of mild to moderate severity, transient and \ncould be controlled in most patients with standard analgesics. \n \nHypersensitivity-type reactions, including skin rash, urticaria, angioedema, dyspnoea, erythaema, \nflushing, and hypotension occurred on initial or subsequent treatment with pegfilgrastim (uncommon \n[≥ 1/1,000 to < 1/100]). Serious allergic reactions, including anaphylaxis can occur in patients \nreceiving pegfilgrastim (uncommon) (see section 4.4). \n \nCapillary leak syndrome, which can be life-threatening if treatment is delayed, has been reported as \nuncommon (≥ 1/1,000 to < 1/100) in cancer patients undergoing chemotherapy following \nadministration of granulocyte colony-stimulating factors; see section 4.4 and section “Description of \nselected adverse reactions” below. \n \nSplenomegaly, generally asymptomatic, is uncommon. \n \nSplenic rupture including some fatal cases is uncommonly reported following administration of \npegfilgrastim (see section 4.4). Uncommon pulmonary adverse reactions including interstitial \npneumonia, pulmonary oedema, pulmonary infiltrates and pulmonary fibrosis have been reported. \nUncommonly, cases have resulted in respiratory failure or Acute Respiratory Distress Syndrome \n(ARDS), which may be fatal (see section 4.4). \n \nIsolated cases of sickle cell crises have been reported in patients with sickle cell trait or sickle cell \ndisease (uncommon in sickle cell patients) (see section 4.4). \n \n\n\n\n7 \n\nTabulated list of adverse reactions \n \nThe data in the table below describe adverse reactions reported from clinical trials and spontaneous \nreporting. Within each frequency grouping, undesirable effects are presented in order of decreasing \nseriousness. \n \n\nMedDRA \nsystem organ \nclass \n\nAdverse reactions \nVery \n\ncommon \nCommon Uncommon Rare Very rare \n\n(≥ 1/10) (≥ 1/100 \nto < 1/10) \n\n(≥ 1/1,000 \nto < 1/100) \n\n(≥ 1/10,000 \nto < 1/1,000) \n\n(< 1/10,000) \n\nBlood and \nlymphatic \nsystem \ndisorders \n\n Thrombocytope\nnia1 \nLeukocytosis1 \n\nSickle cell \ncrisis2; \nSplenomegaly2; \nSplenic rupture2 \n\n \n\nImmune \nsystem \ndisorders \n\n Hypersensitivity \nreactions; \nAnaphylaxis \n\n \n\nMetabolism \nand nutrition \ndisorders \n\n Elevations in \nuric acid \n\n \n\nNervous system \ndisorders \n\nHeadache1 \n\nVascular \ndisorders \n\n Capillary leak \nsyndrome1 \n\nAortitis \n\nRespiratory, \nthoracic and \nmediastinal \ndisorders \n\n Acute \nRespiratory \nDistress \nSyndrome2; \nPulmonary \nadverse \nreactions \n(interstitial \npneumonia, \npulmonary \noedema, \npulmonary \ninfiltrates and \npulmonary \nfibrosis) \nHaemoptysis \n\nPulmonary \nhemorrhage \n\n \n\nGastrointestina\nl disorders \n\nNausea1 \n\nSkin and \nsubcutaneous \ntissue disorders \n\n Sweet’s \nsyndrome (acute \nfebrile \ndermatosis)1,2; \nCutaneous \nvasculitis1,2 \n\nStevens-\nJohnson \nsyndrome \n\n \n\nMusculoskeleta\nl and \nconnective \ntissue disorders \n\nBone pain Musculoskeletal \npain (myalgia, \narthralgia, pain \nin extremity, \nback pain, \nmusculoskeletal \npain, neck pain) \n\n \n\n\n\n8 \n\nMedDRA \nsystem organ \nclass \n\nAdverse reactions \nVery \n\ncommon \nCommon Uncommon Rare Very rare \n\n(≥ 1/10) (≥ 1/100 \nto < 1/10) \n\n(≥ 1/1,000 \nto < 1/100) \n\n(≥ 1/10,000 \nto < 1/1,000) \n\n(< 1/10,000) \n\nRenal and \n urinary \n disorders \n\n Glomerulo-\nnephritis2 \n\n \n\nGeneral \ndisorders and \nadministration \nsite conditions \n\n Injection site \npain, \nNon-cardiac \nchest pain 1 \n\nInjection site \nreactions2 \n\n \n\nInvestigations Elevations in \nlactate \ndehydrogenase \nand alkaline \nphosphatase1; \nTransient \nelevations in \nLFT's for ALT \nor AST1 \n\n \n\n1 See section “Description of selected adverse reactions” below. \n2 This adverse reaction was identified through post-marketing surveillance but not observed in \nrandomised, controlled clinical trials in adults that supported the marketing authorisation. The \nfrequency category was estimated from a statistical calculation based upon 1,576 patients receiving \npegfilgrastim in nine randomised clinical trials. \n \nDescription of selected adverse reactions \n \nUncommon cases of Sweet’s syndrome have been reported, although in some cases underlying \nhaematological malignancies may play a role. \n \nUncommon events of cutaneous vasculitis have been reported in patients treated with pegfilgrastim. \nThe mechanism of vasculitis in patients receiving pegfilgrastim is unknown. \n \nInjection site reactions, including injection site erythaema (uncommon) as well as injection site pain \n(common) have occurred on initial or subsequent treatment with pegfilgrastim. \n \nCommon cases of leukocytosis (White Blood Count [WBC] > 100 × 109/L) have been reported (see \nsection 4.4). \n \nReversible, mild to moderate elevations in uric acid and alkaline phosphatase, with no associated \nclinical effects, were uncommon; reversible, mild to moderate elevations in lactate dehydrogenase, \nwith no associated clinical effects, were uncommon in patients receiving pegfilgrastim following \ncytotoxic chemotherapy. \n \nNausea and headaches were very commonly observed in patients receiving chemotherapy. \n \nUncommon elevations in liver function tests (LFTs) for ALT (alanine aminotransferase) or AST \n(aspartate aminotransferase), have been observed in patients after receiving pegfilgrastim following \ncytotoxic chemotherapy. These elevations are transient and return to baseline. \n \nCommon cases of thrombocytopenia have been reported. \n \nCases of capillary leak syndrome have been reported in the post marketing setting with granulocyte \ncolony-stimulating factor use. These have generally occurred in patients with advanced malignant \n\n\n\n9 \n\ndiseases, sepsis, taking multiple chemotherapy medicinal products or undergoing apheresis (see \nsection 4.4). \n \nPaediatric population \n \nThe experience in children is limited. A higher frequency of serious adverse reactions in younger \nchildren aged 0-5 years (92 %) has been observed compared to older children aged 6-11 and \n12-21 years respectively (80 % and 67 %) and adults. The most common adverse reaction reported \nwas bone pain (see section 5.1 and 5.2). \n \nReporting of suspected adverse reactions \n \nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V. \n \n4.9 Overdose \n \nSingle doses of 300 μg/kg have been administered subcutaneously to a limited number of healthy \nvolunteers and patients with non-small cell lung cancer without serious adverse reactions. The adverse \nevents were similar to those in subjects receiving lower doses of pegfilgrastim. \n \n \n5. PHARMACOLOGICAL PROPERTIES \n \n5.1 Pharmacodynamic properties \n \nPharmacotherapeutic group: immunostimulants, colony stimulating factor; ATC Code: L03AA13 \n \nPelmeg is a biosimilar medicinal product. Detailed information is available on the website of the \nEuropean Medicines Agency http://www.ema.europa.eu. \n \nHuman granulocyte colony stimulating factor (G-CSF) is a glycoprotein, which regulates the \nproduction and release of neutrophils from the bone marrow. Pegfilgrastim is a covalent conjugate of \nrecombinant human G-CSF (r-metHuG-CSF) with a single 20 kd polyethylene glycol (PEG) molecule. \nPegfilgrastim is a sustained duration form of filgrastim due to decreased renal clearance. Pegfilgrastim \nand filgrastim have been shown to have identical modes of action, causing a marked increase in \nperipheral blood neutrophil counts within 24 hours, with minor increases in monocytes and/or \nlymphocytes. Similarly to filgrastim, neutrophils produced in response to pegfilgrastim show normal \nor enhanced function as demonstrated by tests of chemotactic and phagocytic function. As with other \nhaematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial \ncells. G-CSF can promote growth of myeloid cells, including malignant cells, in vitro and similar \neffects may be seen on some non-myeloid cells in vitro. \n \nIn two randomised, double-blind, pivotal studies in patients with high risk stage II-IV breast cancer \nundergoing myelosuppressive chemotherapy consisting of doxorubicin and docetaxel, use of \npegfilgrastim, as a single once per cycle dose, reduced the duration of neutropenia and the incidence of \nfebrile neutropenia similarly to that observed with daily administrations of filgrastim (a median of \n11 daily administrations). In the absence of growth factor support, this regimen has been reported to \nresult in a mean duration of grade 4 neutropenia of 5 to7 days, and a 30-40 % incidence of febrile \nneutropenia. In one study (n = 157), which used a 6 mg fixed dose of pegfilgrastim the mean duration \nof grade 4 neutropenia for the pegfilgrastim group was 1.8 days compared with 1.6 days in the \nfilgrastim group (difference 0.23 days, 95 % CI −0.15, 0.63). Over the entire study, the rate of febrile \nneutropenia was 13 % of pegfilgrastim-treated patients compared with 20 % of filgrastim-treated \npatients (difference 7 %, 95 % CI of −19 %, 5 %). In a second study (n = 310), which used a \nweight-adjusted dose (100 μg /kg), the mean duration of grade 4 neutropenia for the pegfilgrastim \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\nhttp://www.ema.europa.eu/\n\n\n10 \n\ngroup was 1.7 days, compared with 1.8 days in the filgrastim group (difference 0.03 days, 95 % CI \n−0.36, 0.30). The overall rate of febrile neutropenia was 9 % of patients treated with pegfilgrastim and \n18 % of patients treated with filgrastim (difference 9 %, 95 % CI of −16.8 %,−1.1 %). \n \nIn a placebo-controlled, double blind study in patients with breast cancer the effect of pegfilgrastim on \nthe incidence of febrile neutropenia was evaluated following administration of a chemotherapy \nregimen associated with a febrile neutropenia rate of 10-20 % (docetaxel 100 mg/m2 every 3 weeks for \n4 cycles). Nine hundred and twenty eight patients were randomised to receive either a single dose of \npegfilgrastim or placebo approximately 24 hours (Day 2) after chemotherapy in each cycle. The \nincidence of febrile neutropenia was lower for patients randomised to receive pegfilgrastim compared \nwith placebo (1 % versus 17 %, p < 0.001). The incidence of hospitalisations and IV anti-infective use \nassociated with a clinical diagnosis of febrile neutropenia was lower in the pegfilgrastim group \ncompared with placebo (1 % versus 14 %, p < 0.001; and 2 % versus 10 %, p < 0.001). \nA small (n = 83), Phase II, randomised, double-blind study in patients receiving chemotherapy for \nde novo acute myeloid leukaemia compared pegfilgrastim (single dose of 6 mg) with filgrastim, \nadministered during induction chemotherapy. Median time to recovery from severe neutropenia was \nestimated as 22 days in both treatment groups. Long term outcome was not studied (see section 4.4). \n \nIn a phase II (n = 37) multicentre, randomised, open-label study of paediatric sarcoma patients \nreceiving 100 μg/kg pegfilgrastim following cycle 1 of vincristine, doxorubicin and cyclophosphamide \n(VAdriaC/IE) chemotherapy, a longer duration of severe neutropenia (neutrophils < 0.5 × 109) was \nobserved in younger children aged 0-5 years (8.9 days) compared to older children aged 6-11 years \nand 12-21 years (6 days and 3.7 days, respectively) and adults. Additionally a higher incidence of \nfebrile neutropenia was observed in younger children aged 0-5 years (75 %) compared to older \nchildren aged 6-11 years and 12-21 years (70 % and 33 %, respectively) and adults (see sections 4.8 \nand 5.2). \n \n5.2 Pharmacokinetic properties \n \nAfter a single subcutaneous dose of pegfilgrastim, the peak serum concentration of pegfilgrastim \noccurs at 16 to 120 hours after dosing and serum concentrations of pegfilgrastim are maintained \nduring the period of neutropenia after myelosuppressive chemotherapy. The elimination of \npegfilgrastim is non-linear with respect to dose; serum clearance of pegfilgrastim decreases with \nincreasing dose. Pegfilgrastim appears to be mainly eliminated by neutrophil mediated clearance, \nwhich becomes saturated at higher doses. Consistent with a self-regulating clearance mechanism, the \nserum concentration of pegfilgrastim declines rapidly at the onset of neutrophil recovery (see \nfigure 1). \n \nFigure 1: Profile of median pegfilgrastim serum concentration and absolute neutrophil count \n(ANC) in chemotherapy treated patients after a single 6 mg injection \n \n\nM\ned\n\nia\nn \n\nS\ner\n\num\n P\n\neg\nfil\n\ngr\nas\n\ntim\n C\n\non\nc.\n\n (n\ng/\n\nm\nl) \n\n \n\nM\ned\n\nia\nn \n\nA\nbs\n\nol\nut\n\ne \nN\n\neu\ntro\n\nph\nil C\n\nou\nnt\n\n (c\nel\n\nls\n x\n\n 1\n09\n\n/l)\n \n\n Study Day \n\n\n\n11 \n\n \nDue to the neutrophil-mediated clearance mechanism, the pharmacokinetics of pegfilgrastim is not \nexpected to be affected by renal or hepatic impairment. In an open label, single dose study (n = 31) \nvarious stages of renal impairment, including end-stage renal disease, had no impact on the \npharmacokinetics of pegfilgrastim. \n \nElderly \n \nLimited data indicate that the pharmacokinetics of pegfilgrastim in elderly subjects (> 65 years) is \nsimilar to that in adults. \n \nPaediatric population \n \nThe pharmacokinetics of pegfilgrastim were studied in 37 paediatric patients with sarcoma, who \nreceived 100 μg/kg pegfilgrastim after the completion of VAdriaC/IE chemotherapy. The youngest \nage group (0-5 years) had a higher mean exposure to pegfilgrastim (AUC) (± Standard Deviation) \n(47.9 ± 22.5 μg·hr/mL) than older children aged 6-11 years and 12-21 years (22.0 ± 13.1 μg·hr/mL \nand 29.3 ± 23.2 μg·hr/mL, respectively) (see section 5.1). With the exception of the youngest age \ngroup (0-5 years), the mean AUC in paediatric subjects appeared similar to that for adult patients with \nhigh-risk stage II-IV breast cancer and receiving 100 μg/kg pegfilgrastim after the completion of \ndoxorubicin/docetaxel (see sections 4.8 and 5.1). \n \n5.3 Preclinical safety data \n \nPreclinical data from conventional studies of repeated dose toxicity revealed the expected \npharmacological effects including increases in leukocyte count, myeloid hyperplasia in bone marrow, \nextramedullary haematopoiesis and splenic enlargement. \n \nThere were no adverse effects observed in offspring from pregnant rats given pegfilgrastim \nsubcutaneously, but in rabbits pegfilgrastim has been shown to cause embryo/foetal toxicity \n(embryo loss) at cumulative doses approximately 4 times the recommended human dose, which were \nnot seen when pregnant rabbits were exposed to the recommended human dose. In rat studies, it was \nshown that pegfilgrastim may cross the placenta. Studies in rats indicated that reproductive \nperformance, fertility, oestrous cycling, days between pairing and coitus, and intrauterine survival \nwere unaffected by pegfilgrastim given subcutaneously. The relevance of these findings for humans is \nnot known. \n \n \n6. PHARMACEUTICAL PARTICULARS \n \n6.1 List of excipients \n \nSodium acetate* \nSorbitol (E 420) \nPolysorbate 20 \nWater for injections \nHydrochloric acid (for pH adjustment) \nSodium hydroxide (for pH adjustment) \n \n \n*Sodium acetate is prepared by mixing sodium acetate trihydrate and acetic acid. \n \n6.2 Incompatibilities \n \nThis medicinal product must not be mixed with other medicinal products, particularly with sodium \nchloride solutions. \n \n\n\n\n12 \n\n6.3 Shelf life \n \n2 years \n \n6.4 Special precautions for storage \n \nStore in a refrigerator (2 °C – 8 °C). \n \nPelmeg may be exposed to room temperature (not above 30º C) for a maximum single period of up to \n96 hours. Pelmeg left at room temperature for more than 96 hours should be discarded. \n \nDo not freeze. Accidental exposure to freezing temperatures for two periods of less than 72 hours each \ndoes not adversely affect the stability of Pelmeg. \n \nKeep the container in the outer carton in order to protect from light. \n \n6.5 Nature and contents of container \n \nPre-filled syringe (Type I glass), with a bromobutyl rubber stopper and a stainless steel needle with an \nautomatic needle guard. \n \nEach pre-filled syringe contains 0.6 mL of solution for injection. Pack size of one pre-filled syringe in \na blistered packaging. \n \n6.6 Special precautions for disposal and other handling \n \nBefore administration, Pelmeg solution should be inspected visually for particulate matter. Only a \nsolution that is clear and colourless should be injected. \n \nExcessive shaking may aggregate pegfilgrastim, rendering it biologically inactive. \n \nAllow the pre-filled syringe to reach room temperature before injecting. \n \nAny unused product or waste material should be disposed of in accordance with local requirements. \n \n \n7. MARKETING AUTHORISATION HOLDER \n \nMundipharma Biologics S.L. \nCalle García Ximénez, nº3-1º \n31002 Pamplona (Navarra), Spain \n \n8. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/18/1328/001 \n \n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n \nDate of first authorisation: 20 November 2018 \n \n \n10. DATE OF REVISION OF THE TEXT \n \nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency http://www.ema.europa.eu. \n \n \n\nhttp://www.ema.europa.eu/\n\n\n13 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX II \n\n \nA. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND \n\nMANUFACTURER RESPONSIBLE FOR BATCH RELEASE \n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \nAUTHORISATION \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n\n \n \n\n\n\n14 \n\nA. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND \nMANUFACTURER RESPONSIBLE FOR BATCH RELEASE \n\n \n\nName and address of the manufacturer of the biological active substance \n\n3P BIOPHARMACEUTICALS SL \nC/ Mocholi 2, Poligono Industrial Mocholi \n31110 Noain \nSpain \n \nName and address of the manufacturer responsible for batch release \n\nPharmaKorell GmbH \nMarie-Curie-Str. 8 \n79539 Loerrach \nGermany \n \n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n\n \nMedicinal product subject to restricted medical prescription (see Annex I: Summary of Product \nCharacteristics, section 4.2). \n\n \n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \nAUTHORISATION \n\n• Periodic safety update reports \n\nThe requirements for submission of periodic safety update reports for this medicinal product are set \nout in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive \n2001/83/EC and any subsequent updates published on the European medicines web-portal. \n\n \n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n\n• Risk Management Plan (RMP) \n\nThe MAH shall perform the required pharmacovigilance activities and interventions detailed in \nthe agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed \nsubsequent updates of the RMP. \n\nAn updated RMP should be submitted: \n\n• At the request of the European Medicines Agency; \n\nWhenever the risk management system is modified, especially as the result of new information \nbeing received that may lead to a significant change to the benefit/risk profile or as the result of an \nimportant (pharmacovigilance or risk minimisation) milestone being reached. \n\n \n \n \n \n \n\n\n\n15 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX III \n \n\nLABELLING AND PACKAGE LEAFLET \n \n\n \n\n\n\n16 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nA. LABELLING \n \n\n \n\n\n\n17 \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nOUTER CARTON FOR BLISTERED SYRINGE \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nPelmeg 6 mg solution for injection in pre-filled syringe \npegfilgrastim \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nEach pre-filled syringe contains 6 mg of pegfilgrastim in 0.6 mL (10 mg/mL) solution for injection. \n \n \n3. LIST OF EXCIPIENTS \n \nExcipients: sodium acetate, sorbitol (E 420), polysorbate 20, and water for injections. See package \nleaflet for further information. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nSolution for injection \n1 pre-filled syringe with automatic needle guard (0.6 mL). \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor single use only. \nFor subcutaneous use. \nImportant: read the package leaflet before handling pre-filled syringe \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \nAvoid vigorous shaking. \n \n \n8. EXPIRY DATE \n \nEXP \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. \nDo not freeze. \nKeep the container in the outer carton in order to protect from light. \n\n\n\n18 \n\n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nMundipharma Biologics S.L. \nCalle García Ximénez, nº3-1º \n31002 Pamplona (Navarra) \nSpain \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/18/1328/001 \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nPelmeg \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC: \nSN: \nNN: \n \n\n\n\n19 \n\nMINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS \n \nBLISTER PACK WITH SYRINGE \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nPelmeg 6 mg solution for injection \npegfilgrastim \n \n \n2. NAME OF THE MARKETING AUTHORISATION HOLDER \n \nMundipharma \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. OTHER \n \nLogo \n \n \n \n \n\n\n\n20 \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nSYRINGE LABEL \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n \nPelmeg 6 mg \npegfilgrastim \nSC \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n0.6 mL \n \n \n6. OTHER \n \nMundipharma \n \n\n\n\n21 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nB. PACKAGE LEAFLET \n \n\n\n\n22 \n\nPackage leaflet: Information for the user \n \n\nPelmeg 6 mg solution for injection in pre-filled syringe \npegfilgrastim \n\n \n This medicine is subject to additional monitoring. This will allow quick identification of new \nsafety information. You can help by reporting any side effects you may get. See the end of section 4 \nfor how to report side effects. \n \nRead all of this leaflet carefully before you start using this medicine because it contains \nimportant information for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor, pharmacist or nurse. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their symptoms of illness are the same as yours. \n- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible \n\nside effects not listed in this leaflet. See section 4. \n \nWhat is in this leaflet \n \n1. What Pelmeg is and what it is used for \n2. What you need to know before you use Pelmeg \n3. How to use Pelmeg \n4. Possible side effects \n5. How to store Pelmeg \n6. Contents of the pack and other information \n \n \n1. What Pelmeg is and what it is used for \n \nPelmeg contains the active substance pegfilgrastim. Pegfilgrastim is a protein produced by \nbiotechnology in bacteria called E. coli. It belongs to a group of proteins called cytokines, and is very \nsimilar to a natural protein (granulocyte-colony stimulating factor) produced by your own body. \n \nPelmeg is used in adult patients to reduce the duration of neutropenia (low white blood cell count) and \nthe occurrence of febrile neutropenia (low white blood cell count with a fever) which can be caused by \nthe use of cytotoxic chemotherapy (medicines that destroy rapidly growing cells). White blood cells \nare important as they help your body fight infection. These cells are very sensitive to the effects of \nchemotherapy which can cause the number of these cells in your body to decrease. If white blood cells \nfall to a low level there may not be enough left in the body to fight bacteria and you may have an \nincreased risk of infection. \n \nYour doctor has given you Pelmeg to encourage your bone marrow (part of the bone which makes \nblood cells) to produce more white blood cells that help your body fight infection. \n \n \n2. What you need to know before you use Pelmeg \n \nDo not use Pelmeg if \n \n• you are allergic to pegfilgrastim, filgrastim, E. coli derived proteins, or any of the other \n\ningredients of this medicine. \n \n\n\n\n23 \n\nWarnings and precautions \n \nTalk to your doctor, pharmacist or nurse before using Pelmeg: \n \n• if you experience an allergic reaction including weakness, drop in blood pressure, difficulty \n\nbreathing, swelling of the face (anaphylaxis), redness and flushing, skin rash and areas of the \nskin that itch \n\n• if you experience a cough, fever and difficulty breathing. This can be a sign of Acute \nRespiratory Distress Syndrome (ARDS) \n\n• if you have any of the following or combination of the following side effects: \n- swelling or puffiness, which may be associated with passing water less frequently, \n\ndifficulty breathing, abdominal swelling and feeling of fullness, and a general feeling of \ntiredness \n\nThese could be symptoms of condition called “Capillary Leak Syndrome” which causes blood \nto leak from the small blood vessels into your body. See section 4. \n\n• if you get left upper abdominal pain or pain at the tip of your shoulder. This may be a sign of a \nproblem with your spleen (splenomegaly) \n\n• if you have recently had a serious lung infection (pneumonia), fluid in the lungs (pulmonary \noedema), inflammation of the lungs (interstitial lung disease) or an abnormal chest x-ray (lung \ninfiltration) \n\n• if you are aware of any altered blood cell counts (e.g. increase in white blood cells or anaemia) \nor decreased blood platelet counts, which reduces the ability of your blood to clot \n(thrombocytopenia). Your doctor may want to monitor you more closely. \n\n• if you have sickle cell anaemia. Your doctor may monitor your condition more closely. \n• if you have sudden signs of allergy such as rash, itching or hives on the skin, swelling of the \n\nface, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing \nthese could be signs of a severe allergic reaction. \n\n• Inflammation of the aorta (the large blood vessel which transports blood from the heart to the \nbody) has been reported rarely in cancer patients and healthy donors. The symptoms can include \nfever, abdominal pain, malaise, back pain and increased inflammatory markers. Tell your doctor \nif you experience these symptoms. \n\n \n \nYour doctor will check your blood and urine regularly as Pelmeg can harm the tiny filters inside your \nkidneys (glomerulonephritis). \n \nSevere skin reactions (Stevens-Johnson syndrome) have been reported with the use of Pelmeg. Stop \nusing Pelmeg and seek medical attention immediately if you notice any of the symptoms described in \nsection 4. \n\n \nYou should talk to your doctor about your risks of developing cancers of the blood. If you develop or \nare likely to develop cancers of the blood, you should not use Pelmeg, unless instructed by your \ndoctor. \n \nLoss of response to pegfilgrastim \n \nIf you experience a loss of response or failure to maintain a response with pegfilgrastim treatment, \nyour doctor will investigate the reasons why including whether you have developed antibodies which \nneutralise pegfilgrastim’s activity. \n \nOther medicines and Pelmeg \n \nTell your doctor or pharmacist if you are taking, have recently taken or might take any other \nmedicines. \n \n\n\n\n24 \n\nPregnancy and breast-feeding \n \nAsk your doctor or pharmacist for advice before taking any medicine. Pelmeg has not been tested in \npregnant women. It is important to tell your doctor if you: \n• are pregnant; \n• think you may be pregnant; or \n• are planning to have a baby. \n \nIf you become pregnant during Pelmeg treatment, please inform your doctor. \n \nUnless your doctor directs you otherwise, you must stop breast-feeding if you use Pelmeg. \n \nDriving and using machines \n \nPelmeg has no or negligible effect on the ability to drive or use machines. \n \nPelmeg contains sorbitol (E 420) and sodium acetate \n \n \n\nThis medicine contains 30 mg sorbitol in each pre-filed syringe which is equivalent to 50 mg / mL. \n \nThis medicine contains less than 1 mmol (23 mg) sodium per 6 mg dose, that is to say essentially \n‘sodium-free’. \n \n \n3. How to use Pelmeg \n \nPelmeg is for use in adults aged 18 and over. \n \nAlways use Pelmeg exactly as your doctor has told you. You should check with your doctor or \npharmacist if you are unsure. The usual dose is one 6 mg subcutaneous injection (injection under your \nskin) using a pre-filled syringe and it should be given at least 24 hours after your last dose of \nchemotherapy at the end of each chemotherapy cycle. \n \nDo not shake Pelmeg vigorously as this may affect its activity. \n \nInjecting Pelmeg yourself \n \nYour doctor may decide that it would be more convenient for you to inject Pelmeg yourself. Your \ndoctor or nurse will show you how to inject yourself. Do not try to inject yourself if you have not been \ntrained. \n \nFor further instructions on how to inject yourself with Pelmeg, please read the section at the end of \nthis leaflet. \n \nIf you use more Pelmeg than you should \n \nIf you use more Pelmeg than you should contact your doctor, pharmacist or nurse. \n \nIf you forget to inject Pelmeg \n \nIf you have forgotten a dose of Pelmeg, you should contact your doctor to discuss when you should \ninject the next dose. \n \nIf you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. \n \n\n\n\n25 \n\n \n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. \n \nPlease tell your doctor immediately if you have any of the following or combination of the following \nside effects: \n• swelling or puffiness, which may be associated with passing water less frequently, difficulty \n\nbreathing, abdominal swelling and feeling of fullness, and a general feeling of tiredness. These \nsymptoms generally develop in a rapid fashion. \n\nThese could be symptoms of an uncommon (may affect up to 1 in 100 people) condition called \n“Capillary Leak Syndrome” which causes blood to leak from the small blood vessels into your body \nand needs urgent medical attention. \n \nVery common side effects (may affect more than 1 in 10 people): \n• bone pain. Your doctor will tell you what you can take to ease the bone pain. \n• nausea and headaches. \n \nCommon side effects (may affect up to 1 in 10 people): \n• pain at the site of injection. \n• general aches and pains in the joints and muscles. \n• some changes may occur in your blood, but these will be detected by routine blood tests. Your \n\nwhite blood cell count may become high for a short period of time. Your platelet count may \nbecome low which might result in bruising. \n\n \nUncommon side effects (may affect up to 1 in 100 people): \n• allergic-type reactions, including redness and flushing, skin rash, and raised areas of the skin \n\nthat itch. \n• serious allergic reactions, including anaphylaxis (weakness, drop in blood pressure, difficulty \n\nbreathing, swelling of the face). \n• increased spleen size. \n• spleen rupture. Some cases of splenic rupture were fatal. It is important that you contact your \n\ndoctor immediately if you experience pain in the upper left side of the abdomen or left shoulder \npain since this may relate to a problem with your spleen. \n\n• breathing problems. If you have a cough, fever and difficulty breathing please tell your doctor. \n• Sweet’s syndrome (plum-coloured, raised, painful lesions on the limbs and sometimes the face \n\nand neck with fever) has occurred but other factors may play a role. \n• cutaneous vasculitis (inflammation of the blood vessels in the skin). \n• damage to the tiny filters inside your kidneys (glomerulonephritis). \n• redness at the site of injection. \n• coughing up blood (haemoptysis). \n \nRare side effects (may affect up to 1 in 1,000 people) \n• Inflammation of the aorta (the large blood vessel which transports blood from the heart to the \n\nbody), see section 2. \n• Bleeding from the lung (pulmonary haemorrhage). \n• Stevens-Johnson syndrome, which can appear as reddish target-like or circular patches often with \n\ncentral blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and can \nbe preceded by fever and flu-like symptoms. Stop using Pelmeg if you develop these symptoms \nand contact your doctor or seek medical attention immediately. See also section 2. \n \n\n \nReporting of side effects \nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \neffects not listed in this leaflet. You can also report side effects directly via the national reporting \nsystem listed in Appendix V. By reporting side effects you can help provide more information on the \nsafety of this medicine. \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n26 \n\n \n \n5. How to store Pelmeg \n \nKeep this medicine out of the sight and reach of children. \n \nDo not use this medicine after the expiry date which is stated on the carton and on the syringe label \nafter EXP. The expiry date refers to the last day of that month. \n \nStore in a refrigerator (2 °C - 8 °C). \n \nYou may take Pelmeg out of the refrigerator and keep it at room temperature (not above 30° C) for no \nlonger than 4 days. Once a syringe has been removed from the refrigerator and has reached room \ntemperature (not above 30° C) it must either be used within 4 days or disposed of. \n \nDo not freeze. Pelmeg may be used if it is accidentally frozen for two periods of less than 72 hours \neach. \n \nKeep the container in the outer carton in order to protect from light. \n \nDo not use this medicine if you notice it is cloudy or there are particles in it. \n \nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \nthrow away medicines you no longer use. These measures will help to protect the environment. \n \n \n6. Contents of the pack and other infor mation \n \nWhat Pelmeg contains \n• The active substance is pegfilgrastim. Each pre-filled syringe contains 6 mg of pegfilgrastim in \n\n0.6 mL of solution. \n• The other ingredients are sodium acetate, sorbitol (E 420), polysorbate 20 and water for \n\ninjections. See section 2. \n \nWhat Pelmeg looks like and contents of the pack \nPelmeg is a clear, colourless solution for injection in a pre-filled syringe (6 mg/0.6 mL). \n \nEach pack contains 1 pre-filled glass syringe with an attached stainless steel needle and needle cap. \nThe syringe is provided with an automatic needle guard. \n \nMarketing Authorisation Holder \n \nMundipharma Biologics S.L. \nCalle García Ximénez, nº3-1º \n31002 Pamplona (Navarra) \nSpain \n \nManufacturer \nPharmaKorell GmbH \nMarie-Curie-Strasse 8 \nD-79539 Lörrach \nGermany \n \nFor any information about this medicine, please contact the local representative of the Marketing \nAuthorisation Holder: \n \n\n\n\n27 \n\nBelgië/Belgique/Belgien \nMundipharma Comm. VA \nTél/Tel: +32 15 45 11 80 \ninfo@mundipharma.be \n\nLietuva \nEGIS Pharmaceuticals PLC atstovybė \nTel.:+ 370 5 231 4658 \ninfo@egis.lt \n\n \nБългария \nТП„Мундифарма Гезелшафт м.б.Х.“ \nTeл.: + 359 2 962 13 56 \nmundipharma@mundipharma.bg \n \n\n \nLuxembourg/Luxemburg \nMundipharma Comm. VA \nTél/Tel: +32 15 45 11 80 \ninfo@mundipharma.be \n\nČeská republika \nMundipharma GesmbH. Austria - organizační \nsložka ČR \nTel: + 420 222 318 221 \noffice@mundipharma.cz \n\nMagyarország \nEgis Gyógyszergyár Zrt. \nTel.: +36 1 803 5555 \nmailbox@egis.hu \n\nDanmark \nMundipharma A/S \nTlf: + 45 45 17 48 00 \nmundipharma@mundipharma.dk \n\nMalta \nMundipharma Corporation (Ireland) Limited \nTel: +353 1 206 3800 \n\n \nDeutschland \nMundipharma GmbH \nTel: +49 (0) 69 506029-000 \ninfo@mundipharma.de \n\n \nNederland \nMundipharma Pharmaceuticals B.V. \nTel: + 31 (0)33 450 82 70 \ninfo@mundipharma.nl \n\n \nEesti \nKBM Pharma OÜ \nTel: +372 733 8080 \n \n\n \nNorge \nMundipharma AS \nTlf: + 47 67 51 89 00 \npost@mundipharma.no \n\n \nΕλλάδα \nMundipharma Corporation (Ireland) Limited \nΤηλ: + 353 1 206 3800 \n \n\n \nÖsterreich \nMundipharma Gesellschaft m.b.H. \nTel: +43 (0)1 523 25 05-0 \ninfo@mundipharma.at \n\n \nEspaña \nMundipharma Pharmaceuticals, S.L. \nTel: +34 91 3821870 \ninfomed@mundipharma.es \n\n \nPolska \nMundipharma Polska Sp. z o.o. \nTel.: + (48 22) 866 87 12 \nbiuro@mundipharma.pl \n\n \nFrance \nMUNDIPHARMA SAS \nTél: +33 1 40 65 29 29 \ninfomed@mundipharma.fr \n \n\n \nPortugal \nMundipharma Farmacêutica Lda \nTel: +351 21 901 31 62 \nmedinfo@mundipharma.pt \n\nHrvatska \nMedis Adria d.o.o \nTel: + 385 (0) 1 230 34 46 \ninfo@medisadria.hr \n \nIreland \nMundipharma Pharmaceuticals Limited \nTel: +353 1 206 3800 \n \n\nRomânia \nEgis Pharmaceuticals PLC România \nTel: +40 21 412 00 17 \noffice@egis.ro \n \nSlovenija \nMedis, d.o.o. \nTel: +386 158969 00 \ninfo@medis.si \n \n\nmailto:info@mundipharma.be\nmailto:info@egis.lt\nmailto:info@mundipharma.be\nmailto:office@mundipharma.cz\nmailto:mailbox@egis.hu\nmailto:mundipharma@mundipharma.dk\nmailto:info@mundipharma.nl\nmailto:post@mundipharma.no\nmailto:info@mundipharma.at\nmailto:infomed@mundipharma.es\nmailto:biuro@mundipharma.pl\nmailto:infomed@mundipharma.fr\nmailto:info@medisadria.hr\nmailto:office@egis.ro\nmailto:info@medis.si\n\n\n28 \n\nÍsland \nIcepharma hf. \nSími: + 354 540 8000 \nicepharma@icepharma.is \n \n\nSlovenská republika \nMundipharma Ges.m.b.H.-o.z. \nTel: + 4212 6381 1611 \nmundipharma@mundipharma.sk \n\nItalia \nMundipharma Pharmaceuticals Srl \nTel: +39 02 3182881 \ninfomedica@mundipharma.it \n\nSuomi/Finland \nMundipharma Oy \nPuh/Tel: + 358 (0)9 8520 2065 \ninfo@mundipharma.fi \n \n\nΚύπρος \nMundipharma Pharmaceuticals Ltd \nΤηλ: +357 22 815656 \ninfo@mundipharma.com.cy \n\nSverige \nMundipharma AB \nTel: + 46 (0)31 773 75 30 \ninfo@mundipharma.se \n\n \nLatvija \nEGIS Pharmaceuticals PLC parstavniecibas \nTel: + 371 676 13 859 \ninfo@egis.lv \n \n\n \nUnited Kingdom \nNAPP Pharmaceuticals Limited \nTel: +44(0) 1223 424444 \n \n\n \nThis leaflet was last revised in . \n \nOther sources of information \n \nDetailed information on this medicine is available on the European Medicines Agency web site: \nhttp://www.ema.europa.eu. \n \n \nQR code to be included <www.pelmeg.eu> \n \n \n\nmailto:icepharma@icepharma.is\nmailto:mundipharma@mundipharma.sk\nmailto:infomedica@mundipharma.it\nmailto:info@mundipharma.fi\nmailto:info@mundipharma.com.cy\nmailto:info@mundipharma.se\nmailto:info@egis.lv\nhttp://www.ema.europa.eu/\n\n\n29 \n\nInstructions for use \n \n\nGuide to parts \nBefore use After use \n\n \nBefore use \n\n \n\nAfter use \n \n\n \n Used plunger \n\nPlunger \n \n Syringe label \n\nFinger grips \n\nUsed syring barrel \n\nSyringe label \n\nSyringe barrel Used needle \n\nSyringe safety guard Used needle safety spring \n\nNeedle safety spring \n\nNeedle cap on Needle cap off \n\n \n \n\nImportant \n\nBefore you use a Pelmeg pre-filled syringe with automatic needle guard, read this important \ninformation: \n• It is important that you do not try to give yourself the injection unless you have received training \n\nfrom your doctor or healthcare provider. \n• Pelmeg is given as an injection into the tissue just under the skin (subcutaneous injection). \n\n Do not remove the needle cap from the pre-filled syringe until you are ready to inject. \n\n Do not use the pre-filled syringe if it has been dropped on a hard surface. Use a new \npre-filled syringe and call your doctor or healthcare provider. \n\n Do not attempt to activate the pre-filled syringe prior to injection. \n\n Do not attempt to remove the clear pre-filled syringe safety guard from the pre-filled syringe \n\n Do not attempt to remove the peelable label on the pre-filled syringe barrel before administering \nyour injection. \n\nCall your doctor or healthcare provider if you have any questions. \n \n \n\n\n\n30 \n\nStep 1: Prepare \nA Remove the pre-filled syringe tray from the package and gather the supplies needed for your \n\ninjection: alcohol wipes, a cotton ball or gauze pad, a plaster and a sharps disposal container \n(not included). \n\nFor a more comfortable injection, leave the pre-filled syringe at room temperature for about 30 minutes \nbefore injecting. Wash your hands thoroughly with soap and water. \n \nOn a clean, well-lit work surface, place the new pre-filled syringe and the other supplies. \n\n Do not try to warm the syringe by using a heat source such as hot water or microwave. \n Do not leave the pre-filled syringe exposed to direct sunlight. \n Do not shake the pre-filled syringe. \n Keep pre-filled syringes out of the sight and reach of children. \n \n\nB Open the tray, peeling away the cover. Grab the pre-filled syringe safety guard to remove \nthe pre-filled syringe from the tray. \n\n \n \n \n \n \n \n \n \n \n \n \n\nFor safety reasons: \n\n Do not grasp the plunger. \n\n Do not grasp the needle cap. \n \n\nC Inspect the medicine and pre-filled syringe. \n \n \n \n \n \n \n \n \n \n\n Do not use the pre-filled syringe if: \n • The medicine is cloudy or there are particles in it. It must be a clear and colourless \n\nliquid. \n • Any part appears cracked or broken. \n • The needle cap is missing or not securely attached. \n • The expiry date printed on the label has passed the last day of the month shown. \nIn all cases, call your doctor or healthcare provider. \n\nGrab here \n\nMedicine \n\n\n\n31 \n\nStep 2: Get ready \nA Wash your hands thoroughly. Prepare and clean your injection site. \n\n \n\nUpper arm \n\nBelly \n\nUpper thigh \n\nYou can use: \n• Upper part of your thigh. \n• Belly, except for a 5 cm (2-inch) area right around your belly button. \n• Outer area of upper arm (only if someone else is giving you the injection). \nClean the injection site with an alcohol wipe. Let your skin dry. \n\n Do not touch the injection site before injecting. \n Do not inject into areas where the skin is tender, bruised, red, or hard. \n\nAvoid injecting into areas with scars or stretch marks. \n \n\n\n\n32 \n\nB Carefully pull the needle cap straight out and away from your body. \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\n \nC Pinch your injection site to create a firm surface. \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nIts important to keep the skin pinched when injecting. \n\n \nStep 3: Inject \n\nA Hold the pinch. INSERT the needle into skin. \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\n Do not touch the cleaned area of the skin. \n\n\n\n33 \n\n \nB PUSH the plunger with slow and constant pressure until you feel or hear a “snap”. Push all the \n\nway down through the snap. \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n It is important to push down through the “snap” to deliver your full dose. \n\n \n \nC RELEASE your thumb. Then LIFT the syringe off skin. \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nAfter releasing the plunger, the pre-filled syringe safety guard will safely cover the injection needle. \n\n Do not put the needle cap back on used pre-filled syringes \n \n \n \n \n \n \n \n \n \n \n \n\n \n\n“SNAP” \n\n\n\n34 \n\n \nHealthcare professionals only \n\nThe trade name and the batch number of the administered product should be clearly recorded \nin the patient file. \n\nRemove and save the pre-filled syringe label \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nTurn the plunger to move the label into a position where you can remove the syringe label \n \n\n \n \n \n \n\n\n\n35 \n\n \nStep 4: Finish \n\nA Discard the used pre-filled syringe and other supplies in a sharps disposal container. \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nMedicines should be disposed of in accordance with local requirements. Ask your pharmacist how to \ndispose of medicines no longer required. These measures will help to protect the environment. \nKeep the syringe and sharps disposal container out of sight and reach of children. \n\n Do not reuse the pre-filled syringe. \n Do not recycle pre-filled syringes or throw them into household waste. \n\n \nB Examine the injection site. \nIf there is blood, press a cotton ball or gauze pad on your injection site. Do not rub the injection site. \nApply a plaster if needed. \n \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\n \n \n\n\n\n36 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX IV \n \n\nSCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS \nOF THE MARKETING AUTHORISATION(S) \n\n \n \n \n \n \n\n\n\n37 \n\nScientific conclusions \n \nTaking into account the PRAC Assessment Report on the PSUR(s) for pegfilgrastim, the scientific \nconclusions of the CHMP are as follows: \n \nThree reported cases show a causal relationship between the adverse drug reaction (ADR) Stevens-\nJohnson syndrome and pegfilgrastim. The number of cases is small, but because of the seriousness of \nthe ADR, the PRAC recommends that the Product Information should be updated accordingly. \n \nThe CHMP agrees with the scientific conclusions made by the PRAC. \n \nGrounds for the variation to the terms of the marketing authorisation(s) \n \nOn the basis of the scientific conclusions for pegfilgrastim the CHMP is of the opinion that the \nbenefit-risk balance of the medicinal product(s) containing pegfilgrastim is unchanged subject to the \nproposed changes to the product information. \n \nThe CHMP recommends that the terms of the marketing authorisation(s) should be varied. \n \n \n \n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. PACKAGE LEAFLET\n\tANNEX IV SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)"},"Section_1":{"kind":"string","value":"{'Title': '1. what pelmeg is and what it is used for', 'Section_Content': 'pelmeg contains the active substance pegfilgrastim. pegfilgrastim is a protein produced by biotechnology in bacteria called e. coli. it belongs to a group of proteins called cytokines, and is very similar to a natural protein (granulocyte-colony stimulating factor) produced by your own body. pelmeg is used in adult patients to reduce the duration of neutropenia (low white blood cell count) and the occurrence of febrile neutropenia (low white blood cell count with a fever) which can be caused by the use of cytotoxic chemotherapy (medicines that destroy rapidly growing cells). white blood cells are important as they help your body fight infection. these cells are very sensitive to the effects of chemotherapy which can cause the number of these cells in your body to decrease. if white blood cells fall to a low level there may not be enough left in the body to fight bacteria and you may have an increased risk of infection. your doctor has given you pelmeg to encourage your bone marrow (part of the bone which makes blood cells) to produce more white blood cells that help your body fight infection.', 'Entity_Recognition': [{'Text': 'pelmeg', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the active substance pegfilgrastim', 'Type': 'TREATMENT', 'BeginOffset': 16, 'EndOffset': 50}, {'Id': 3, 'BeginOffset': 52, 'EndOffset': 65, 'Score': 0.9634522199630737, 'Text': 'pegfilgrastim', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a protein', 'Type': 'PROBLEM', 'BeginOffset': 69, 'EndOffset': 78}, {'Text': 'bacteria', 'Type': 'PROBLEM', 'BeginOffset': 108, 'EndOffset': 116}, {'Text': 'e. coli', 'Type': 'PROBLEM', 'BeginOffset': 124, 'EndOffset': 131}, {'Id': 4, 'BeginOffset': 352, 'EndOffset': 363, 'Score': 0.9826478362083435, 'Text': 'neutropenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9310688376426697}]}, {'Text': 'low white blood cell count', 'Type': 'PROBLEM', 'BeginOffset': 365, 'EndOffset': 391}, {'Id': 5, 'BeginOffset': 415, 'EndOffset': 434, 'Score': 0.7473416924476624, 'Text': 'febrile neutropenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9294565320014954}]}, {'Id': 6, 'BeginOffset': 436, 'EndOffset': 462, 'Score': 0.4244369864463806, 'Text': 'low white blood cell count', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6309845447540283}]}, {'Text': 'a fever', 'Type': 'PROBLEM', 'BeginOffset': 468, 'EndOffset': 475}, {'Id': 14, 'BeginOffset': 511, 'EndOffset': 533, 'Score': 0.9141808152198792, 'Text': 'cytotoxic chemotherapy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 535, 'EndOffset': 544}, {'Id': 15, 'BeginOffset': 582, 'EndOffset': 599, 'Score': 0.4193421006202698, 'Text': 'white blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'your body fight infection', 'Type': 'PROBLEM', 'BeginOffset': 627, 'EndOffset': 652}, {'Text': 'these cells', 'Type': 'PROBLEM', 'BeginOffset': 654, 'EndOffset': 665}, {'Id': 16, 'BeginOffset': 703, 'EndOffset': 715, 'Score': 0.923709511756897, 'Text': 'chemotherapy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 17, 'BeginOffset': 787, 'EndOffset': 804, 'Score': 0.3899598717689514, 'Text': 'white blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_VALUE', 'Score': 0.5636240243911743, 'RelationshipScore': 0.9999697208404541, 'RelationshipType': 'TEST_VALUE', 'Id': 18, 'BeginOffset': 815, 'EndOffset': 818, 'Text': 'low', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': 'fight bacteria', 'Type': 'PROBLEM', 'BeginOffset': 869, 'EndOffset': 883}, {'Id': 9, 'BeginOffset': 922, 'EndOffset': 931, 'Score': 0.9830544590950012, 'Text': 'infection', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7930824160575867}]}, {'Text': 'your bone marrow', 'Type': 'PROBLEM', 'BeginOffset': 979, 'EndOffset': 995}, {'Id': 1, 'BeginOffset': 1009, 'EndOffset': 1013, 'Score': 0.7745674848556519, 'Text': 'bone', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 20, 'BeginOffset': 1026, 'EndOffset': 1037, 'Score': 0.3161998391151428, 'Text': 'blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'white blood cells', 'Type': 'TREATMENT', 'BeginOffset': 1055, 'EndOffset': 1072}, {'Text': 'your body fight infection', 'Type': 'PROBLEM', 'BeginOffset': 1083, 'EndOffset': 1108}]}"},"Section_2":{"kind":"string","value":"{'Title': '2. what you need to know before you use pelmeg', 'Section_Content': 'do not use pelmeg if you are allergic to pegfilgrastim, filgrastim, e. coli derived proteins, or any of the other ingredients of this medicine. warnings and precautions talk to your doctor, pharmacist or nurse before using pelmeg: if you experience an allergic reaction including weakness, drop in blood pressure, difficulty breathing, swelling of the face (anaphylaxis), redness and flushing, skin rash and areas of the skin that itch if you experience a cough, fever and difficulty breathing. this can be a sign of acute respiratory distress syndrome (ards) if you have any of the following or combination of the following side effects: - swelling or puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal swelling and feeling of fullness, and a general feeling of tiredness these could be symptoms of condition called \"capillary leak syndrome\" which causes blood to leak from the small blood vessels into your body. see section 4. if you get left upper abdominal pain or pain at the tip of your shoulder. this may be a sign of a problem with your spleen (splenomegaly) if you have recently had a serious lung infection (pneumonia), fluid in the lungs (pulmonary oedema), inflammation of the lungs (interstitial lung disease) or an abnormal chest x-ray (lung infiltration) if you are aware of any altered blood cell counts (e.g. increase in white blood cells or anaemia) or decreased blood platelet counts, which reduces the ability of your blood to clot (thrombocytopenia). your doctor may want to monitor you more closely. if you have sickle cell anaemia. your doctor may monitor your condition more closely. if you have sudden signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing these could be signs of a severe allergic reaction. inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) has been reported rarely in cancer patients and healthy donors. the symptoms can include fever, abdominal pain, malaise, back pain and increased inflammatory markers. tell your doctor if you experience these symptoms. your doctor will check your blood and urine regularly as pelmeg can harm the tiny filters inside your kidneys (glomerulonephritis). severe skin reactions (stevens-johnson syndrome) have been reported with the use of pelmeg. stop using pelmeg and seek medical attention immediately if you notice any of the symptoms described in section 4. you should talk to your doctor about your risks of developing cancers of the blood. if you develop or are likely to develop cancers of the blood, you should not use pelmeg, unless instructed by your doctor. loss of response to pegfilgrastim if you experience a loss of response or failure to maintain a response with pegfilgrastim treatment, your doctor will investigate the reasons why including whether you have developed antibodies which neutralise pegfilgrastim\\'s activity. other medicines and pelmeg tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. pregnancy and breast-feeding ask your doctor or pharmacist for advice before taking any medicine. pelmeg has not been tested in pregnant women. it is important to tell your doctor if you: are pregnant; think you may be pregnant; or are planning to have a baby. if you become pregnant during pelmeg treatment, please inform your doctor. unless your doctor directs you otherwise, you must stop breast-feeding if you use pelmeg. driving and using machines pelmeg has no or negligible effect on the ability to drive or use machines. pelmeg contains sorbitol (e 420) and sodium acetate this medicine contains 30 mg sorbitol in each pre-filed syringe which is equivalent to 50 mg / ml. this medicine contains less than 1 mmol (23 mg) sodium per 6 mg dose, that is to say essentially \\'sodium-free\\'.', 'Entity_Recognition': [{'Text': 'pelmeg', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 29, 'EndOffset': 37}, {'Id': 23, 'BeginOffset': 41, 'EndOffset': 54, 'Score': 0.9776966571807861, 'Text': 'pegfilgrastim', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 24, 'BeginOffset': 56, 'EndOffset': 66, 'Score': 0.9964362382888794, 'Text': 'filgrastim', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'e. coli derived proteins', 'Type': 'TREATMENT', 'BeginOffset': 68, 'EndOffset': 92}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 129, 'EndOffset': 142}, {'Text': 'an allergic reaction', 'Type': 'PROBLEM', 'BeginOffset': 249, 'EndOffset': 269}, {'Id': 26, 'BeginOffset': 280, 'EndOffset': 288, 'Score': 0.9975115060806274, 'Text': 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'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'the skin that itch', 'Type': 'PROBLEM', 'BeginOffset': 417, 'EndOffset': 435}, {'Text': 'a cough', 'Type': 'PROBLEM', 'BeginOffset': 454, 'EndOffset': 461}, {'Id': 36, 'BeginOffset': 463, 'EndOffset': 468, 'Score': 0.9911235570907593, 'Text': 'fever', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.950127899646759}]}, {'Id': 37, 'BeginOffset': 473, 'EndOffset': 493, 'Score': 0.9879652261734009, 'Text': 'difficulty breathing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.953623354434967}]}, {'Text': 'acute respiratory distress syndrome', 'Type': 'PROBLEM', 'BeginOffset': 517, 'EndOffset': 552}, {'Id': 40, 'BeginOffset': 554, 'EndOffset': 558, 'Score': 0.615556001663208, 'Text': 'ards', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'ACUITY', 'Score': 0.968615710735321, 'RelationshipScore': 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'3. how to use pelmeg', 'Section_Content': 'pelmeg is for use in adults aged 18 and over. always use pelmeg exactly as your doctor has told you. you should check with your doctor or pharmacist if you are unsure. the usual dose is one 6 mg subcutaneous injection (injection under your skin) using a pre-filled syringe and it should be given at least 24 hours after your last dose of chemotherapy at the end of each chemotherapy cycle. do not shake pelmeg vigorously as this may affect its activity. injecting pelmeg yourself your doctor may decide that it would be more convenient for you to inject pelmeg yourself. your doctor or nurse will show you how to inject yourself. do not try to inject yourself if you have not been trained. for further instructions on how to inject yourself with pelmeg, please read the section at the end of this leaflet. if you use more pelmeg than you should if you use more pelmeg than you should contact your doctor, pharmacist or nurse. if you forget to inject pelmeg if you have forgotten a dose of pelmeg, you should contact your doctor to discuss when you should inject the next dose. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.', 'Entity_Recognition': None}"},"Section_4":{"kind":"string","value":"{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. please tell your doctor immediately if you have any of the following or combination of the following side effects: swelling or puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal swelling and feeling of fullness, and a general feeling of tiredness. these symptoms generally develop in a rapid fashion. these could be symptoms of an uncommon (may affect up to 1 in 100 people) condition called \"capillary leak syndrome\" which causes blood to leak from the small blood vessels into your body and needs urgent medical attention. very common side effects (may affect more than 1 in 10 people): bone pain. your doctor will tell you what you can take to ease the bone pain. nausea and headaches. common side effects (may affect up to 1 in 10 people): pain at the site of injection. general aches and pains in the joints and muscles. some changes may occur in your blood, but these will be detected by routine blood tests. your white blood cell count may become high for a short period of time. your platelet count may become low which might result in bruising. uncommon side effects (may affect up to 1 in 100 people): allergic-type reactions, including redness and flushing, skin rash, and raised areas of the skin that itch. serious allergic reactions, including anaphylaxis (weakness, drop in blood pressure, difficulty breathing, swelling of the face). increased spleen size. spleen rupture. some cases of splenic rupture were fatal. it is important that you contact your doctor immediately if you experience pain in the upper left side of the abdomen or left shoulder pain since this may relate to a problem with your spleen. breathing problems. if you have a cough, fever and difficulty breathing please tell your doctor. sweet\\'s syndrome (plum-coloured, raised, painful lesions on the limbs and sometimes the face and neck with fever) has occurred but other factors may play a role. cutaneous vasculitis (inflammation of the blood vessels in the skin). damage to the tiny filters inside your kidneys (glomerulonephritis). redness at the site of injection. coughing up blood (haemoptysis). rare side effects (may affect up to 1 in 1,000 people) inflammation of the aorta (the large blood vessel which transports blood from the heart to the body), see section 2. bleeding from the lung (pulmonary haemorrhage). stevens-johnson syndrome, which can appear as reddish target-like or circular patches often with central blisters on the trunk, skin peeling, ulcers of mouth, throat, nose, genitals and eyes and can be preceded by fever and flu-like symptoms. stop using pelmeg if you develop these symptoms and contact your doctor or seek medical attention immediately. see also section 2. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'pelmeg', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 20, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9616335034370422, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 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NAME OF THE MEDICINAL PRODUCT \n \nIDflu 15 microgram/strain suspension for injection \nInfluenza vaccine (split virion, inactivated) \n \n \n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \nInfluenza virus (inactivated, split) of the following strains*: \n \nA/California/7/2009 (H1N1)pdm09 - like strain (A/California/7/2009, NYMC X-179A)\n .............................................................................................................................. 15 micrograms HA** \n \nA/Hong Kong/4801/2014 (H3N2) - like strain (A/Hong Kong/4801/2014, NYMC X-263B)\n .............................................................................................................................. 15 micrograms HA** \n \nB/Brisbane/60/2008 - like strain (B/Brisbane/60/2008, wild type) ..................... 15 micrograms HA** \n \nPer 0.1 ml dose \n \n* propagated in fertilised hens’ eggs from healthy chicken flocks \n** haemagglutinin \n \nThis vaccine complies with the WHO recommendations (Northern Hemisphere) and EU decision for \nthe 2016/2017 season. \n \nFor the full list of excipients, see section 6.1. \n \nIDflu may contain residues of eggs such as ovalbumin and residues of neomycin, formaldehyde and \noctoxinol 9, which are used during the manufacturing process (see section 4.3). \n \n \n3. PHARMACEUTICAL FORM \n \nSuspension for injection. \nColourless and opalescent suspension. \n \n \n4. CLINICAL PARTICULARS \n \n4.1 Therapeutic indications \n \nProphylaxis of influenza in individuals 60 years of age and over, especially in those who run an \nincreased risk of associated complications. \n \nThe use of IDflu should be based on official recommendations. \n \n4.2 Posology and method of administration \n \nPosology \nIndividuals 60 years of age and over: 0.1 ml. \n \nPaediatric population \nIDflu is not recommended for use in children and adolescents below 18 years due to insufficient data \non safety and efficacy. \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n3 \n\nMethod of administration \nImmunisation should be carried out by intradermal route. \nThe recommended site of administration is the region of the deltoid. \n \nPrecautions to be taken before handling or administering the medicinal product \nFor instructions on preparation of the medicinal product before administration, see section 6.6. \n \n4.3 Contraindications \n \nHypersensitivity to the active substances, to any of the excipients listed in section 6.1, or to any \nresidues such as eggs (ovalbumin, chicken proteins), neomycin, formaldehyde and octoxinol 9. \n \nImmunisation shall be postponed in subjects with febrile illness or acute infection. \n \n4.4 Special warnings and precautions for use \n \nAs with all injectable vaccines, appropriate medical treatment and supervision should always be \nreadily available in case of an anaphylactic event following the administration of the vaccine (see \nsection 4.8). \n \nIDflu should under no circumstances be administered intravascularly. \n \nAntibody response in patients with endogenous or iatrogenic immunosuppression may be insufficient. \n \nVery limited data in immunocompromised patients are available for IDflu. \n \nIn case of presence of liquid at the injection site after vaccine administration, re-vaccination is not \nrequired. \n \nInterference with serological testing: See section 4.5. \n \n4.5 Interaction with other medicinal products and other forms of interaction \n \nIDflu may be given at the same time as other vaccines. Immunisation should be carried out on \nseparate limbs. It should be noted that the adverse reactions may be intensified. \n \nThe immunological response may be diminished if the patient is undergoing immunosuppressant \ntreatment. \n \nFollowing influenza vaccination, false positive results in serology tests using the ELISA method to \ndetect antibodies against HIV1, Hepatitis C and especially HTLV1 have been observed. The Western \nBlot technique disproves the false-positive ELISA test results. The transient false positive reactions \ncould be due to the IgM response by the vaccine. \n \n4.6 Fertility, pregnancy and lactation \n \nThis vaccine is intended for individuals 60 years of age and over. Therefore, this information is not \napplicable. \n \n4.7 Effects on ability to drive and use machines \n \nIDflu has no or negligible influence on the ability to drive and use machines. \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n4 \n\n4.8 Undesirable effects \n \na. Summary of the safety profile \n \nThe safety of IDflu has been assessed in 3 open-label randomised clinical trials, 3,372 vaccinees \nreceived an injection of IDflu. \n \nSafety evaluation was performed for all subjects during the first 3 weeks following vaccination and \nserious adverse reactions were collected during six months of follow-up for 2,974 subjects \n(population of two out of the three clinical trials). \n \nThe most common reactions occurring after vaccine administration were local reactions at injection \nsite. \nApparent local reactions after intradermal administration were more frequent than after intramuscular \nadministration of an adjuvanted or non-adjuvanted comparator vaccine. \nMost reactions resolved spontaneously within 1 to 3 days after onset. \n \nSystemic safety profile of IDflu is similar to the comparator vaccine, adjuvanted or non-adjuvanted, \nadministered intramuscularly. \n \nAfter repetitive yearly injections the safety profile of IDflu is similar to the previous injections. \n \nb. Tabulated summary of adverse reactions \n \nThe data below summarizes the frequencies of the adverse reactions that were recorded following \nvaccination during clinical trials and worldwide post-marketing experience, using the following \nconvention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare \n(≥1/10,000 to <1/1000); very rare (<1/10,000), not known (cannot be estimated from available data). \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n5 \n\nOrgan class Very \ncommon \n\nCommon Uncommon Rare Very \nrare \n\nNot known \n\nImmune system \ndisorders \n \n\n Allergic \nreactions \nincluding \ngeneralized \nskin reactions \nsuch as \nurticaria, \nanaphylactic \nreactions, \nangioedema, \nshock \n\nNervous system \ndisorders \n\nHeadache Paresthesia, \nneuritis \n \n\n \n\nSkin and \nsubcutaneous \ntissue disorders \n\n Sweating Pruritus, \nrash \n\n \n\nMusculoskeletal \nand connective \ntissue disorders \n\nMyalgia Arthralgia \n\nGeneral \ndisorders and \nadministration \nsite conditions \n\nLocal \nreactions: \nredness*, \ninduration \nswelling, \npruritus, pain \n\nMalaise, \nshivering, \nfever, \n \nLocal \nreactions: \necchymosis \n\nFatigue \n\n* In some cases, local redness lasted up to 7 days. \n \nc. Potential adverse events \n \nBased on the experience with trivalent inactivated influenza vaccines administered by intramuscular \nor deep subcutaneous injection, the following events may be reported: \n \nBlood and lymphatic system disorders \nTransient thrombocytopenia, transient lymphadenopathy \n \nNervous system disorders \nNeuralgia, febrile convulsions, neurological disorders, such as encephalomyelitis and Guillain-Barré \nsyndrome \n \nVascular disorders \nVasculitis associated in very rare cases with transient renal involvement \n \nReporting of suspected adverse reactions \nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V. \n \n4.9 Overdose \n \nOverdose is unlikely to have any untoward effect. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n6 \n\n \n \n5. PHARMACOLOGICAL PROPERTIES \n \n5.1 Pharmacodynamic properties \n \nPharmacotherapeutic group: Influenza vaccines, ATC code: J07BB02 \n \nImmunogenicity \nSeroprotection is generally obtained within 2 to 3 weeks. The duration of postvaccinal immunity to \nhomologous strains or to strains closely related to the vaccine strains varies but is usually \n6-12 months. \n \nIn a pivotal randomised comparative phase III trial, 2,606 subjects over 60 years of age received \n0.1 ml of IDflu by intradermal route and 1,089 subjects over 60 years of age received 0.5 ml of a \ntrivalent inactivated influenza vaccine administered by intramuscular route. \n \nIn this comparative trial the geometric mean titres (GMTs), seroprotection rate*, seroconversion or \nsignificant increase rate** and the geometric mean titre ratio (GMTR) for anti-HA antibody \n(measured by HI) were assessed according to predefined criteria. \n \nData were as follows (values in brackets show the 95% confidence intervals): \n \n\n Intradermal 15µg \n\n A/H1N1 A/H3N2 B \n\n A/New Caledonia/ 20/99 A/Wisconsin/ 67/2005 B/Malaysia/ 2506/2004 \n N = 2,585 N = 2,586 N = 2,582 \n\nGeometric mean of titre (1/dil) 81.7 \n(78.0 ; 85.6) \n\n298.0 \n(282 ; 315) \n\n39.9 \n(38.3 ; 41.6) \n\nSeroprotection rate (%) * 77.0 \n(75.3 ; 78.6) \n\n93.3 \n(92.3 ; 94.3) \n\n55.7 \n(53.8 ; 57.6) \n\nSeroconversion or significant \nincrease rate (%) ** \n\n38.7 \n(36.8 ; 40.6) \n\n61.3 \n(59.3 ; 63.1) \n\n36.4 \n(34.5 ; 38.3) \n\nGeometric mean of titre ratio \n(GMTR) \n\n3.97 \n(3.77 ; 4.18) \n\n8.19 \n(7.68 ; 8.74) \n\n3.61 \n(3.47 ; 3.76) \n\n* Seroprotection = HI titre ≥ 40 \n** Seroconversion = negative pre-vaccination HI titre and post vaccination HI titre ≥ 40, Significant \nincrease = positive pre-vaccination HI titre and at least a 4-fold increase in post-vaccination HI titre \nGMTR: Geometric mean titre ratio of individual (post-/pre-vaccination titre). \n \nIDflu is at least as immunogenic as the comparator trivalent inactivated influenza vaccine \nadministered by intramuscular route for each of the 3 influenza strains in subjects from 60 years of \nage and over. \n \nAcross all three influenza strains, for the comparator intramuscular vaccine GMTs ranged between \n34.8 (1/dil) and 181.0 (1/dil), seroprotection rates ranged between 48.9% and 87.9%, seroconversion \nor significant increase rates ranged between 30.0% and 46.9% and GMTRs ranged between 3.04 and \n5.35-fold over baseline HI titres. \n \nIn a randomised comparative phase III trial, 398 subjects over 65 years of age received 0.1 ml of IDflu \nby intradermal route and 397 subjects over 65 years of age received 0.5 ml of a trivalent inactivated \nadjuvanted (MF-59 containing) influenza vaccine at the same dosage administered by intramuscular \nroute. \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n7 \n\nIDflu is as immunogenic as the comparator trivalent adjuvanted (MF-59 containing) vaccine in terms \nof GMT for each of the 3 influenza strains with the SRH method and for 2 strains with the HI method. \n \n5.2 Pharmacokinetic properties \n \nNot applicable \n \n5.3 Preclinical safety data \n \nNon-clinical data revealed no special hazard for humans based on animal studies. The vaccine was \nimmunogenic in mice and rabbits. In repeated-dose toxicity studies in rabbits there was no significant \nevidence of systemic toxicity. Nevertheless, single and repeated administrations led to transient local \nerythema and oedema. Genotoxicity and carcinogenic potential were not assessed because these \nstudies are not appropriate for a vaccine. Fertility and toxicity studies to reproduction in females have \nnot identified any specific potential hazard for humans. \n \n \n6. PHARMACEUTICAL PARTICULARS \n \n6.1 List of excipients \n \nSodium chloride \nPotassium chloride \nDisodium phosphate dihydrate \nPotassium dihydrogen phosphate \nWater for injections \n \n6.2 Incompatibilities \n \nIn the absence of compatibility studies, this medicinal product must not be mixed with other \nmedicinal products. \n \n6.3 Shelf-life \n \n1 year \n \n6.4 Special precautions for storage \n \nStore in a refrigerator (2°C-8°C). Do not freeze. \nKeep the syringe in the outer carton in order to protect from light. \n \n6.5 Nature and contents of container \n \n0.1 ml of suspension in a pre-filled syringe (glass) with a Micro-Injection System, with attached \nmicro-needle, equipped with an elastomer plunger stopper (chlorobutyl), a tip cap (thermoplastic \nelastomer and polypropylene) and a needle shielding system. Pack size of 1 or 10 or 20. \n \nNot all pack sizes may be marketed. \n \n6.6 Special precautions for disposal and other handling \n \nAny unused medicinal product or waste material should be disposed of in accordance with local \nrequirements. \n \nThe vaccine should be allowed to reach room temperature before use. \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n8 \n\nMicro-needle \n\nWindow \n\nFinger pads \n\nVaccine \n\n Needle shield \n\nNeedle cap Flange \n\nPlunger \n\nThe vaccine should not be used if foreign particles are present in the suspension. \n \nIt is not necessary to shake the vaccine before use. \n \nThe Micro-Injection System for intradermal injection consists of a pre-filled syringe with a \nmicro-needle (1.5 mm) and a needle shielding system. \nThe needle shielding system is designed to cover the micro-needle after use. \n \n \n\nMicro-Injection System \n \n \n\n \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n9 \n\nINSTRUCTION FOR USE \n\n \n\nPlease read the instructions before use \n\n \n1/ REMOVE NEEDLE CAP \n\n \n\n2/ HOLD MICRO-INJECTION SYSTEM \nBETWEEN THUMB & MIDDLE FINGER \n\n \n\nRemove the needle cap \nfrom the \nMicro-Injection System. \n\n \n\nDo not purge air \nthrough the needle. \n\n \n \n\nHold the system by \nplacing the thumb and \nmiddle finger only on the \nfinger pads; the index \nfinger remains free. \n\nDo not place fingers on \nthe windows. \n\n \n\n3/ INSERT NEEDLE RAPIDLY \nPERPENDICULAR TO THE SKIN \n\n4/ INJECT USING THE INDEX FINGER \n\n \n\nInsert the needle \nperpendicular to the skin, \nin the region of the \ndeltoid, in a short, quick \nmovement. \n\n \n\n \n\nOnce the micro-needle \nhas been inserted, \nmaintain a light pressure \non the surface of the skin \nand inject using the index \nfinger to push on the \nplunger. \n\nThe vein test is \nunnecessary. \n\n \n5/ ACTIVATE NEEDLE SHIELD BY PUSHING FIRMLY ON PLUNGER \n\n \n \n\nRemove the needle from the skin. \n\nOrient the needle away from you and others. \n\nWith the same hand, push very firmly with the thumb on the plunger to activate the \nneedle shield. \n\nYou hear a click and a shield comes out to cover the needle. \n\nImmediately dispose of the system in the nearest sharps collector. \n\nInjection is considered successful whether or not the presence of a wheal is \nobserved. \n\nIn case of presence of liquid at the injection site after vaccine administration, re-\nvaccination is not required. \n\nActivated needle shield \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n10 \n\n7. MARKETING AUTHORISATION HOLDER \n \nSanofi Pasteur SA, 2, avenue Pont Pasteur, F-69007 Lyon, France. \n \n \n8. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/08/507/004 \nEU/1/08/507/005 \nEU/1/08/507/006 \n \n \n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n \nDate of first authorisation: 24 February 2009 \nDate of latest renewal: 24 February 2014 \n \n \n10. DATE OF REVISION OF THE TEXT \n \n \n \nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency http://www.ema.europa.eu. \n \n \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n11 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX II \n \n\nA. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE \nSUBSTANCE(S) AND MANUFACTURER(S) \nRESPONSIBLE FOR BATCH RELEASE \n\n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY \n\nAND USE \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE \n\nMARKETING AUTHORISATION \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO \n\nTHE SAFE AND EFFECTIVE USE OF THE MEDICINAL \nPRODUCT \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n12 \n\nA. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND \nMANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE \n\n \nName and address of the manufacturer(s) of the biological active substance(s) \n \nSanofi Pasteur \nParc Industriel d’Incarville \n27100 Val-de-Reuil \nFrance \n \nName and address of the manufacturer(s) responsible for batch release \n \nSanofi Pasteur \nParc Industriel d’Incarville \n27100 Val-de-Reuil \nFrance \n \nSanofi Pasteur \nCampus Mérieux \n1541, avenue Marcel Mérieux \n69280 Marcy l’Etoile \nFrance \n \nThe printed package leaflet of the medicinal product must state the name and address of the \nmanufacturer responsible for the release of the concerned batch. \n \n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n \nMedicinal product subject to medical prescription. \n \n• Official batch release \n \nIn accordance with Article 114 of Directive 2001/83/EC, the official batch release will be \nundertaken by a state laboratory or a laboratory designated for that purpose. \n \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n \n• Periodic Safety Update Reports \n \nThe requirements for submission of periodic safety update reports for this medicinal product are set \nout in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive \n2001/83/EC and any subsequent updates published on the European medicines web-portal. \n \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n \n• Risk Management Plan (RMP) \n \nThe MAH shall perform the required pharmacovigilance activities and interventions detailed in the \nagreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent \nupdates of the RMP. \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n13 \n\nAn updated RMP should be submitted: \n• At the request of the European Medicines Agency; \n• Whenever the risk management system is modified, especially as the result of new \n\ninformation is received that may lead to a significant change to benefit/risk profile or as \nthe result of an important (pharmacovigilance or risk minimisation) milestone being \nreached. \n\n \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n14 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX III \n \n\nLABELLING AND PACKAGE LEAFLET \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n15 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nA. LABELLING \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n16 \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nPack of 1 or 10 or 20 pre-filled syringe(s) with a Micro-Injection System \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nIDflu 15 microgram/strain, suspension for injection \nInfluenza vaccine (split virion, inactivated) \nStrains 2016/2017 \n \n \n2. STATEMENT OF ACTIVE SUBSTANCES \n \nInfluenza virus (inactivated, split) of the following strains: \n \nA/California/7/2009 (H1N1)pdm09 - like strain \n \nA/Hong Kong/4801/2014 (H3N2) - like strain \n \nB/Brisbane/60/2008 - like strain \n \n15 µg haemagglutinin per strain per 0.1 ml dose \n \n \n3. LIST OF EXCIPIENTS \n \nSodium chloride, potassium chloride, disodium phosphate dihydrate, potassium dihydrogen \nphosphate, water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nSuspension for injection \n1 pre-filled syringe (0.1 ml) with a Micro-Injection System \n10 pre-filled syringes (0.1 ml) with a Micro-Injection System \n20 pre-filled syringes (0.1 ml) with a Micro-Injection System \n \n \n5. METHOD AND ROUTE OF ADMINISTRATION \n \nIntradermal use \nRead the package leaflet before use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n17 \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in refrigerator. Do not freeze. \nKeep the syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nSanofi Pasteur SA, \n2, avenue Pont Pasteur \nF-69007 Lyon \nFrance \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/08/507/004 - pack of 1 pre-filled syringe with a Micro-Injection System \nEU/1/08/507/005 - pack of 10 pre-filled syringes with a Micro-Injection System \nEU/1/08/507/006 - pack of 20 pre-filled syringes with a Micro-Injection System \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nJustification for not including Braille is accepted. \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n18 \n\n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC: \nSN: \nNN: \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n19 \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nPre-filled syringe label text \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n \nIDflu 15 µg/strain 2016/2017 \nInfluenza vaccine \nIntradermal use \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n0.1 ml \n \n \n6. OTHER \n \nSanofi Pasteur SA \n \n \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n20 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nB. PACKAGE LEAFLET \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n21 \n\n \nPackage leaflet: Information for the user \n\n \nIDflu 15 microgram/strain suspension for injection \n\nInfluenza vaccine (split virion, inactivated) \n \n\nRead all of this leaflet carefully before you receive this vaccine because it contains important \ninformation for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor, pharmacist or nurse. \n- This vaccine has been prescribed for you only. Do not pass it on to others. \n- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible \n\nside effects not listed in this leaflet. See section 4. \n \nWhat is in this leaflet: \n \n1. What IDflu is and what it is used for \n2. What you need to know before you use IDflu \n3. How to use IDflu \n4. Possible side effects \n5. How to store IDflu \n6. Contents of the pack and other information \n \n \n1. What IDflu is and what it is used for \n \nIDflu is a vaccine.This vaccine is recommended to help to protect you against flu. \nThe vaccine may be administered to individuals of 60 years of age and over, especially in those who \nrun an increased risk of associated complications. \n \nWhen an injection of IDflu is given, the immune system (body's natural defences) will develop \nprotection against flu infection. \nIDflu will help to protect you against the three strains of virus contained in the vaccine, or other \nstrains closely related to them. Full effect of the vaccine is generally achieved 2-3 weeks after the \nvaccination. \n \n \n2. What you need to know before you use IDflu \n \nDo not use IDflu: \n- If you are allergic to: \n\n• The active substances, \n• Any of the other ingredients of this vaccine (listed in section 6), \n• Any component that may be present in very small amounts such as eggs (ovalbumin, \n\nchicken proteins), neomycin, formaldehyde and octoxinol 9. \n- If you have an illness with fever or acute infection, the vaccination shall be postponed until \n\nafter you have recovered. \n \nWarnings and precautions \nTalk to your doctor, pharmacist or nurse before using IDflu. \n \n- You should tell your doctor before vaccination if you have a poor immune response \n\n(immunosuppression) due to disease or medicines, because the vaccine may not work very well \nin this case. \n\n \n- This vaccine should under no circumstances be administered into a vein (intravascularly). \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n22 \n\n \n- If, for any reason, you have a blood test within a few days following an influenza vaccination, \n\nplease tell your doctor. Tests for HIV-1, hepatitis C virus and HTLV-1 may be affected. \n \nChildren and adolescents \nIDflu is not recommended for use in children and adolescents below 18 years. \n \nOther vaccines or medicines and IDflu \nTell your doctor or pharmacist if you are using, have recently used or might use any other medicines. \n \n- Other vaccines: IDflu can be given at the same time as other vaccines by using separate limbs. \n\nIt should be noted that the side effects may be intensified. \n- Tell your doctor if you have been treated with medicines that may reduce your immune \n\nresponse such as corticosteroids (for example cortisone), medicines against cancer \n(chemotherapy), radiotherapy or other medicines affecting the immune system. In this case, the \nvaccine may not work very well. \n\n \nPregnancy, breast-feeding and fertility \nThis vaccine is intended for individuals 60 years of age and over. Therefore, this information is not \napplicable. \n \nDriving and using machines \nThis vaccine has no or negligible influence on the ability to drive and use machines. \n \n \n3. How to use IDflu \n \nAlways use this vaccine exactly as your doctor or pharmacist has told you. Check with your doctor or \npharmacist if you are not sure. \n \nThe recommended dose is 0.1 ml for individuals 60 years of age and over. \n \nIDflu is administered to you by your doctor or nurse. \n \nIDflu is given as an injection into the upper layer of the skin (preferably the muscle of the upper arm). \n \nIf you have any further questions on the use of this vaccine, ask your doctor, pharmacist or nurse. \n \n \n4. Possible side effects \n \nLike all medicines, this vaccine can cause side effects, although not everybody gets them. \n \nYou should see your doctor immediately if you experience symptoms of angioedema, such as: \n\n• Swollen face, tongue or pharynx \n• Difficulty to swallow \n• Hives and difficulties to breathe. \n\n \nDuring clinical trials and after the vaccine came on the market, the following side effects were \nreported with the use of IDflu. \n \nVery common reactions (may affect more than 1 in 10 people) \n- At the injection site: redness, hardness, swelling, itching and pain. \n- Headache and muscular pain. \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n23 \n\nCommon reactions (may affect up to 1 in 10 people) \n- Bruising at the injection site. \n- Feeling generally unwell, fever (38.0°C or higher) and shivering. \n \nUncommon reactions (may affect up to 1 in 100 people) \n- Tiredness, joint pain and increased sweating. \n \nRare reactions (may affect up to 1 in 1000 people) \n- Tingling or numbness, inflammation of nerves, itching and rash. \n \nReactions of not known frequency (frequency cannot be estimated from the available data) \n- Allergic reactions including skin reactions that may spread throughout the body such as hives, \n\nsevere allergic reactions (anaphylactic reactions), swollen face, tongue or pharynx, difficulty to \nswallow, hives and difficulties to breathe (angioedema), failure of the circulatory system \n(shock) leading to medical emergency. \n\n \nMost of side effects listed above disappeared without treatment within 1 to 3 days after onset. In some \ncases, redness at the injection site lasted up to 7 days. \n \nThe following side effects have been reported with other vaccines given to prevent flu. These side \neffects may occur with IDflu. \n• Temporary reduction in the number of blood particles called platelets which can result in \n\nbruising or bleeding, temporary swelling of the glands in the neck, armpit or groin. \n• Pain located on the nerve route, convulsions associated with fever, nervous system disorders \n\nincluding inflammation of the brain or spinal cord or Guillain-Barré syndrome which causes \nextreme weakness and paralysis. \n\n• Vessel inflammation which may result in very rare cases in temporary kidney problems. \n \nReporting of side effects \nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \neffects not listed in this leaflet. You can also report side effects directly via the national reporting \nsystem listed in Appendix V. By reporting side effects you can help provide more information on the \nsafety of this medicine. \n \n \n5. How to store IDflu \n \nKeep this vaccine out of the sight and reach of children. \n \nDo not use this vaccine after the expiry date which is stated on the carton after EXP. The expiry date \nrefers to the last day of that month. \n \nStore in a refrigerator (2°C - 8°C). Do not freeze. Keep the syringe in the outer carton in order to \nprotect from light. \n \nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \nthrow away medicines you no longer use. These measures will help to protect the environment. \n \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n24 \n\n6. Contents of the pack and other information \n \nWhat IDflu contains \n \nThe active substances are Influenza virus (inactivated split) of the following strains*: \n \nA/California/7/2009 (H1N1)pdm09 - like strain (A/California/7/2009, NYMC X-179A)\n .............................................................................................................................. 15 micrograms HA** \n \nA/Hong Kong/4801/2014 (H3N2) - like strain (A/Hong Kong/4801/2014, NYMC X-263B)\n .............................................................................................................................. 15 micrograms HA** \n \nB/Brisbane/60/2008 - like strain (B/Brisbane/60/2008, wild type) ..................... 15 micrograms HA** \n \nPer 0.1 ml dose \n \n* propagated in fertilised hens’ eggs from healthy chicken flocks \n** haemagglutinin \n \nThis vaccine complies with the WHO recommendations (Northern Hemisphere) and EU decision for \nthe 2016/2017 season. \n \nThe other ingredients are: sodium chloride, potassium chloride, disodium phosphate dihydrate, \npotassium dihydrogen phosphate and water for injections. \n \nWhat IDflu looks like and contents of the pack \n \nThe vaccine is a colourless and opalescent suspension. \n \nIDflu is a suspension for injection in a pre-filled syringe of 0.1 ml with a Micro-Injection System in \npacks of 1, 10 or 20. \n \nNot all pack sizes may be marketed. \n \nMarketing Authorisation Holder and Manufacturer \n \nMarketing Authorisation Holder: Sanofi Pasteur SA, 2, avenue Pont Pasteur, F-69007 Lyon, France. \n \nManufacturer: \nSanofi Pasteur - Parc Industriel d’Incarville - 27100 Val-de-Reuil - France \nSanofi Pasteur, Campus Mérieux – 1541, avenue Marcel Mérieux – 69280 Marcy l’Etoile - France \n \nFor any information about this medicine, please contact the local representative of the Marketing \nAuthorisation Holder: \n \nBelgië/Belgique/Belgien \nSanofi Belgium \ntel.: +32 2 710.54.00 \n \n\nLietuva \nSanofi – Aventis Lietuva, UAB \nTel.: +370 5 2730967 \n \n\nБългария \nSanofi Bulgaria EOOD \nTeл.: +359 2 970 53 00 \n \n\nLuxembourg/Luxemburg \nSanofi Belgium \ntel.: +32 2 710.54.00 \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n25 \n\nČeská republika \nSanofi Pasteur \ndivize vakcín sanofi-aventis, s.r.o. \nTel: +420 233 086 111 \n \n\nMagyarország \nsanofi-aventis zrt \nTel.: +36 1 505 0055 \n \n\nDanmark \nsanofi-aventis Denmark A/S \nTel: +45 4516 7000 \n \n\nMalta \nCherubino Ltd \nTel.: +356 21 343270 \n \n\nDeutschland \nSanofi-Aventis Deutschland GmbH \nTel.: 0800 54 54 010 \nTel. aus dem Ausland: +49 69 305 21 130 \n \n\nNederland \nsanofi-aventis Netherlands B.V. \nTel: +31 182 557 755 \n \n\nEesti \nSanofi-Aventis Estonia OÜ \nTel.: +372 627 3488 \n \n\nNorge \nSanofi-aventis Norge AS \nTel: + 47 67 10 71 00 \n \n\nΕλλάδα \nΒΙΑΝΕΞ Α.Ε. \nΤηλ: +30.210.8009111 \n \n\nÖsterreich \nSanofi-Aventis GmbH \nTel: +43 (1) 80185-0. \n \n\nEspaña \nsanofi-aventis, S.A. \nTel: +34 93 485 94 00 \n \n\nPolska \nSanofi Pasteur Sp. z o.o. \nTel.: +48 22 280 05 00 \n \n\nFrance \n Sanofi Pasteur Europe \nTél: 0800 42 43 46 \nAppel depuis l’étranger : +33 1 57 63 23 23 \n \n\nPortugal \nSanofi – Produtos Farmacêuticos, Lda. \nTel: + 351 21 35 89 400 \n \n\nHrvatska \nsanofi-aventis Croatia d.o.o \nTel: + 385 1 6003 400 \n\nRomânia \nsanofi - aventis Romania SRL \nTel.: +40(21) 317 31 36 \n \n\nIreland \nsanofi-aventis Ireland T/A SANOFI \nTel: + 353 (0) 1 4035 600 \n \n\nSlovenija \nALPE s.p. \nTel.: +386 (0)1 432 62 38 \n \n\nÍsland \nVistor \nTel : +354 535 7000 \n \n\nSlovenská republika \nsanofi-aventis Pharma Slovakia s.r.o. \ndivízia vakcín Sanofi Pasteur \nTel.: +421 2 33 100 100 \n \n\nItalia \nSanofi S.p.A. \nTel: 800536389 \nTel dall'estero: +39 02 39394983 \n \n\nSuomi/Finland \nSanofi Oy \nTel: +358 (0) 201 200 300 \n \n\nΚύπρος \nΓ. Α. Σταμάτης & Σια Λτδ. \nΤηλ.: +357 - 22 76 62 76 \n \n\nSverige \nSanofi AB \nTel: +46 8-634 50 00 \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n26 \n\nLatvija \nSanofi Aventis Latvia SIA Vakcīnu nodaļa \nTel.: +371 67114978 \n \n\nUnited Kingdom \nSanofi \nTel: +44 845 372 7101 \n \n\n \nThis leaflet was last revised in {MM/YYYY}. \n \nOther sources of information \n \nDetailed information on this vaccine is available on the European Medicines Agency web site: \nhttp://www.ema.europa.eu. \n--------------------------------------------------------------------------------------------------------------------------- \nThe following information is intended for healthcare professionals only: \n \n• As with all injectable vaccines, appropriate medical treatment and supervision should always be \n\nreadily available in case of anaphylactic event following the administration of the vaccine. \n• The vaccine should be allowed to reach room temperature before use. \n• The vaccine should not be used if foreign particles are present in the suspension. \n• It is not necessary to shake the vaccine before use. \n• The Micro-Injection System for intradermal injection consists of a pre-filled syringe with a \n\nmicro-needle (1.5 mm) and a needle shielding system. \nThe needle shielding system is designed to cover the micro-needle after use. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\nhttp://www.ema.europa.eu/\n\n\n27 \n\nMicro-needle \n\nWindow \n\nFinger pads \n\nVaccine \n\n Needle shield \n\nNeedle cap Flange \n\nPlunger \n\n \n \n \n\nMicro-Injection System \n \n \n \n \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n28 \n\nINSTRUCTION FOR USE \n\n \n\nPlease read the instructions before use \n\n \n1/ REMOVE NEEDLE CAP \n\n \n\n2/ HOLD MICRO-INJECTION SYSTEM \nBETWEEN THUMB & MIDDLE FINGER \n\n \n\nRemove the needle cap \nfrom the \nMicro-Injection System. \n\n \n\nDo not purge air \nthrough the needle. \n\n \n \n\nHold the system by \nplacing the thumb and \nmiddle finger only on the \nfinger pads; the index \nfinger remains free. \n\nDo not place fingers on \nthe windows. \n\n \n\n3/ INSERT NEEDLE RAPIDLY \nPERPENDICULAR TO THE SKIN \n\n4/ INJECT USING THE INDEX FINGER \n\n \n\nInsert the needle \nperpendicular to the skin, \nin the region of the \ndeltoid, in a short, quick \nmovement. \n\n \n\n \n\nOnce the micro-needle \nhas been inserted, \nmaintain a light pressure \non the surface of the skin \nand inject using the index \nfinger to push on the \nplunger. \n\nThe vein test is \nunnecessary. \n\n \n5/ ACTIVATE NEEDLE SHIELD BY PUSHING FIRMLY ON PLUNGER \n\n \n \n\nRemove the needle from the skin. \n\nOrient the needle away from you and others. \n\nWith the same hand, push very firmly with the thumb on the plunger to activate the \nneedle shield. \n\nYou hear a click and a shield comes out to cover the needle. \n\nImmediately dispose of the system in the nearest sharps collector. \n\nInjection is considered successful whether or not the presence of a wheal is \nobserved. \n\nIn case of presence of liquid at the injection site after vaccine administration, re-\nvaccination is not required. \n\n \n \nSee also section 3. HOW TO USE IDflu \n \n \n\nActivated needle shield \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. PACKAGE LEAFLET"},"Section_1":{"kind":"string","value":"{'Title': '1. what idflu is and what it is used for', 'Section_Content': \"idflu is a vaccine.this vaccine is recommended to help to protect you against flu. the vaccine may be administered to individuals of 60 years of age and over, especially in those who run an increased risk of associated complications. when an injection of idflu is given, the immune system (body's natural defences) will develop protection against flu infection. idflu will help to protect you against the three strains of virus contained in the vaccine, or other strains closely related to them. full effect of the vaccine is generally achieved 2-3 weeks after the vaccination.\", 'Entity_Recognition': [{'Text': 'idflu', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'a vaccine', 'Type': 'TREATMENT', 'BeginOffset': 9, 'EndOffset': 18}, {'Text': 'this vaccine', 'Type': 'TREATMENT', 'BeginOffset': 19, 'EndOffset': 31}, {'Id': 2, 'BeginOffset': 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'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8989234566688538}]}, {'Text': 'virus', 'Type': 'PROBLEM', 'BeginOffset': 422, 'EndOffset': 427}, {'Text': 'the vaccine', 'Type': 'TREATMENT', 'BeginOffset': 441, 'EndOffset': 452}, {'Text': 'other strains', 'Type': 'PROBLEM', 'BeginOffset': 457, 'EndOffset': 470}, {'Text': 'the vaccine', 'Type': 'TREATMENT', 'BeginOffset': 511, 'EndOffset': 522}, {'Id': 12, 'BeginOffset': 545, 'EndOffset': 554, 'Score': 0.9545033574104309, 'Text': '2-3 weeks', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_TREATMENT_NAME', 'Traits': [], 'Attributes': [{'Type': 'TREATMENT_NAME', 'Score': 0.645965039730072, 'RelationshipScore': 0.6450042724609375, 'RelationshipType': 'OVERLAP', 'Id': 10, 'BeginOffset': 515, 'EndOffset': 522, 'Text': 'vaccine', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': 'the vaccination', 'Type': 'TREATMENT', 'BeginOffset': 561, 'EndOffset': 576}]}"},"Section_2":{"kind":"string","value":"{'Title': '2. what you need to know before you use idflu', 'Section_Content': 'do not use idflu: - if you are allergic to: the active substances, any of the other ingredients of this vaccine (listed in section 6), any component that may be present in very small amounts such as eggs (ovalbumin, chicken proteins), neomycin, formaldehyde and octoxinol 9. - if you have an illness with fever or acute infection, the vaccination shall be postponed until after you have recovered. warnings and precautions talk to your doctor, pharmacist or nurse before using idflu. - you should tell your doctor before vaccination if you have a poor immune response (immunosuppression) due to disease or medicines, because the vaccine may not work very well in this case. - this vaccine should under no circumstances be administered into a vein (intravascularly). - if, for any reason, you have a blood test within a few days following an influenza vaccination, please tell your doctor. tests for hiv-1, hepatitis c virus and htlv-1 may be affected. children and adolescents idflu is not recommended for use in children and adolescents below 18 years. other vaccines or medicines and idflu tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. - other vaccines: idflu can be given at the same time as other vaccines by using separate limbs. it should be noted that the side effects may be intensified. - tell your doctor if you have been treated with medicines that may reduce your immune response such as corticosteroids (for example cortisone), medicines against cancer (chemotherapy), radiotherapy or other medicines affecting the immune system. in this case, the vaccine may not work very well. pregnancy, breast-feeding and fertility this vaccine is intended for individuals 60 years of age and over. therefore, this information is not applicable. driving and using machines this vaccine has no or negligible 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426}]}"},"Section_4":{"kind":"string","value":"{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this vaccine can cause side effects, although not everybody gets them. you should see your doctor immediately if you experience symptoms of angioedema, such as: swollen face, tongue or pharynx difficulty to swallow hives and difficulties to breathe. during clinical trials and after the vaccine came on the market, the following side effects were reported with the use of idflu. very common reactions (may affect more than 1 in 10 people) - at the injection site: redness, hardness, swelling, itching and pain. - headache and muscular pain. common reactions (may affect up to 1 in 10 people) - bruising at the injection site. - feeling generally unwell, fever (38.0 or higher) and shivering. uncommon reactions (may affect up to 1 in 100 people) - tiredness, joint pain and increased sweating. rare reactions (may affect up to 1 in 1000 people) - tingling or numbness, inflammation of nerves, itching and rash. reactions of not known frequency (frequency cannot be estimated from the available data) - allergic reactions including skin reactions that may spread throughout the body such as hives, severe allergic reactions (anaphylactic reactions), swollen face, tongue or pharynx, difficulty to swallow, hives and difficulties to breathe (angioedema), failure of the circulatory system (shock) leading to medical emergency. most of side effects listed above disappeared without treatment within 1 to 3 days after onset. in some cases, redness at the injection site lasted up to 7 days. the following side effects have been reported with other vaccines given to prevent flu. these side effects may occur with idflu. temporary reduction in the number of blood particles called platelets which can result in bruising or bleeding, temporary swelling of the glands in the neck, armpit or groin. pain located on the nerve route, convulsions associated with fever, nervous system disorders including inflammation of the brain or spinal cord or guillain-barré syndrome which causes extreme weakness and paralysis. vessel inflammation which may result in very rare cases in temporary kidney problems. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'idflu', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this vaccine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 32}, {'Id': 25, 'BeginOffset': 43, 'EndOffset': 55, 'Score': 0.9653733372688293, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 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0.996637225151062, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8898354768753052}]}, {'Text': 'temporary swelling of the glands in the neck, armpit or groin', 'Type': 'PROBLEM', 'BeginOffset': 1748, 'EndOffset': 1809}, {'Id': 77, 'BeginOffset': 1811, 'EndOffset': 1815, 'Score': 0.969804584980011, 'Text': 'pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7674415111541748}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.6986154317855835, 'RelationshipScore': 0.9992524981498718, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 18, 'BeginOffset': 1831, 'EndOffset': 1836, 'Text': 'nerve', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 18, 'BeginOffset': 1831, 'EndOffset': 1836, 'Score': 0.6986154317855835, 'Text': 'nerve', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'convulsions', 'Type': 'PROBLEM', 'BeginOffset': 1844, 'EndOffset': 1855}, {'Id': 78, 'BeginOffset': 1872, 'EndOffset': 1877, 'Score': 0.9780714511871338, 'Text': 'fever', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7160308361053467}]}, {'Id': 79, 'BeginOffset': 1879, 'EndOffset': 1903, 'Score': 0.9304865598678589, 'Text': 'nervous system disorders', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7693601250648499}]}, {'Text': 'inflammation of the brain', 'Type': 'PROBLEM', 'BeginOffset': 1914, 'EndOffset': 1939}, {'Id': 81, 'BeginOffset': 1943, 'EndOffset': 1981, 'Score': 0.7629947066307068, 'Text': 'spinal cord or guillain-barré syndrome', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9592407941818237}]}, {'Text': 'extreme weakness', 'Type': 'PROBLEM', 'BeginOffset': 1995, 'EndOffset': 2011}, {'Id': 83, 'BeginOffset': 2016, 'EndOffset': 2025, 'Score': 0.9925092458724976, 'Text': 'paralysis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5597049593925476}]}, {'Text': 'vessel inflammation', 'Type': 'PROBLEM', 'BeginOffset': 2027, 'EndOffset': 2046}, {'Text': 'temporary kidney problems', 'Type': 'PROBLEM', 'BeginOffset': 2086, 'EndOffset': 2111}, {'Id': 95, 'BeginOffset': 2126, 'EndOffset': 2138, 'Score': 0.9447035789489746, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.701688826084137}]}, {'Id': 96, 'BeginOffset': 2154, 'EndOffset': 2166, 'Score': 0.9064189195632935, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7201143503189087}]}, {'Id': 97, 'BeginOffset': 2237, 'EndOffset': 2249, 'Score': 0.9506289958953857, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6105943918228149}]}, {'Id': 98, 'BeginOffset': 2298, 'EndOffset': 2310, 'Score': 0.854573130607605, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6849924325942993}]}, {'Id': 99, 'BeginOffset': 2364, 'EndOffset': 2375, 'Score': 0.37086233496665955, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5928104519844055}]}, {'Id': 100, 'BeginOffset': 2389, 'EndOffset': 2401, 'Score': 0.8563477396965027, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7272924184799194}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2457, 'EndOffset': 2470}]}"},"Section_5":{"kind":"string","value":"{'Title': '5. how to store idflu', 'Section_Content': None, 'Entity_Recognition': None}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': \"what idflu contains the active substances are influenza virus (inactivated split) of the following strains*: a/california/7/2009 (h1n1)pdm09 - like strain (a/california/7/2009, nymc x-179a) .............................................................................................................................. micrograms ha** a/hong kong/4801/2014 (h3n2) - like strain (a/hong kong/4801/2014, nymc x-263b) .............................................................................................................................. micrograms ha** b/brisbane/60/2008 - like strain (b/brisbane/60/2008, wild type) ..................... micrograms ha** per 0.1 ml dose * propagated in fertilised hens' eggs from healthy chicken flocks ** haemagglutinin this vaccine complies with the who recommendations (northern hemisphere) and eu decision for the 2016/2017 season. the other ingredients are: sodium chloride, potassium chloride, disodium phosphate dihydrate, potassium dihydrogen phosphate and water for injections. what idflu looks like and contents of the pack the vaccine is a colourless and opalescent suspension. idflu is a suspension for injection in a pre-filled syringe of 0.1 ml with a micro-injection system in packs of 1, 10 or 20. not all pack sizes may be marketed.\", 'Entity_Recognition': [{'Text': 'idflu', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 6, 'BeginOffset': 46, 'EndOffset': 61, 'Score': 0.43353623151779175, 'Text': 'influenza virus', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8514743447303772}]}, {'Id': 8, 'BeginOffset': 111, 'EndOffset': 121, 'Score': 0.38800621032714844, 'Text': 'california', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'ADDRESS', 'Traits': []}, {'Id': 9, 'BeginOffset': 122, 'EndOffset': 128, 'Score': 0.9996139407157898, 'Text': '7/2009', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Text': 'pdm09', 'Type': 'PROBLEM', 'BeginOffset': 135, 'EndOffset': 140}, {'Id': 10, 'BeginOffset': 158, 'EndOffset': 168, 'Score': 0.8499430418014526, 'Text': 'california', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'ADDRESS', 'Traits': []}, {'Id': 11, 'BeginOffset': 169, 'EndOffset': 175, 'Score': 0.9991645812988281, 'Text': '7/2009', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Id': 12, 'BeginOffset': 340, 'EndOffset': 354, 'Score': 0.2635149657726288, 'Text': 'kong/4801/2014', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Id': 7, 'BeginOffset': 369, 'EndOffset': 375, 'Score': 0.3758178949356079, 'Text': 'strain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 384, 'EndOffset': 398, 'Score': 0.3565746545791626, 'Text': 'kong/4801/2014', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Text': 'nymc', 'Type': 'TEST', 'BeginOffset': 400, 'EndOffset': 404}, {'Text': 'micrograms ha', 'Type': 'TEST', 'BeginOffset': 540, 'EndOffset': 553}, {'Id': 14, 'BeginOffset': 567, 'EndOffset': 574, 'Score': 0.9968035221099854, 'Text': '60/2008', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Id': 15, 'BeginOffset': 601, 'EndOffset': 608, 'Score': 0.9925596714019775, 'Text': '60/2008', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Text': '0.1', 'Type': 'NUMBER', 'BeginOffset': 663, 'EndOffset': 666}, {'Text': 'haemagglutinin this vaccine', 'Type': 'TREATMENT', 'BeginOffset': 744, 'EndOffset': 771}, {'Id': 16, 'BeginOffset': 856, 'EndOffset': 860, 'Score': 0.643774151802063, 'Text': '2016', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Id': 17, 'BeginOffset': 861, 'EndOffset': 865, 'Score': 0.4123981297016144, 'Text': '2017', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'DATE', 'Traits': []}, {'Id': 0, 'BeginOffset': 901, 'EndOffset': 916, 'Score': 0.9909080266952515, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 918, 'EndOffset': 936, 'Score': 0.9980193376541138, 'Text': 'potassium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 2, 'BeginOffset': 938, 'EndOffset': 966, 'Score': 0.9843010306358337, 'Text': 'disodium phosphate dihydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.34031933546066284, 'RelationshipScore': 0.9608170390129089, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 4, 'BeginOffset': 1013, 'EndOffset': 1023, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 3, 'BeginOffset': 968, 'EndOffset': 998, 'Score': 0.9898550510406494, 'Text': 'potassium dihydrogen phosphate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.34031933546066284, 'RelationshipScore': 0.9999654293060303, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 4, 'BeginOffset': 1013, 'EndOffset': 1023, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 1013, 'EndOffset': 1023}, {'Text': 'the pack the vaccine', 'Type': 'TREATMENT', 'BeginOffset': 1063, 'EndOffset': 1083}, {'Text': 'opalescent suspension', 'Type': 'TREATMENT', 'BeginOffset': 1104, 'EndOffset': 1125}, {'Text': 'a pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 1166, 'EndOffset': 1186}, {'Text': '0.1', 'Type': 'NUMBER', 'BeginOffset': 1190, 'EndOffset': 1193}, {'Text': 'a micro-injection system', 'Type': 'TREATMENT', 'BeginOffset': 1202, 'EndOffset': 1226}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 1239, 'EndOffset': 1240}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 1242, 'EndOffset': 1244}, {'Text': '20.', 'Type': 'NUMBER', 'BeginOffset': 1248, 'EndOffset': 1251}]}"}}},{"rowIdx":1058,"cells":{"ID":{"kind":"string","value":"E6A99A8422B8B26B49739D643ED1FAA0"},"URL":{"kind":"string","value":"https://www.ema.europa.eu/documents/product-information/revolade-epar-product-information_en.pdf"},"Product_Name":{"kind":"string","value":"Revolade"},"Full_Content":{"kind":"string","value":"1 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX I \n \n\nSUMMARY OF PRODUCT CHARACTERISTICS \n\n \n\n\n\n2 \n\n1. NAME OF THE MEDICINAL PRODUCT \n \n\nRevolade 12.5 mg film-coated tablets \n\nRevolade 25 mg film-coated tablets \n\nRevolade 50 mg film-coated tablets \n\nRevolade 75 mg film-coated tablets \n\n \n\n \n\n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \n\nRevolade 12.5 mg film-coated tablets \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 12.5 mg eltrombopag. \n\n \n\nRevolade 25 mg film-coated tablets \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 25 mg eltrombopag. \n\n \n\nRevolade 50 mg film-coated tablets \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 50 mg eltrombopag. \n\n \n\nRevolade 75 mg film-coated tablets \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 75 mg eltrombopag. \n\n \n\nFor the full list of excipients, see section 6.1. \n\n \n\n \n\n3. PHARMACEUTICAL FORM \n\n \n\nFilm-coated tablet. \n\n \n\nRevolade 12.5 mg film-coated tablets \n\nWhite, round, biconvex film-coated tablet (approximately 7.9 mm in diameter) debossed with ‘GS \n\nMZ1’ and ‘12.5’ on one side. \n\n \n\nRevolade 25 mg film-coated tablets \n\nWhite, round, biconvex film-coated tablet (approximately 10.3 mm in diameter) debossed with ‘GS \n\nNX3’ and ‘25’ on one side. \n\n \n\nRevolade 50 mg film-coated tablets \n\nBrown, round, biconvex film-coated tablet (approximately 10.3 mm in diameter) debossed with ‘GS \n\nUFU’ and ‘50’ on one side. \n\n \n\nRevolade 75 mg film-coated tablets \n\nPink, round, biconvex film-coated tablet (approximately 10.3 mm in diameter) debossed with ‘GS \n\nFFS’ and ‘75’ on one side. \n\n \n\n \n\n \n\n\n\n3 \n\n4. CLINICAL PARTICULARS \n \n\n4.1 Therapeutic indications \n \n\nRevolade is indicated for the treatment of patients aged 1 year and above with primary immune \n\nthrombocytopenia (ITP) lasting 6 months or longer from diagnosis and who are refractory to other \n\ntreatments (e.g. corticosteroids, immunoglobulins) (see sections 4.2 and 5.1). \n\n \n\nRevolade is indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment \n\nof thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the \n\ninitiation or limiting the ability to maintain optimal interferon-based therapy (see sections 4.4 and 5.1). \n\n \n\nRevolade is indicated in adult patients with acquired severe aplastic anaemia (SAA) who were either \n\nrefractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for \n\nhaematopoietic stem cell transplantation (see section 5.1). \n\n \n\n4.2 Posology and method of administration \n\n \n\nEltrombopag treatment should be initiated by and remain under the supervision of a physician who is \n\nexperienced in the treatment of haematological diseases or the management of chronic hepatitis C and \n\nits complications. \n\n \n\nPosology \n\n \n\nEltrombopag dosing requirements must be individualised based on the patient’s platelet counts. The \n\nobjective of treatment with eltrombopag should not be to normalise platelet counts. \n\n \n\nThe powder for oral suspension may lead to higher eltrombopag exposure than the tablet formulation \n\n(see section 5.2). When switching between the tablet and powder for oral suspension formulations, \n\nplatelet counts should be monitored weekly for 2 weeks. \n\n \n\nImmune (primary) thrombocytopenia \n\n \n\nThe lowest dose of eltrombopag to achieve and maintain a platelet count ≥50,000/µl should be used. \n\nDose adjustments are based upon the platelet count response. Eltrombopag must not be used to \n\nnormalise platelet counts. In clinical studies, platelet counts generally increased within 1 to 2 weeks \n\nafter starting eltrombopag and decreased within 1 to 2 weeks after discontinuation. \n\n \n\nAdults and paediatric population aged 6 to 17 years \n\nThe recommended starting dose of eltrombopag is 50 mg once daily. For patients of Asian ancestry \n\n(such as Chinese, Japanese, Taiwanese, Korean or Thai), eltrombopag should be initiated at a reduced \n\ndose of 25 mg once daily (see section 5.2). \n\n \n\nPaediatric population aged 1 to 5 years \n\nThe recommended starting dose of eltrombopag is 25 mg once daily. \n\n \n\n \n\n\n\n4 \n\nMonitoring and dose adjustment \n\nAfter initiating eltrombopag, the dose must be adjusted to achieve and maintain a platelet count \n\n≥50,000/µl as necessary to reduce the risk for bleeding. A daily dose of 75 mg must not be exceeded. \n\n \n\nClinical haematology and liver tests should be monitored regularly throughout therapy with \n\neltrombopag and the dose regimen of eltrombopag modified based on platelet counts as outlined in \n\nTable 1. During therapy with eltrombopag full blood counts (FBCs), including platelet count and \n\nperipheral blood smears, should be assessed weekly until a stable platelet count (≥50,000/µl for at \n\nleast 4 weeks) has been achieved. FBCs including platelet counts and peripheral blood smears should \n\nbe obtained monthly thereafter. \n\n \n\nTable 1 Dose adjustments of eltrombopag in ITP patients \n\n \n\nPlatelet count Dose adjustment or response \n\n<50,000/µl following at least \n\n2 weeks of therapy \n\nIncrease daily dose by 25 mg to a maximum of 75 mg/day*. \n\n50,000/µl to 150,000/µl Use lowest dose of eltrombopag and/or concomitant ITP \n\ntreatment to maintain platelet counts that avoid or reduce \n\nbleeding. \n\n>150,000/µl to 250,000/µl Decrease the daily dose by 25 mg. Wait 2 weeks to assess the \n\neffects of this and any subsequent dose adjustments♦. \n\n>250,000/µl Stop eltrombopag; increase the frequency of platelet monitoring \n\nto twice weekly. \n\n \n\nOnce the platelet count is ≤ 100,000/µl, reinitiate therapy at a \n\ndaily dose reduced by 25 mg. \n\n* For patients taking 25 mg eltrombopag once every other day, increase dose to 25 mg once daily. \n\n♦ For patients taking 25 mg eltrombopag once daily, consideration should be given to dosing at \n\n12.5 mg once daily or alternatively a dose of 25 mg once every other day. \n\n \n\nEltrombopag can be administered in addition to other ITP medicinal products. The dose regimen of \n\nconcomitant ITP medicinal products should be modified, as medically appropriate, to avoid excessive \n\nincreases in platelet counts during therapy with eltrombopag. \n\n \n\nIt is necessary to wait for at least 2 weeks to see the effect of any dose adjustment on the patient’s \n\nplatelet response prior to considering another dose adjustment. \n\n \n\nThe standard eltrombopag dose adjustment, either decrease or increase, would be 25 mg once daily. \n\n \n\nDiscontinuation \n\nTreatment with eltrombopag should be discontinued if the platelet count does not increase to a level \n\nsufficient to avoid clinically important bleeding after 4 weeks of eltrombopag therapy at 75 mg once \n\ndaily. \n\n \n\nPatients should be clinically evaluated periodically and continuation of treatment should be decided on \n\nan individual basis by the treating physician. In non-splenectomised patients this should include \n\nevaluation relative to splenectomy. The reoccurrence of thrombocytopenia is possible upon \n\ndiscontinuation of treatment (see section 4.4). \n\n \n\nChronic hepatitis C (HCV) associated thrombocytopenia \n\n \n\nWhen eltrombopag is given in combination with antivirals reference should be made to the full \n\nsummary of product characteristics of the respective coadministered medicinal products for \n\ncomprehensive details of relevant safety information or contraindications. \n\n \n\nIn clinical studies, platelet counts generally began to increase within 1 week of starting eltrombopag. \n\nThe aim of treatment with eltrombopag should be to achieve the minimum level of platelet counts \n\n\n\n5 \n\nneeded to initiate antiviral therapy, in adherence to clinical practice recommendations. During antiviral \n\ntherapy, the aim of treatment should be to keep platelet counts at a level that prevents the risk of \n\nbleeding complications, normally around 50,000-75,000/µl. Platelet counts >75,000/µl should be \n\navoided. The lowest dose of eltrombopag needed to achieve the targets should be used. Dose \n\nadjustments are based upon the platelet count response. \n\n \n\nInitial dose regimen \n\nEltrombopag should be initiated at a dose of 25 mg once daily. No dosage adjustment is necessary for \n\nHCV patients of East Asian ancestry or patients with mild hepatic impairment (see section 5.2). \n\n \n\nMonitoring and dose adjustment \n\nThe dose of eltrombopag should be adjusted in 25 mg increments every 2 weeks as necessary to \n\nachieve the target platelet count required to initiate antiviral therapy. Platelet counts should be \n\nmonitored every week prior to starting antiviral therapy. On initiation of antiviral therapy the platelet \n\ncount may fall, so immediate eltrombopag dose adjustments should be avoided (see Table 2). \n\n \n\nDuring antiviral therapy, the dose of eltrombopag should be adjusted as necessary to avoid dose \n\nreductions of peginterferon due to decreasing platelet counts that may put patients at risk of bleeding \n\n(see Table 2). Platelet counts should be monitored weekly during antiviral therapy until a stable \n\nplatelet count is achieved, normally around 50,000-75,000/µl. FBCs including platelet counts and \n\nperipheral blood smears should be obtained monthly thereafter. Dose reductions on the daily dose by \n\n25 mg should be considered if platelet counts exceed the required target. It is recommended to wait for \n\n2 weeks to assess the effects of this and any subsequent dose adjustments. \n\n \n\nA dose of 100 mg eltrombopag once daily must not be exceeded. \n\n \n\nTable 2 Dose adjustments of eltrombopag in HCV patients during antiviral therapy \n\n \n\nPlatelet count Dose adjustment or response \n\n<50,000/µl following at least \n\n2 weeks of therapy \n\nIncrease daily dose by 25 mg to a maximum of 100 mg/day. \n\n≥50,000/µl to ≤100,000/µl Use lowest dose of eltrombopag as necessary to avoid dose \n\nreductions of peginterferon. \n\n>100,000/µl to ≤150,000/µl Decrease the daily dose by 25 mg. Wait 2 weeks to assess the \n\neffects of this and any subsequent dose adjustments♦. \n\n>150,000/µl Stop eltrombopag; increase the frequency of platelet monitoring to \n\ntwice weekly. \n\n \n\nOnce the platelet count is ≤100,000/µl, reinitiate therapy at a daily \n\ndose reduced by 25 mg*. \n\n* For patients taking 25 mg eltrombopag once daily, consideration should be given to reinitiating \n\ndosing at 25 mg every other day. \n♦ On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose \n\nreductions should be avoided. \n\n \n\nDiscontinuation \n\nIf after 2 weeks of eltrombopag therapy at 100 mg the required platelet level to initiate antiviral \n\ntherapy is not achieved, eltrombopag should be discontinued. \n\n \n\nEltrombopag treatment should be terminated when antiviral therapy is discontinued unless otherwise \n\njustified. Excessive platelet count responses or important liver test abnormalities also necessitate \n\ndiscontinuation. \n\n \n\n \n\n\n\n6 \n\nSevere aplastic anaemia \n\n \n\nInitial dose regimen \n\nEltrombopag should be initiated at a dose of 50 mg once daily. For patients of Asian ancestry, \n\neltrombopag should be initiated at a reduced dose of 25 mg once daily (see section 5.2). The treatment \n\nshould not be initiated when the patients has existing cytogenetic abnormalities of chromosome 7. \n\n \n\nMonitoring and dose adjustment \n\nHaematological response requires dose titration, generally up to 150 mg, and may take up to 16 weeks \n\nafter starting eltrombopag (see section 5.1). The dose of eltrombopag should be adjusted in 50 mg \n\nincrements every 2 weeks as necessary to achieve the target platelet count ≥50,000/µl. For patients \n\ntaking 25 mg once daily, the dose should be increased to 50 mg daily before increasing the dose \n\namount by 50 mg. A dose of 150 mg daily must not be exceeded. Clinical haematology and liver tests \n\nshould be monitored regularly throughout therapy with eltrombopag and the dosage regimen of \n\neltrombopag modified based on platelet counts as outlined in Table 3. \n\n \n\nTable 3 Dose adjustments of eltrombopag in patients with severe aplastic anaemia \n\n \n\nPlatelet count Dose adjustment or response \n\n<50,000/µl following at least \n\n2 weeks of therapy \n\nIncrease daily dose by 50 mg to a maximum of 150 mg/day. \n\n \n\nFor patients taking 25 mg once daily, increase the dose to \n\n50 mg daily before increasing the dose amount by 50 mg. \n\n50,000/µl to 150,000/µl Use lowest dose of eltrombopag to maintain platelet counts. \n\n>150,000/µl to 250,000/µl Decrease the daily dose by 50 mg. Wait 2 weeks to assess the \n\neffects of this and any subsequent dose adjustments. \n\n>250,000/µl Stop eltrombopag; for at least one week. \n\n \n\nOnce the platelet count is ≤100,000/µl, reinitiate therapy at a \n\ndaily dose reduced by 50 mg. \n\n \n\nTapering for tri-lineage (white blood cells, red blood cells, and platelets) responders \n\nFor patients who achieve tri-lineage response, including transfusion independence, lasting at least \n\n8 weeks: the dose of eltrombopag may be reduced by 50%. \n\n \n\nIf counts remain stable after 8 weeks at the reduced dose, then eltrombopag must be discontinued and \n\nblood counts monitored. If platelet counts drop to <30,000/µl, haemoglobin drops to < 9 g/dl or \n\nabsolute neutrophil count (ANC) <0.5 x 109/l, eltrombopag may be reinitiated at the previous effective \n\ndose. \n\n \n\nDiscontinuation \n\nIf no haematological response has occurred after 16 weeks of therapy with eltrombopag, therapy \n\nshould be discontinued. If new cytogenetic abnormalities are detected, it must be evaluated whether \n\ncontinuation of eltrombopag is appropriate (see sections 4.4 and 4.8). Excessive platelet count \n\nresponses (as outlined in Table 3) or important liver test abnormalities also necessitate discontinuation \n\nof eltrombopag (see section 4.8). \n\n \n\nSpecial populations \n\n \n\nRenal impairment \n\nNo dose adjustment is necessary in patients with renal impairment. Patients with impaired renal \n\nfunction should use eltrombopag with caution and close monitoring, for example by testing serum \n\ncreatinine and/or performing urine analysis (see section 5.2). \n\n \n\n \n\n\n\n7 \n\nHepatic impairment \n\nEltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless \n\nthe expected benefit outweighs the identified risk of portal venous thrombosis (see section 4.4). \n\n \n\nIf the use of eltrombopag is deemed necessary for ITP patients with hepatic impairment the starting \n\ndose must be 25 mg once daily. After initiating the dose of eltrombopag in patients with hepatic \n\nimpairment an interval of 3 weeks should be observed before increasing the dose. \n\n \n\nNo dose adjustment is required for thrombocytopenic patients with chronic HCV and mild hepatic \n\nimpairment (Child-Pugh score ≤6). Chronic HCV patients and severe aplastic anaemia patients with \n\nhepatic impairment should initiate eltrombopag at a dose of 25 mg once daily (see section 5.2). After \n\ninitiating the dose of eltrombopag in patients with hepatic impairment an interval of 2 weeks should be \n\nobserved before increasing the dose. \n\n \n\nThere is an increased risk for adverse events, including hepatic decompensation and thromboembolic \n\nevents, in thrombocytopenic patients with advanced chronic liver disease treated with eltrombopag, \n\neither in preparation for invasive procedure or in HCV patients undergoing antiviral therapy (see \n\nsections 4.4 and 4.8). \n\n \n\nElderly \n\nThere are limited data on the use of eltrombopag in ITP patients aged 65 years and older and no \n\nclinical experience in ITP patients aged over 85 years. In the clinical studies of eltrombopag, overall \n\nno clinically significant differences in safety of eltrombopag were observed between patients aged at \n\nleast 65 years and younger patients. Other reported clinical experience has not identified differences in \n\nresponses between the elderly and younger patients, but greater sensitivity of some older individuals \n\ncannot be ruled out (see section 5.2). \n\n \n\nThere are limited data on the use of eltrombopag in HCV and SAA patients aged over 75 years. \n\nCaution should be exercised in these patients (see section 4.4). \n\n \n\nAsian patients \n\nFor patients of Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean or Thai), including \n\nthose with hepatic impairment, eltrombopag should be initiated at a dose of 25 mg once daily (see \n\nsection 5.2). \n\n \n\nPatient platelet count should continue to be monitored and the standard criteria for further dose \n\nmodification followed. \n\n \n\nPaediatric population \n\nRevolade is not recommended for use in children under the age of one year with ITP due to \n\ninsufficient data on safety and efficacy. The safety and efficacy of eltrombopag has not been \n\nestablished in children and adolescents (<18 years) with chronic HCV related thrombocytopenia or \n\nSAA. No data are available. \n\n \n\nMethod of administration \n\n \n\nOral use. \n\nThe tablets should be taken at least two hours before or four hours after any products such as antacids, \n\ndairy products (or other calcium containing food products), or mineral supplements containing \n\npolyvalent cations (e.g. iron, calcium, magnesium, aluminium, selenium and zinc) (see sections 4.5 \n\nand 5.2). \n\n \n\n \n\n\n\n8 \n\n4.3 Contraindications \n \n\nHypersensitivity to eltrombopag or to any of the excipients listed in section 6.1. \n\n \n\n4.4 Special warnings and precautions for use \n\n \n\nThere is an increased risk for adverse reactions, including potentially fatal hepatic decompensation and \n\nthromboembolic events, in thrombocytopenic HCV patients with advanced chronic liver disease, as \n\ndefined by low albumin levels ≤35 g/l or model for end stage liver disease (MELD) score ≥10, when \n\ntreated with eltrombopag in combination with interferon-based therapy. In addition, the benefits of \n\ntreatment in terms of the proportion achieving sustained virological response (SVR) compared with \n\nplacebo were modest in these patients (especially for those with baseline albumin ≤35g/l) compared \n\nwith the group overall. Treatment with eltrombopag in these patients should be initiated only by \n\nphysicians experienced in the management of advanced HCV, and only when the risks of \n\nthrombocytopenia or withholding antiviral therapy necessitate intervention. If treatment is considered \n\nclinically indicated, close monitoring of these patients is required. \n\n \n\nCombination with direct-acting antiviral agents \n\n \n\nSafety and efficacy have not been established in combination with direct-acting antiviral agents \n\napproved for treatment of chronic hepatitis C infection. \n\n \n\nRisk of hepatotoxicity \n\n \n\nEltrombopag administration can cause abnormal liver function and severe hepatotoxicity, which might \n\nbe life-threatening (see section 4.8). \n\n \n\nSerum alanine aminotransferase (ALT), aspartate aminotrasferase (AST) and bilirubin should be \n\nmeasured prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase and \n\nmonthly following establishment of a stable dose. Eltrombopag inhibits UGT1A1 and OATP1B1, \n\nwhich may lead to indirect hyperbilirubinaemia. If bilirubin is elevated fractionation should be \n\nperformed. Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. If \n\nthe abnormalities are confirmed, serum liver tests should be monitored until the abnormalities resolve, \n\nstabilise, or return to baseline levels. Eltrombopag should be discontinued if ALT levels increase \n\n(3 times the upper limit of normal [x ULN] in patients with normal liver function, or ≥3 x baseline or \n\n>5 x ULN, whichever is the lower, in patients with pre-treatment elevations in transaminases) and are: \n\n progressive, or \n\n persistent for ≥4 weeks, or \n\n accompanied by increased direct bilirubin, or \n\n accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. \n \n\nCaution is required when administering eltrombopag to patients with hepatic disease. In ITP and SAA \n\npatients a lower starting dose of eltrombopag should be used. Close monitoring is required when \n\nadministering to patients with hepatic impairment (see section 4.2). \n\n \n\nHepatic decompensation (use with interferon) \n\n \n\nHepatic decompensation in patients with chronic hepatitis C: Monitoring is required in patients with \n\nlow albumin levels (≤35 g/l) or with MELD score ≥10 at baseline. \n\n \n\nChronic HCV patients with cirrhosis may be at risk of hepatic decompensation when receiving alfa \n\ninterferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV, hepatic \n\ndecompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial \n\nperitonitis) occurred more frequently in the eltrombopag arm (11%) than in the placebo arm (6%). In \n\npatients with low albumin levels (≤ 35 g/l) or with a MELD score ≥10 at baseline, there was a 3-fold \n\ngreater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared to \n\nthose with less advanced liver disease. In addition, the benefits of treatment in terms of the proportion \n\n\n\n9 \n\nachieving SVR compared with placebo were modest in these patients (especially for those with \n\nbaseline albumin ≤35 g/l) compared with the group overall. Eltrombopag should only be administered \n\nto such patients after careful consideration of the expected benefits in comparison with the risks. \n\nPatients with these characteristics should be closely monitored for signs and symptoms of hepatic \n\ndecompensation. The respective interferon summary of product characteristics should be referenced \n\nfor discontinuation criteria. Eltrombopag should be terminated if antiviral therapy is discontinued for \n\nhepatic decompensation. \n\n \n\nThrombotic/thromboembolic complications \n\n \n\nIn controlled studies in thrombocytopenic patients with HCV receiving interferon-based therapy \n\n(n=1,439), 38 out of 955 patients (4%) treated with eltrombopag and 6 out of 484 patients (1%) in the \n\nplacebo group experienced thromboembolic events (TEEs). Reported thrombotic/thromboembolic \n\ncomplications included both venous and arterial events. The majority of TEEs were non-serious and \n\nresolved by the end of the study. Portal vein thrombosis was the most common TEE in both treatment \n\ngroups (2% in patients treated with eltrombopag versus <1% for placebo). No specific temporal \n\nrelationship between start of treatment and event of TEE were observed. Patients with low albumin \n\nlevels (≤35 g/l) or MELD ≥10 had a 2-fold greater risk of TEEs than those with higher albumin levels; \n\nthose aged ≥60 years had a 2-fold greater risk of TEEs compared to younger patients. Eltrombopag \n\nshould only be administered to such patients after careful consideration of the expected benefits in \n\ncomparison with the risks. Patients should be closely monitored for signs and symptoms of TEE. \n\n \n\nThe risk of TEEs has been found to be increased in patients with chronic liver disease (CLD) treated \n\nwith 75 mg eltrombopag once daily for 2 weeks in preparation for invasive procedures. Six of 143 \n\n(4%) adult patients with CLD receiving eltrombopag experienced TEEs (all of the portal venous \n\nsystem) and 2 of 145 (1%) patients in the placebo group experienced TEEs (one in the portal venous \n\nsystem and one myocardial infarction). Five of the 6 patients treated with eltrombopag experienced the \n\nthrombotic complication at a platelet count >200,000/µl and within 30 days of the last dose of \n\neltrombopag. Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with \n\nchronic liver disease in preparation for invasive procedures. \n\n \n\nIn eltrombopag clinical studies in ITP thromboembolic events were observed at low and normal \n\nplatelet counts. Caution should be used when administering eltrombopag to patients with known risk \n\nfactors for thromboembolism including but not limited to inherited (e.g. Factor V Leiden) or acquired \n\nrisk factors (e.g. ATIII deficiency, antiphospholipid syndrome), advanced age, patients with prolonged \n\nperiods of immobilisation, malignancies, contraceptives and hormone replacement therapy, \n\nsurgery/trauma, obesity and smoking. Platelet counts should be closely monitored and consideration \n\ngiven to reducing the dose or discontinuing eltrombopag treatment if the platelet count exceeds the \n\ntarget levels (see section 4.2). The risk-benefit balance should be considered in patients at risk of TEEs \n\nof any aetiology. \n\n \n\nNo case of TEE was identified from a clinical study in refractory SAA, however the risk of these \n\nevents cannot be excluded in this patient population due to the limited number of exposed patients. As \n\nthe highest authorised dose is indicated for patients with SAA (150 mg/day) and due to the nature of \n\nthe reaction, TEEs might be expected in this patient population. \n\n \n\nEltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless \n\nthe expected benefit outweighs the identified risk of portal venous thrombosis. When treatment is \n\nconsidered appropriate, caution is required when administering eltrombopag to patients with hepatic \n\nimpairment (see sections 4.2 and 4.8). \n\n \n\n \n\n\n\n10 \n\nBleeding following discontinuation of eltrombopag \n\n \n\nThrombocytopenia is likely to reoccur in ITP patients upon discontinuation of treatment with \n\neltrombopag. Following discontinuation of eltrombopag, platelet counts return to baseline levels \n\nwithin 2 weeks in the majority of patients, which increases the bleeding risk and in some cases may \n\nlead to bleeding. This risk is increased if eltrombopag treatment is discontinued in the presence of \n\nanticoagulants or anti-platelet agents. It is recommended that, if treatment with eltrombopag is \n\ndiscontinued, ITP treatment be restarted according to current treatment guidelines. Additional medical \n\nmanagement may include cessation of anticoagulant and/or anti-platelet therapy, reversal of \n\nanticoagulation, or platelet support. Platelet counts must be monitored weekly for 4 weeks following \n\ndiscontinuation of eltrombopag. \n\n \n\nIn HCV clinical studies, a higher incidence of gastrointestinal bleeding, including serious and fatal \n\ncases, was reported following discontinuation of peginterferon, ribavirin, and eltrombopag. Following \n\ndiscontinuation of therapy, patients should be monitored for any signs or symptoms of gastrointestinal \n\nbleeding. \n\n \n\nBone marrow reticulin formation and risk of bone marrow fibrosis \n\n \n\nEltrombopag may increase the risk for development or progression of reticulin fibres within the bone \n\nmarrow. The relevance of this finding, as with other thrombopoietin receptor (TPO-R) agonists, has \n\nnot been established yet. \n\n \n\nPrior to initiation of eltrombopag, the peripheral blood smear should be examined closely to establish \n\na baseline level of cellular morphologic abnormalities. Following identification of a stable dose of \n\neltrombopag, full blood count (FBC) with white blood cell count (WBC) differential should be \n\nperformed monthly. If immature or dysplastic cells are observed, peripheral blood smears should be \n\nexamined for new or worsening morphological abnormalities (e.g. teardrop and nucleated red blood \n\ncells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening \n\nmorphological abnormalities or cytopenia(s), treatment with eltrombopag should be discontinued and \n\na bone marrow biopsy considered, including staining for fibrosis. \n\n \n\nProgression of existing myelodysplastic syndrome (MDS) \n\n \n\nThere is a theoretical concern that TPO-R agonists may stimulate the progression of existing \n\nhaematological malignancies such as MDS. TPO-R agonists are growth factors that lead to \n\nthrombopoietic progenitor cell expansion, differentiation and platelet production. The TPO-R is \n\npredominantly expressed on the surface of cells of the myeloid lineage. For TPO-R agonists there is a \n\nconcern that they may stimulate the progression of existing haematopoietic malignancies such as \n\nMDS. \n\n \n\nIn clinical studies with a TPO-R agonist in patients with MDS, cases of transient increases in blast cell \n\ncounts were observed and cases of MDS disease progression to acute myeloid leukaemia (AML) were \n\nreported. \n\n \n\nThe diagnosis of ITP or SAA in adults and elderly patients should be confirmed by the exclusion of \n\nother clinical entities presenting with thrombocytopenia, in particular the diagnosis of MDS must be \n\nexcluded. Consideration should be given to performing a bone marrow aspirate and biopsy over the \n\ncourse of the disease and treatment, particularly in patients over 60 years of age, those with systemic \n\nsymptoms, or abnormal signs such as increased peripheral blast cells. \n\n \n\nThe effectiveness and safety of Revolade have not been established for the treatment of \n\nthrombocytopenia due to MDS. Revolade should not be used outside of clinical studies for the \n\ntreatment of thrombocytopenia due to MDS. \n\n \n\n\n\n11 \n\nCytogenetic abnormalities and progression to MDS/AML in patients with SAA \n\n \n\nCytogenetic abnormalities are known to occur in SAA patients. It is not known whether eltrombopag \n\nincreases the risk of cytogenetic abnormalities in patients with SAA. In the phase II refractory SAA \n\nclinical study with eltrombopag with a starting dose of 50 mg/day (escalated every 2 weeks to a \n\nmaximum of 150 mg/day) (ELT112523), the incidence of new cytogenetic abnormalities was \n\nobserved in 17.1% of adult patients [7/41 (where 4 of them had changes in chromosome 7)]. The \n\nmedian time on study to a cytogenetic abnormality was 2.9 months. \n \n\nIn the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic or \n\nage related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities \n\nwas observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All \n\n7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of \n\neltrombopag therapy and one patient had cytogenetic abnormality at Month 6. \n \n\nIn clinical studies with eltrombopag in SAA, 4% of patients (5/133) were diagnosed with MDS. The \n\nmedian time to diagnosis was 3 months from the start of eltrombopag treatment. \n\n \n\nFor SAA patients refractory to or heavily pretreated with prior immunosuppressive therapy, bone \n\nmarrow examination with aspirations for cytogenetics is recommended prior to initiation of \n\neltrombopag, at 3 months of treatment and 6 months thereafter. If new cytogenetic abnormalities are \n\ndetected, it must be evaluated whether continuation of eltrombopag is appropriate. \n\n \n\nOcular changes \n\n \n\nCataracts were observed in toxicology studies of eltrombopag in rodents (see section 5.3). In \n\ncontrolled studies in thrombocytopenic patients with HCV receiving interferon therapy (n=1,439), \n\nprogression of pre-existing baseline cataract(s) or incident cataracts was reported in 8% of the \n\neltrombopag group and 5% of the placebo group. Retinal haemorrhages, mostly Grade 1 or 2, have \n\nbeen reported in HCV patients receiving interferon, ribavirin and eltrombopag (2% of the eltrombopag \n\ngroup and 2% of the placebo group. Haemorrhages occurred on the surface of the retina (preretinal), \n\nunder the retina (subretinal), or within the retinal tissue. Routine ophthalmologic monitoring of \n\npatients is recommended. \n\n \n\nQT/QTc prolongation \n\n \n\nA QTc study in healthy volunteers dosed 150 mg eltrombopag per day did not show a clinically \n\nsignificant effect on cardiac repolarisation. QTc interval prolongation has been reported in clinical \n\nstudies of patients with ITP and thrombocytopenic patients with HCV. The clinical significance of \n\nthese QTc prolongation events is unknown. \n\n \n\nLoss of response to eltrombopag \n\n \n\nA loss of response or failure to maintain a platelet response with eltrombopag treatment within the \n\nrecommended dosing range should prompt a search for causative factors, including an increased bone \n\nmarrow reticulin. \n\n \n\nPaediatric population \n\n \n\nThe above warnings and precautions for ITP also apply to the paediatric population. \n\n \n\nInterference with laboratory tests \n\n \n\nEltrombopag is highly coloured and so has the potential to interfere with some laboratory tests. Serum \n\ndiscolouration and interference with total bilirubin and creatinine testing have been reported in \n\npatients taking Revolade. If the laboratory results and clinical observations are inconsistent, re-testing \n\nusing another method may help in determining the validity of the result. \n\n\n\n12 \n\n \n\n4.5 Interaction with other medicinal products and other forms of interaction \n \n\nEffects of eltrombopag on other medicinal products \n\n \n\nHMG CoA reductase inhibitors \n\n \n\nAdministration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1 \n\nand BCRP substrate rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin Cmax 103% \n\n(90% confidence interval [CI]: 82%, 126%) and AUC0- 55% (90% CI: 42%, 69%). Interactions are \n\nalso expected with other HMG-CoA reductase inhibitors, including atorvastatin, fluvastatin, lovastatin, \n\npravastatin and simvastatin. When co-administered with eltrombopag, a reduced dose of statins should \n\nbe considered and careful monitoring for statin adverse reactions should be undertaken (see \n\nsection 5.2). \n\n \n\nOATP1B1 and BCRP substrates \n\n \n\nConcomitant administration of eltrombopag and OATP1B1 (e.g. methotrexate) and BCRP (e.g. \n\ntopotecan and methotrexate) substrates should be undertaken with caution (see section 5.2). \n\n \n\nCytochrome P450 substrates \n\n \n\nIn studies utilising human liver microsomes, eltrombopag (up to 100 M) showed no in vitro \n\ninhibition of the CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11 and was an \n\ninhibitor of CYP2C8 and CYP2C9 as measured using paclitaxel and diclofenac as the probe \n\nsubstrates. Administration of eltrombopag 75 mg once daily for 7 days to 24 healthy male subjects did \n\nnot inhibit or induce the metabolism of probe substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 \n\n(flurbiprofen), or 3A4 (midazolam) in humans. No clinically significant interactions are expected \n\nwhen eltrombopag and CYP450 substrates are co-administered (see section 5.2). \n\n \n\nHCV protease inhibitors \n\n \n\nDose adjustment is not required when eltrombopag is co-administered with either telaprevir or \n\nboceprevir. Co-administration of a single dose of eltrombopag 200 mg with telaprevir 750 mg every \n\n8 hours did not alter plasma telaprevir exposure. \n\n \n\nCo-administration of a single dose of eltrombopag 200 mg with boceprevir 800 mg every 8 hours did \n\nnot alter plasma boceprevir AUC(0-), but increased Cmax by 20%, and decreased Cmin by 32%. The \n\nclinical relevance of the decrease in Cmin has not been established, increased clinical and laboratory \n\nmonitoring for HCV suppression is recommended. \n\n \n\nEffects of other medicinal products on eltrombopag \n\n \n\nCiclosporin \n\n \nA decrease in eltrombopag exposure was observed with co-administration of 200 mg and 600 mg \n\nciclosporin (a BCRP inhibitor). The co-administration of 200 mg ciclosporin decreased the Cmax and \n\nthe AUCinf of eltrombopag by 25% and 18%, respectively. The co-administration of 600 mg \n\nciclosporin decreased the Cmax and the AUCinf of eltrombopag by 39% and 24%, respectively. \n\nEltrombopag dose adjustment is permitted during the course of the treatment based on the patient’s \n\nplatelet count (see section 4.2). Platelet count should be monitored at least weekly for 2 to 3 weeks \n\nwhen eltrombopag is co-administered with ciclosporin. Eltrombopag dose may need to be increased \n\nbased on these platelet counts. \n\n \n\n \n\n\n\n13 \n\nPolyvalent cations (chelation) \n\n \n\nEltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium \n\nand zinc. Administration of a single dose of eltrombopag 75 mg with a polyvalent cation-containing \n\nantacid (1524 mg aluminium hydroxide and 1425 mg magnesium carbonate) decreased plasma \n\neltrombopag AUC0- by 70% (90% CI: 64%, 76%) and Cmax by 70% (90% CI: 62%, 76%). \n\nEltrombopag should be taken at least two hours before or four hours after any products such as \n\nantacids, dairy products or mineral supplements containing polyvalent cations to avoid significant \n\nreduction in eltrombopag absorption due to chelation (see sections 4.2 and 5.2). \n\n \n\nLopinavir/ritonavir \n\n \n\nCo-administration of eltrombopag with lopinavir/ritonavir may cause a decrease in the concentration \n\nof eltrombopag. A study in 40 healthy volunteers showed that the co-administration of a single 100 mg \n\ndose of eltrombopag with repeat dose lopinavir/ritonavir 400/100 mg twice daily resulted in a \n\nreduction in eltrombopag plasma AUCinf by 17% (90% CI: 6.6%, 26.6%). Therefore, caution should \n\nbe used when co-administration of eltrombopag with lopinavir/ritonavir takes place. Platelet count \n\nshould be closely monitored in order to ensure appropriate medical management of the dose of \n\neltrombopag when lopinavir/ritonavir therapy is initiated or discontinued. \n\n \n\nCYP1A2 and CYP2C8 inhibitors and inducers \n\n \n\nEltrombopag is metabolised through multiple pathways including CYP1A2, CYP2C8, UGT1A1, and \n\nUGT1A3 (see section 5.2). Medicinal products that inhibit or induce a single enzyme are unlikely to \n\nsignificantly affect plasma eltrombopag concentrations, whereas medicinal products that inhibit or \n\ninduce multiple enzymes have the potential to increase (e.g. fluvoxamine) or decrease (e.g. rifampicin) \n\neltrombopag concentrations. \n\n \n\nHCV protease inhibitors \n\n \n\nResults of a drug-drug pharmacokinetic (PK) interaction study show that co-administration of repeat \n\ndoses of boceprevir 800 mg every 8 hours or telaprevir 750 mg every 8 hours with a single dose of \n\neltrombopag 200 mg did not alter plasma eltrombopag exposure to a clinically significant extent. \n\n \n\nMedicinal products for treatment of ITP \n\n \n\nMedicinal products used in the treatment of ITP in combination with eltrombopag in clinical studies \n\nincluded corticosteroids, danazol, and/or azathioprine, intravenous immunoglobulin (IVIG), and \n\nanti-D immunoglobulin. Platelet counts should be monitored when combining eltrombopag with other \n\nmedicinal products for the treatment of ITP in order to avoid platelet counts outside of the \n\nrecommended range (see section 4.2). \n\n \n\nFood interaction \n\n \n\nThe administration of eltrombopag tablet or powder for oral suspension formulations with a high-\n\ncalcium meal (e.g. a meal that included dairy products) significantly reduced plasma eltrombopag \n\nAUC0-∞ and Cmax. In contrast, the administration of eltrombopag 2 hours before or 4 hours after a high-\n\ncalcium meal or with low-calcium food [<50 mg calcium] did not alter plasma eltrombopag exposure \n\nto a clinically significant extent (see section 4.2). \n\n \n\nAdministration of a single 50 mg dose of eltrombopag in tablet form with a standard high-calorie, \n\nhigh-fat breakfast that included dairy products reduced plasma eltrombopag mean AUC0-∞ by 59% and \n\nmean Cmax by 65%. \n\n \n\n \n\n\n\n14 \n\nAdministration of a single 25 mg dose of eltrombopag as powder for oral suspension with a high-\n\ncalcium, moderate-fat and moderate-calorie meal reduced plasma eltrombopag mean AUC0-∞ by 75% \n\nand mean Cmax by 79%. This decrease of exposure was attenuated when a single 25 mg dose of \n\neltrombopag powder for oral suspension was administered 2 hours before a high-calcium meal (mean \n\nAUC0-∞ was decreased by 20% and mean Cmax by 14%). \n\n \n\nFood low in calcium (<50 mg calcium), including fruit, lean ham, beef and unfortified (no added \n\ncalcium, magnesium or iron) fruit juice, unfortified soya milk and unfortified grain, did not \n\nsignificantly impact plasma eltrombopag exposure, regardless of calorie and fat content (see \n\nsections 4.2 and 4.5). \n\n \n\n4.6 Fertility, pregnancy and lactation \n \n\nPregnancy \n\n \n\nThere are no or limited amount of data from the use of eltrombopag in pregnant women. Studies in \n\nanimals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. \n\n \n\nRevolade is not recommended during pregnancy. \n\n \n\nWomen of childbearing potential / Contraception in males and females \n\n \n\nRevolade is not recommended in women of childbearing potential not using contraception. \n\n \n\nBreast-feeding \n\n \n\nIt is not known whether eltrombopag/metabolites are excreted in human milk. Studies in animals have \n\nshown that eltrombopag is likely secreted into milk (see section 5.3); therefore a risk to the suckling \n\nchild cannot be excluded. A decision must be made whether to discontinue breast-feeding or to \n\ncontinue/abstain from Revolade therapy, taking into account the benefit of breast-feeding for the child \n\nand the benefit of therapy for the woman. \n\n \n\nFertility \n\n \n\nFertility was not affected in male or female rats at exposures that were comparable to those in humans. \n\nHowever a risk for humans cannot be ruled out (see section 5.3). \n\n \n\n4.7 Effects on ability to drive and use machines \n \n\nEltrombopag has negligible influence on the ability to drive and use machines. The clinical status of \n\nthe patient and the adverse reaction profile of eltrombopag, including dizziness and lack of alertness, \n\nshould be borne in mind when considering the patient’s ability to perform tasks that require \n\njudgement, motor and cognitive skills. \n\n \n\n \n\n\n\n15 \n\n4.8 Undesirable effects \n\n \n\nSummary of the safety profile \n\n \n\nImmune thrombocytopenia in adult and paediatric patients \n\n \n\nThe safety of Revolade was assessed using the pooled double-blind, placebo-controlled studies \n\nTRA100773A and B, TRA102537 (RAISE) and TRA113765, in which 403 patients were exposed to \n\nRevolade and 179 to placebo, in addition to data from the completed open-label studies TRA108057, \n\nTRA105325 (EXTEND) and TRA112940. Patients received study medication for up to 8 years (in \n\nEXTEND). The most important serious adverse reactions were hepatotoxicity and \n\nthrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of \n\npatients included nausea, diarrhoea and increased alanine aminotransferase. \n\n \n\nThe safety of Revolade in paediatric patients (aged 1 to 17 years) with previously treated ITP has been \n\ndemonstrated in two studies. PETIT2 (TRA115450) was a 2-part, double-blind and open-label, \n\nrandomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=63) or \n\nplacebo (n=29) for up to 13 weeks in the randomised period of the study. PETIT (TRA108062) was a \n\n3-part, staggered-cohort, open-label and double-blind, randomised, placebo-controlled study. Patients \n\nwere randomised 2:1 and received Revolade (n=44) or placebo (n=21), for up to 7 weeks. The profile \n\nof adverse reactions was comparable to that seen in adults with some additional adverse reactions, \n\nmarked ♦ in the table below. The most common adverse reactions in paediatric ITP patients 1 year and \n\nolder (≥3% and greater than placebo) were upper respiratory tract infection, nasopharyngitis, cough, \n\npyrexia, abdominal pain, oropharyngeal pain, toothache and rhinorrhoea. \n\n \n\nThrombocytopenia with HCV infection in adult patients \n\n \n\nENABLE 1 (TPL103922 n=716) and ENABLE 2 (TPL108390 n=805) were randomised, \n\ndouble-blind, placebo-controlled, multicentre studies to assess the efficacy and safety of Revolade in \n\nthrombocytopenic patients with HCV infection who were otherwise eligible to initiate antiviral \n\ntherapy. In the HCV studies the safety population consisted of all randomised patients who received \n\ndouble-blind study medicinal product during Part 2 of ENABLE 1 (Revolade treatment n=450, \n\nplacebo treatment n=232) and ENABLE 2 (Revolade treatment n=506, placebo treatment n=253). \n\nPatients are analysed according to the treatment received (total safety double-blind population, \n\nRevolade n=955 and placebo n=484). The most important serious adverse reactions identified were \n\nhepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring \n\nin at least 10% of patients included headache, anaemia, decreased appetite, cough, nausea, diarrhoea, \n\nhyperbilirubinaemia, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-like illness, asthenia, \n\nchills and oedema. \n\n \n\nSevere aplastic anaemia in adult patients \n\n \n\nThe safety of eltrombopag in severe aplastic anaemia was assessed in a single-arm, open-label study \n\n(N=43) in which 11 patients (26%) were treated for >6 months and 7 patients (21%) were treated for \n\n>1 year. The most important serious adverse reactions were febrile neutropenia and sepsis/infection. \n\nThe most common adverse reactions occurring in at least 10% of patients included headache, \n\ndizziness, cough, oropharyngeal pain, nausea, diarrhoea, abdominal pain, transaminases increased, \n\narthralgia, pain in extremity, fatigue and pyrexia. \n\n \n\n \n\n\n\n16 \n\nList of adverse reactions \n\n \n\nThe adverse reactions in the adult ITP studies (N=763), paediatric ITP studies (N=171), the HCV \n\nstudies (N=1,520), the SAA studies (N=43) and post-marketing reports are listed below by MedDRA \n\nsystem organ class and by frequency. Within each system organ class, the adverse drug reactions are \n\nranked by frequency, with the most frequent reactions first. The corresponding frequency category for \n\neach adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); \n\ncommon (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known \n\n(cannot be estimated from the available data). \n\n \n\nITP study population \n\n \n\nSystem organ class Frequency Adverse reaction \n\nInfections and infestations Very \n\ncommon \n\nNasopharyngitis♦, upper respiratory tract infection♦ \n\nCommon Pharyngitis, influenza, oral herpes, pneumonia, sinusitis, tonsillitis, \n\nrespiratory tract infection, gingivitis \n\nUncommon Skin infection \n\nNeoplasms benign, \n\nmalignant and unspecified \n\n(incl cysts and polyps) \n\nUncommon Rectosigmoid cancer \n\nBlood and lymphatic system \n\ndisorders \n\nCommon Anaemia, eosinophilia, leukocytosis, thrombocytopenia, \n\nhaemoglobin decreased, white blood cell count decreased \n\nUncommon Anisocytosis, haemolytic anaemia, myelocytosis, band neutrophil \n\ncount increased, myelocyte present, platelet count increased, \n\nhaemoglobin increased \n\nImmune system disorders Uncommon Hypersensitivity \n\nMetabolism and nutrition \n\ndisorders \n\nCommon Hypokalaemia, decreased appetite, blood uric acid increased \n\nUncommon Anorexia, gout, hypocalcaemia \n\nPsychiatric disorders Common Sleep disorder, depression \n\nUncommon Apathy, mood altered, tearfulness \n\nNervous system disorders Common Paraesthesia, hypoaesthesia, somnolence, migraine \n\nUncommon Tremor, balance disorder, dysaesthesia, hemiparesis, migraine with \n\naura, neuropathy peripheral, peripheral sensory neuropathy, speech \n\ndisorder, toxic neuropathy, vascular headache \n\nEye disorders Common Dry eye, vision blurred, eye pain, visual acuity reduced \n\nUncommon Lenticular opacities, astigmatism, cataract cortical, lacrimation \n\nincreased, retinal haemorrhage, retinal pigment epitheliopathy, \n\nvisual impairment, visual acuity tests abnormal, blepharitis, \n\nkeratoconjunctivitis sicca \n\nEar and labyrinth disorders Common Ear pain, vertigo \n\nCardiac disorders Uncommon Tachycardia, acute myocardial infarction, cardiovascular disorder, \n\ncyanosis, sinus tachycardia, electrocardiogram QT prolonged \n\n\n\n17 \n\nVascular disorders Common Deep vein thrombosis, haematoma, hot flush \n\nUncommon Embolism, thrombophlebitis superficial, flushing \n\nRespiratory, thoracic and \n\nmediastinal disorders \n\nVery \n\ncommon \n\nCough♦ \n\nCommon Oropharyngeal pain, rhinorrhoea♦ \n\nUncommon Pulmonary embolism, pulmonary infarction, nasal discomfort, \n\noropharyngeal blistering, sinus disorder, sleep apnoea syndrome \n\nGastrointestinal disorders Very \n\ncommon \n\nNausea, diarrhoea♦ \n\nCommon Mouth ulceration, toothache♦, vomiting, abdominal pain*, mouth \n\nhaemorrhage, flatulence \n\n* Very common in paediatric ITP \n\nUncommon Dry mouth, glossodynia, abdominal tenderness, faeces discoloured, \n\nfood poisoning, frequent bowel movements, haematemesis, oral \n\ndiscomfort \n\nHepatobiliary disorders Very \n\ncommon \n\nAlanine aminotransferase increased† \n\nCommon Aspartate aminotransferase increased†, hyperbilirubinaemia, hepatic \n\nfunction abnormal \n\nUncommon Cholestasis, hepatic lesion, hepatitis, drug-induced liver injury \n\nSkin and subcutaneous tissue \n\ndisorders \n\nCommon Rash, alopecia, hyperhidrosis, pruritus generalised, petechiae \n\nUncommon Urticaria, dermatosis, cold sweat, erythema, melanosis, \n\npigmentation disorder, skin discolouration, skin exfoliation \n\nMusculoskeletal and \n\nconnective tissue disorders \n\nCommon Myalgia, muscle spasm, musculoskeletal pain, bone pain, back pain \n\nUncommon Muscular weakness \n\nRenal and urinary disorders Common Proteinuria, blood creatinine increased, thrombotic microangiopathy \n\nwith renal failure‡ \n\nUncommon Renal failure, leukocyturia, lupus nephritis, nocturia, blood urea \n\nincreased, urine protein/creatinine ratio increased \n\nReproductive system and \n\nbreast disorders \n\nCommon Menorrhagia \n\nGeneral disorders and \n\nadministration site \n\nconditions \n\nCommon Pyrexia*, chest pain, asthenia \n\n*Very common in paediatric ITP \n\nUncommon Feeling hot, vessel puncture site haemorrhage, feeling jittery, \n\ninflammation of wound, malaise, sensation of foreign body \n\nInvestigations Common Blood alkaline phosphatase increased \n\nUncommon Blood albumin increased, protein total increased, blood albumin \n\ndecreased, pH urine increased \n\nInjury, poisoning and \n\nprocedural complications \n\nUncommon Sunburn \n\n♦ Additional adverse reactions observed in paediatric studies (aged 1to 17 years). \n† Increase of alanine aminotransferase and aspartate aminotransferase may occur simultaneously, \n\nalthough at a lower frequency. \n‡ Grouped term with preferred terms acute kidney injury and renal failure \n\n \n\nHCV study population (in combination with anti-viral interferon and ribavirin therapy) \n\n \n\nSystem organ class Frequency Adverse reaction \n\nInfections and infestations Common Urinary tract infection, upper respiratory tract infection, \n\nbronchitis, nasopharyngitis, influenza, oral herpes \n\nUncommon Gastroenteritis, pharyngitis \n\nNeoplasms benign, malignant \n\nand unspecified (incl cysts and \n\npolyps) \n\nCommon Hepatic neoplasm malignant \n\n\n\n18 \n\nBlood and lymphatic system \n\ndisorders \n\nVery \n\ncommon \n\nAnaemia \n\nCommon Lymphopenia \n\nUncommon Haemolytic anaemia \n\nMetabolism and nutrition \n\ndisorders \n\nVery \n\ncommon \n\nDecreased appetite \n\nCommon Hyperglycaemia, abnormal loss of weight \n\nPsychiatric disorders Common Depression, anxiety, sleep disorder \n\nUncommon Confusional state, agitation \n\nNervous system disorders Very \n\ncommon \n\nHeadache \n\nCommon Dizziness, disturbance in attention, dysgeusia, hepatic \n\nencephalopathy, lethargy, memory impairment, paraesthesia \n\nEye disorders Common Cataract, retinal exudates, dry eye, ocular icterus, retinal \n\nhaemorrhage \n\nEar and labyrinth disorders Common Vertigo \n\nCardiac disorders Common Palpitations \n\nRespiratory, thoracic and \n\nmediastinal disorders \n\nVery \n\ncommon \n\nCough \n\nCommon Dyspnoea, oropharyngeal pain, dyspnoea exertional, productive \n\ncough \n\nGastrointestinal disorders Very \n\ncommon \n\nNausea, diarrhoea \n\nCommon Vomiting, ascites, abdominal pain, abdominal pain upper, \n\ndyspepsia, dry mouth, constipation, abdominal distension, \n\ntoothache, stomatitis, gastrooesophagal reflux disease, \n\nhaemorrhoids, abdominal discomfort, varices oesophageal \n\nUncomon Oesophageal varices haemorrhage, gastritis, aphthous stomatitis \n\nHepatobiliary disorders Common Hyperbilirubinaemia, jaundice, drug-induced liver injury \n\nUncommon Portal vein thrombosis, hepatic failure \n\nSkin and subcutaneous tissue \n\ndisorders \n\nVery \n\ncommon \n\nPruritus \n\nCommon Rash, dry skin, eczema, rash pruritic, erythema, hyperhidrosis, \n\npruritus generalised, alopecia \n\nUncommon Skin lesion, skin discolouration, skin hyperpigmentation, night \n\nsweats \n\nMusculoskeletal and \n\nconnective tissue disorder \n\nVery \n\ncommon \n\nMyalgia \n\nCommon Arthralgia, muscle spasms, back pain, pain in extremity, \n\nmusculoskeletal pain, bone pain \n\nRenal and urinary disorders Uncommon Thrombotic microangiopathy with acute renal failure†, dysuria \n\nGeneral disorders and \n\nadministration site conditions \n\nVery \n\ncommon \n\nPyrexia, fatigue, influenza-like illness, asthenia, chills \n\nCommon Irritability, pain, malaise, injection site reaction, non-cardiac chest \n\npain, oedema, oedema peripheral \n\nUncommon Injection site pruritus, injection site rash, chest discomfort \n\nInvestigations Common Blood bilirubin increased, weight decreased, white blood cell \n\ncount decreased, haemoglobin decreased, neutrophil count \n\ndecreased, international normalised ratio increased, activated \n\npartial thromboplastin time prolonged, blood glucose increased, \n\nblood albumin decreased \n\nUncommon Electrocardiogram QT prolonged \n† Grouped term with preferred terms oliguria, renal failure and renal impairment \n\n \n\n\n\n19 \n\nSAA study population \n\n \n\nSystem organ class Frequency Adverse reaction \n\nBlood and lymphatic system \n\ndisorders \n\nCommon Neutropenia, splenic infarction \n\nMetabolism and nutrition \n\ndisorders \n\nCommon Iron overload, decreased appetite, hypoglycaemia, increased \n\nappetite \n\nPsychiatric disorders Common Anxiety, depression \n\nNervous system disorders Very \n\ncommon \n\nHeadache, dizziness \n\nCommon Syncope \n\nEye disorders Common Dry eye, cataract, ocular icterus, vision blurred, visual \n\nimpairment, vitreous floaters \n\nRespiratory, thoracic and \n\nmediastinal disorders \n\nVery \n\ncommon \n\nCough, oropharyngeal pain, rhinorrhoea \n\nCommon Epistaxis \n\nGastrointestinal disorders Very \n\ncommon \n\nDiarrhoea, nausea, gingival bleeding, abdominal pain \n\nCommon Oral mucosal blistering, oral pain, vomiting, abdominal \n\ndiscomfort, constipation, abdominal distension, dysphagia, faeces \n\ndiscoloured, swollen tongue, gastrointestinal motility disorder, \n\nflatulence \n\nHepatobiliary disorders Very \n\ncommon \n\nTransaminases increased \n\nCommon Blood bilirubin increased (hyperbilirubinemia), jaundice \n\nNot known Drug-induced liver injury* \n\n* Cases of drug-induced liver injury have been reported in \n\npatients with ITP and HCV \n\nSkin and subcutaneous tissue \n\ndisorders \n\nCommon Petechiae, rash, pruritus, urticaria, skin lesion, rash macular \n\nNot known Skin discolouration, skin hyperpigmentation \n\nMusculosketal and connective \n\ntissue disorders \n\nVery \n\ncommon \n\nArthralgia, pain in extremity, muscle spasms \n\nCommon Back pain, myalgia, bone pain \n\nRenal and urinary disorders Common Chromaturia \n\nGeneral disorders and \n\nadministration site conditions \n\nVery \n\ncommon \n\nFatigue, pyrexia, chills \n\nCommon Asthenia, oedema peripheral, malaise \n\nInvestigations Common Blood creatine phosphokinase increased \n\n \n\nDescription of selected adverse reactions \n\n \n\nThrombotic/thromboembolic events (TEEs) \n\n \n\nIn 3 controlled and 2 uncontrolled clinical studies among adult ITP patients receiving eltrombopag \n\n(n=446), 17 patients experienced a total of 19 TEEs, which included (in descending order of \n\noccurrence) deep vein thrombosis (n=6), pulmonary embolism (n=6), acute myocardial infarction \n\n(n=2), cerebral infarction (n=2), embolism (n=1) (see section 4.4). \n\n \n\nIn a placebo-controlled study (n=288, Safety population), following 2 weeks’ treatment in preparation \n\nfor invasive procedures, 6 of 143 (4%) adult patients with chronic liver disease receiving eltrombopag \n\nexperienced 7 TEEs of the portal venous system and 2 of 145 (1%) patients in the placebo group \n\nexperienced 3 TEEs. Five of the 6 patients treated with eltrombopag experienced the TEE at a platelet \n\ncount >200,000/µl \n\n \n\nNo specific risk factors were identified in those patients who experienced a TEE with the exception of \n\nplatelet counts ≥200,000/µl (see section 4.4). \n\n\n\n20 \n\n \n\nIn controlled studies in thrombocytopenic patients with HCV (n=1,439), 38 out of 955 patients (4%) \n\ntreated with eltrombopag experienced a TEE and 6 out of 484 patients (1%) in the placebo group \n\nexperienced TEEs. Portal vein thrombosis was the most common TEE in both treatment groups (2% in \n\npatients treated with eltrombopag versus < 1% for placebo) (see section 4.4). Patients with low \n\nalbumin levels (≤ 35 g/l) or MELD ≥10 had a 2-fold greater risk of TEEs than those with higher \n\nalbumin levels; those aged ≥60 years had a 2-fold greater risk of TEEs compared to younger patients. \n\n \n\nHepatic decompensation (use with interferon) \n\n \n\nChronic HCV patients with cirrhosis may be at risk of hepatic decompensation when receiving alfa \n\ninterferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV, hepatic \n\ndecompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial \n\nperitonitis) was reported more frequently in the eltrombopag arm (11%) than in the placebo arm (6%). \n\nIn patients with low albumin levels (≤35 g/l) or MELD score ≥10 at baseline, there was a 3-fold \n\ngreater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared to \n\nthose with less advanced liver disease. Eltrombopag should only be administered to such patients after \n\ncareful consideration of the expected benefits in comparison with the risks. Patients with these \n\ncharacteristics should be closely monitored for signs and symptoms of hepatic decompensation (see \n\nsection 4.4). \n\n \n\nHepatotoxixity \n\n \n\nIn the controlled clinical studies in chronic ITP with eltrombopag, increases in serum ALT, AST and \n\nbilirubin were observed (see section 4.4). \n\n \n\nThese findings were mostly mild (Grade 1-2), reversible and not accompanied by clinically significant \n\nsymptoms that would indicate an impaired liver function. Across the 3 placebo-controlled studies in \n\nadults with chronic ITP, 1 patient in the placebo group and 1 patient in the eltrombopag group \n\nexperienced a Grade 4 liver test abnormality. In two placebo-controlled studies in paediatric patients \n\n(aged 1 to 17 years) with chronic ITP, ALT 3 x ULN was reported in 4.7% and 0% of the \n\neltrombopag and placebo groups, respectively. \n\n \n\nIn 2 controlled clinical studies in patients with HCV, ALT or AST 3 x ULN was reported in 34% and \n\n38% of the eltrombopag and placebo groups, respectively. Most patients receiving eltrombopag in \n\ncombination with peginterferon / ribavirin therapy will experience indirect hyperbilirubinaemia. \n\nOverall, total bilirubin ≥1.5 x ULN was reported in 76% and 50% of the eltrombopag and placebo \n\ngroups, respectively. \n\n \n\nIn the single-arm phase II monotherapy refractory SAA study, concurrent ALT or AST >3 x ULN \n\nwith total (indirect) bilirubin >1.5 x ULN were reported in 5% of patients. Total bilirubin >1.5 x ULN \n\noccurred in 14% of patients. \n\n \n\nThrombocytopenia following discontinuation of treatment \n\n \n\nIn the 3 controlled clinical ITP studies, transient decreases in platelet counts to levels lower than \n\nbaseline were observed following discontinuation of treatment in 8% and 8% of the eltrombopag and \n\nplacebo groups, respectively (see section 4.4). \n\n \n\nIncreased bone marrow reticulin \n\n \n\nAcross the programme, no patients had evidence of clinically relevant bone marrow abnormalities or \n\nclinical findings that would indicate bone marrow dysfunction. In a small number of ITP patients, \n\neltrombopag treatment was discontinued due to bone marrow reticulin (see section 4.4). \n\n \n\n\n\n21 \n\nCytogenetic abnormalities \n\n \n\nIn the phase II refractory SAA clinical study with eltrombopag with a starting dose of 50 mg/day \n\n(escalated every 2 weeks to a maximum of 150 mg/day) (ELT112523), the incidence of new \n\ncytogenetic abnormalities was observed in 17.1% of adult patients [7/41 (where 4 of them had changes \n\nin chromosome 7)]. The median time on study to a cytogenetic abnormality was 2.9 months. \n\n \n\nIn the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic or \n\nage related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities \n\nwas observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All \n\n7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of \n\neltrombopag therapy and one patient had cytogenetic abnormality at Month 6. \n\n \n\nHaematologic malignancies \n\n \n\nIn the single-arm, open-label study in SAA, three (7%) patients were diagnosed with MDS following \n\ntreatment with eltrombopag, in the two ongoing studies (ELT116826 and ELT116643), 1/28 (4%) and \n\n1/62 (2%) patient has been diagnosed with MDS or AML in each study. \n\n \n\nReporting of suspected adverse reactions \n\n \n\nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \n\nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \n\nprofessionals are asked to report any suspected adverse reactions via the national reporting system \n\nlisted in Appendix V. \n\n \n\n4.9 Overdose \n \n\nIn the event of overdose, platelet counts may increase excessively and result in \n\nthrombotic/thromboembolic complications. In case of an overdose, consideration should be given to \n\noral administration of a metal cation-containing preparation, such as calcium, aluminium, or \n\nmagnesium preparations to chelate eltrombopag and thus limit absorption. Platelet counts should be \n\nclosely monitored. Treatment with eltrombopag should be reinitiated in accordance with dosing and \n\nadministration recommendations (see section 4.2). \n\n \n\nIn the clinical studies there was one report of overdose where the patient ingested 5000 mg of \n\neltrombopag. Reported adverse reactions included mild rash, transient bradycardia, ALT and AST \n\nelevation, and fatigue. Liver enzymes measured between Days 2 and 18 after ingestion peaked at a \n\n1.6-fold ULN in AST, a 3.9-fold ULN in ALT, and a 2.4-fold ULN in total bilirubin, The platelet \n\ncounts were 672,000/µl on Day 18 after ingestion and the maximum platelet count was 929,000/µl. All \n\nevents were resolved without sequelae following treatment. \n\n \n\nBecause eltrombopag is not significantly renally excreted and is highly bound to plasma proteins, \n\nhaemodialysis would not be expected to be an effective method to enhance the elimination of \n\neltrombopag. \n\n \n\n \n\n \n\n\n\n22 \n\n5. PHARMACOLOGICAL PROPERTIES \n \n\n5.1 Pharmacodynamic properties \n \n\nPharmacotherapeutic group: Antihemorrhagics, other systemic hemostatics. ATC code: B02BX 05. \n\n \n\nMechanism of action \n\n \n\nTPO is the main cytokine involved in regulation of megakaryopoiesis and platelet production, and is \n\nthe endogenous ligand for the TPO-R. Eltrombopag interacts with the transmembrane domain of the \n\nhuman TPO-R and initiates signalling cascades similar but not identical to that of endogenous \n\nthrombopoietin (TPO), inducing proliferation and differentiation from bone marrow progenitor cells. \n\n \n\nClinical efficacy and safety \n\n \n\nImmune (primary) thrombocytopenia (ITP) studies \n\n \n\nTwo phase III, randomised, double-blind, placebo-controlled studies RAISE (TRA102537) and \n\nTRA100773B and two open-label studies REPEAT (TRA108057) and EXTEND (TRA105325) \n\nevaluated the safety and efficacy of eltrombopag in adult patients with previously treated ITP. Overall, \n\neltrombopag was administered to 277 ITP patients for at least 6 months and 202 patients for at least \n\n1 year. \n\n \n\nDouble-blind placebo-controlled studies \n\nRAISE: 197 ITP patients were randomised 2:1, eltrombopag (n=135) to placebo (n=62), and \n\nrandomisation was stratified based upon splenectomy status, use of ITP medicinal products at baseline \n\nand baseline platelet count. The dose of eltrombopag was adjusted during the 6-month treatment \n\nperiod based on individual platelet counts. All patients initiated treatment with eltrombopag 50 mg. \n\nFrom Day 29 to the end of treatment, 15 to 28% of eltrombopag-treated patients were maintained on \n\n≤25 mg and 29 to 53% received 75 mg. \n\n \n\nIn addition, patients could taper off concomitant ITP medicinal products and receive rescue treatments \n\nas dictated by local standard of care. More than half of all patients in each treatment group had ≥3 \n\nprior ITP therapies and 36% had a prior splenectomy. \n\n \n\nMedian platelet counts at baseline were 16,000/l for both treatment groups and in the eltrombopag \n\ngroup were maintained above 50,000/µl at all on-therapy visits starting at Day 15; in contrast, median \n\nplatelet counts in the placebo group remained <30,000/µl throughout the study. \n\n \n\nPlatelet count response between 50,000-400,000/l in the absence of rescue treatment was achieved by \n\nsignificantly more patients in the eltrombopag treated group during the 6 month treatment period, \n\np <0.001. Fifty-four percent of the eltrombopag-treated patients and 13% of placebo-treated patients \n\nachieved this level of response after 6 weeks of treatment. A similar platelet response was maintained \n\nthroughout the study, with 52% and 16% of patients responding at the end of the 6-month treatment \n\nperiod. \n\n \n\n\n\n23 \n\nTable 4 Secondary efficacy results from RAISE \n\n \n\n \n\nEltrombopag \n\nN=135 \n\nPlacebo \n\nN=62 \n\nKey secondary endpoints \n\nNumber of cumulative weeks with platelet counts \n\n50,000-400,000/µl, Mean (SD) \n11.3 (9.46) 2.4 (5.95) \n\nPatients with ≥75% of assessments in the target range (50,000 to \n\n400,000/l), n (%) \n\np-value a \n\n51 (38) 4 (7) \n\n<0.001 \n\nPatients with bleeding (WHO Grades 1-4) at any time during \n\n6 months, n (%) \n\n p-value a \n\n106 (79) 56 (93) \n\n0.012 \n\nPatients with bleeding (WHO Grades 2-4) at any time during \n\n6 months, n (%) \n\n p-value a \n\n44 (33) 32 (53) \n\n0.002 \n\nRequiring rescue therapy, n (%) \n\n p-value a \n\n24 (18) 25 (40) \n\n0.001 \n\nPatients receiving ITP therapy at baseline (n) 63 31 \n\nPatients who attempted to reduce or discontinue baseline \n\ntherapy, n (%)b \n\n p-value a \n\n37 (59) 10 (32) \n\n0.016 \n\na Logistic regression model adjusted for randomisation stratification variables \n\nb 21 out of 63 (33%) patients treated with eltrombopag who were taking an ITP medicinal product \n\nat baseline permanently discontinued all baseline ITP medicinal products. \n\n \n\nAt baseline, more than 70% of ITP patients in each treatment group reported any bleeding (WHO \n\nGrades 1-4) and more than 20% reported clinically significant bleeding (WHO Grades 2-4), \n\nrespectively. The proportion of eltrombopag-treated patients with any bleeding (Grades 1-4) and \n\nclinically significant bleeding (Grades 2-4) was reduced from baseline by approximately 50% from \n\nDay 15 to the end of treatment throughout the 6-month treatment period. \n\n \n\nTRA100773B: The primary efficacy endpoint was the proportion of responders, defined as ITP \n\npatients who had an increase in platelet counts to 50,000/l at Day 43 from a baseline of <30,000/l; \n\npatients who withdrew prematurely due to a platelet count 200,000/l were considered responders, \n\nthose that discontinued for any other reason were considered non-responders irrespective of platelet \n\ncount. A total of 114 patients with previously treated ITP were randomised 2:1 eltrombopag (n=76) to \n\nplacebo (n=38). \n\n \n\nTable 5 Efficacy results from TRA100773B \n\n \n\n \n\nEltrombopag \n\nN=74 \n\nPlacebo \n\nN=38 \n\nKey primary endpoints \n\nEligible for efficacy analysis, n 73 37 \n\nPatients with platelet count 50,000/l after up to 42 days \n\nof dosing (compared to a baseline count of <30,000/l), n \n\n(%) \n\n \n\np-valuea \n\n43 (59) 6 (16) \n\n<0.001 \n\nKey secondary endpoints \n\nPatients with a Day 43 bleeding assessment, n 51 30 \n\nBleeding (WHO Grades 1-4) n (%) \n\n \n\np-valuea \n\n20 (39) 18 (60) \n\n0.029 \n\na Logistic regression model adjusted for randomisation stratification variables \n\n\n\n24 \n\n \n\nIn both RAISE and TRA100773B the response to eltrombopag relative to placebo was similar \n\nirrespective of ITP medicinal product use, splenectomy status and baseline platelet count (≤15,000/µl, \n\n>15,000/µl) at randomisation. \n\n \n\nIn RAISE and TRA100773B studies, in the subgroup of ITP patients with baseline platelet count \n\n≤15,000/μl the median platelet counts did not reach the target level (>50,000/l), although in both \n\nstudies 43% of these patients treated with eltrombopag responded after 6 weeks of treatment. In \n\naddition, in the RAISE study, 42% of patients with baseline platelet count ≤15,000/μl treated with \n\neltrombopag responded at the end of the 6 month treatment period. Forty-two to 60% of the \n\neltrombopag-treated patients in the RAISE study were receiving 75 mg from Day 29 to the end of \n\ntreatment. \n\n \n\nAn open-label, repeat-dose study (3 cycles of 6 weeks of treatment, followed by 4 weeks off \n\ntreatment) showed that episodic use with multiple courses of eltrombopag has demonstrated no loss of \n\nresponse. \n\n \n\nEltrombopag was administered to 302 ITP patients in the open-label extension study EXTEND \n\n(TRA105325), 218 patients completed 1 year, 180 completed 2 years, 107 completed 3 years, 75 \n\ncompleted 4 years, 34 completed 5 years and 18 completed 6 years. The median baseline platelet count \n\nwas 19,000/l prior to eltrombopag administration. Median platelet counts at 1, 2, 3, 4, 5, 6 and \n\n7 years on study were 85,000/l, 85,000/l, 105,000/l, 64,000/l, 75,000/l, 119,000/l and \n\n76,000/l, respectively. \n\n \n\nClinical studies comparing eltrombopag to other treatment options (e.g. splenectomy) have not been \n\nconducted. The long-term safety of eltrombopag should be considered prior to starting therapy. \n\n \n\nPaediatric population (aged 1 to 17 years) \n\nThe safety and efficacy of eltrombopag in paediatric patients have been investigated in two studies. \n\n \n\nTRA115450 (PETIT2): The primary endpoint was a sustained response, defined as the proportion of \n\npatients receiving eltrombopag, compared to placebo, achieving platelet counts ≥50,000/µl for at least \n\n6 out of 8 weeks (in the absence of rescue therapy), between weeks 5 to 12 during the double-blind \n\nrandomised period. Patients were diagnosed with chronic ITP for at least 1 year and were refractory or \n\nrelapsed to at least one prior ITP therapy or unable to continue other ITP treatments for a medical \n\nreason and had platelet count <30,000/µl. Ninety-two patients were randomised by three age cohort \n\nstrata (2:1) to eltrombopag (n=63) or placebo (n=29). The dose of eltrombopag could be adjusted \n\nbased on individual platelet counts. \n\n \n\nOverall, a significantly greater proportion of eltrombopag patients (40%) compared with placebo \n\npatients (3%) achieved the primary endpoint (Odds Ratio: 18.0 [95% CI: 2.3, 140.9] p <0.001) which \n\nwas similar across the three age cohorts (Table 6). \n\n \n\nTable 6 Sustained platelet response rates by age cohort in paediatric patients with chronic \n\nITP \n\n \n\n Eltrombopag \n\nn/N (%) \n\n[95% CI] \n\nPlacebo \n\nn/N (%) \n\n[95% CI] \n\nCohort 1 (12 to 17 years) \n\n \n\nCohort 2 (6 to 11 years) \n\n \n\nCohort 3 (1 to 5 years) \n\n9/23 (39%) \n\n[20%, 61%] \n\n11/26 (42%) \n\n[23%, 63%] \n\n5/14 (36%) \n\n[13%, 65%] \n\n1/10 (10%) \n\n[0%, 45%] \n\n0/13 (0%) \n\n[N/A] \n\n0/6 (0%) \n\n[N/A] \n\n \n\n\n\n25 \n\nStatistically fewer eltrombopag patients required rescue treatment during the randomised period \n\ncompared to placebo patients (19% [12/63] vs. 24% [7/29], p=0.032). \n\n \n\nAt baseline, 71% of patients in the eltrombopag group and 69% in the placebo group reported any \n\nbleeding (WHO Grades 1-4). At Week 12, the proportion of eltrombopag patients reporting any \n\nbleeding was decreased to half of baseline (36%). In comparison, at Week 12, 55% of placebo patients \n\nreported any bleeding. \n\n \n\nPatients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase \n\nof the study and 53% (8/15) of patients were able to reduce (n=1) or discontinue (n=7) baseline ITP \n\ntherapy, mainly corticosteroids, without needing rescue therapy. \n\n \n\nTRA108062 (PETIT): The primary endpoint was the proportion of patients achieving platelet counts \n\n≥50,000/µl at least once between weeks 1 and 6 of the randomised period. Patients were diagnosed \n\nwith ITP for at least 6 months and were refractory or relapsed to at least one prior ITP therapy with a \n\nplatelet count <30,000/µl (n=67). During the randomised period of the study, patients were \n\nrandomised by three age cohort strata (2:1) to eltrombopag (n=45) or placebo (n=22). The dose of \n\neltrombopag could be adjusted based on individual platelet counts. \n\n \n\nOverall, a significantly greater proportion of eltrombopag patients (62%) compared with placebo \n\npatients (32%) met the primary endpoint (Odds Ratio: 4.3 [95% CI: 1.4, 13.3] p=0.011). \n\n \n\nSustained response was seen in 50% of the initial responders during 20 out of 24 weeks in the \n\nPETIT 2 study and 15 out of 24 weeks in the PETIT study. \n\n \n\nChronic hepatitis C associated thrombocytopenia studies \n\n \n\nThe efficacy and safety of eltrombopag for the treatment of thrombocytopenia in patients with HCV \n\ninfection were evaluated in two randomised, double-blind, placebo-controlled studies. ENABLE 1 \n\nutilised peginterferon alfa-2a plus ribavirin for antiviral treatment and ENABLE 2 utilised \n\npeginterferon alfa-2b plus ribavirin. Patients did not receive direct acting antiviral agents. In both \n\nstudies, patients with a platelet count of <75,000/µl were enrolled and stratified by platelet count \n\n(<50,000/µl and ≥50,000/µl to <75,000/µl), screening HCV RNA (<800,000 IU/ml and \n\n≥800,000 IU/ml), and HCV genotype (genotype 2/3, and genotype 1/4/6). \n\n \n\nBaseline disease characteristics were similar in both studies and were consistent with compensated \n\ncirrhotic HCV patient population. The majority of patients were HCV genotype 1 (64%) and had \n\nbridging fibrosis/cirrhosis. Thirty-one percent of patients had been treated with prior HCV therapies, \n\nprimarily pegylated interferon plus ribavirin. The median baseline platelet count was 59,500/µl in both \n\ntreatment groups: 0.8%, 28% and 72% of the patients recruited had platelet counts <20,000/µl, \n\n<50.000/µl and ≥50,000/µl respectively. \n\n \n\nThe studies consisted of two phases – a pre-antiviral treatment phase and an antiviral treatment phase. \n\nIn the pre-antiviral treatment phase, patients received open-label eltrombopag to increase the platelet \n\ncount to ≥90,000/µl for ENABLE 1 and ≥100,000/µl for ENABLE 2. The median time to achieve the \n\ntarget platelet count ≥90,000/µl (ENABLE 1) or ≥100,000/µl (ENABLE 2) was 2 weeks. \n\n \n\nThe primary efficacy endpoint for both studies was sustained virologic response (SVR), defined as the \n\npercentage of patients with no detectable HCV-RNA at 24 weeks after completion of the planned \n\ntreatment period. \n\n \n\n \n\n\n\n26 \n\nIn both HCV studies, a significantly greater proportion of patients treated with eltrombopag (n=201, \n\n21%) achieved SVR compared to those treated with placebo (n=65, 13%) (see Table 7). The \n\nimprovement in the proportion of patients who achieved SVR was consistent across all subgroups in \n\nthe randomisation strata (baseline platelet counts (<50,000 vs. >50,000), viral load (<800,000 IU/ml \n\nvs. ≥800,000 IU/ml) and genotype (2/3 vs. 1/4/6)). \n\n \n\nTable 7 Virologic response in HCV patients in ENABLE 1 and ENABLE 2 \n\n \n\n Pooled data ENABLE 1a ENABLE 2b \n\nPatients achieving \n\ntarget platelet counts \n\nand initiating antiviral \n\ntherapy c \n\n \n\n1,439/1,520 (95%) \n\n \n\n680/715 (95%) \n\n \n\n759/805 (94%) \n\n Eltrombopag Placebo Eltrombopag Placebo Eltrombopag Placebo \n\nTotal number of \n\npatients entering \n\nantiviral treatment \n\nphase \n\nn=956 n=485 n=450 n=232 n=506 n=253 \n\n % patients achieving virologic response \n\nOverall SVR d 21 13 23 14 19 13 \n\nHCV RNA Genotype \n\nGenotype 2/3 35 25 35 24 34 25 \n\nGenotype 1/4/6e 15 8 18 10 13 7 \n\nAlbumin levels f \n\n≤ 35g/l 11 8 \n\n> 35g/l 25 16 \n\nMELD scoref \n\n≥ 10 18 10 \n\n< 10 23 17 \n\na Eltrombopag given in combination with peginterferon alfa-2a (180 μg once weekly for \n\n48 weeks for genotypes 1/4/6; 24 weeks for genotype 2/3) plus ribavirin (800 to 1200 mg daily \n\nin 2 divided doses orally) \n\nb Eltrombopag given in combination with peginterferon alfa-2b (1.5 μg/kg once weekly for \n\n48 weeks for genotype 1/4/6; 24 weeks for genotype 2/3) plus ribavirin (800 to 1400 mg orally \n\nin 2 divided doses) \n\nc Target platelet count was 90,000/µl for ENABLE 1 and 100,000/µl for ENABLE 2. For \n\nENABLE 1, 682 patients were randomised to the antiviral treatment phase; however 2 patients \n\nthen withdrew consent prior to receiving antiviral therapy \n\nd p-value <0.05 for eltrombopag versus placebo \n\ne 64% patients participating in ENABLE 1 and ENABLE 2 were genotype 1 \n\nf Post-hoc analyses \n\n \n\nOther secondary findings of the studies included the following: significantly fewer patients treated \n\nwith eltrombopag prematurely discontinued antiviral therapy compared to placebo (45% vs. 60%, \n\np=<0.0001). A greater proportion of patients on eltrombopag did not require any antiviral dose \n\nreduction as compared to placebo (45% vs. 27%). Eltrombopag treatment delayed and reduced the \n\nnumber of peginterferon dose reductions. \n\n \n\n \n\n\n\n27 \n\nSevere aplastic anaemia \n\n \n\nEltrombopag was studied in a single-arm, single-centre open-label study in 43 patients with severe \n\naplastic anaemia with refractory thrombocytopenia following at least one prior immunosuppressive \n\ntherapy (IST) and who had a platelet count ≤30,000/µl. \n\n \n\nThe majority of patients, 33 (77%), were considered to have ‘primary refractory disease’, defined as \n\nhaving no prior adequate response to IST in any lineage. The remaining 10 patients had insufficient \n\nplatelet response to prior therapies. All 10 had received at least 2 prior IST regimens and 50% had \n\nreceived at least 3 prior IST regimens. Patients with diagnosis of Fanconi anaemia, infection not \n\nresponding to appropriate therapy, PNH clone size in neutrophils of ≥50%, where excluded from \n\nparticipation. \n\n \n\nAt baseline the median platelet count was 20,000/µl, haemoglobin was 8.4 g/dl, ANC was 0.58 x 109/l \n\nand absolute reticulocyte count was 24.3 x 109/l. Eighty-six percent of patients were RBC transfusion \n\ndependent, and 91% were platelet transfusion dependent. The majority of patients (84%) had received \n\nat least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline. \n\n \n\nThe primary endpoint was haematological response assessed after 12 weeks of eltrombopag treatment. \n\nHaematological response was defined as meeting one or more of the following criteria: 1) platelet \n\ncount increases to 20,000/µl above baseline or stable platelet counts with transfusion independence for \n\na minimum of 8 weeks; 2) haemoglobin increase by >1.5g/dl, or a reduction in ≥4 units of red blood \n\ncell (RBC) transfusions for 8 consecutive weeks; 3) absolute neutrophil count (ANC) increase of \n\n100% or an ANC increase >0.5 x 109/l. \n\n \n\nThe haematological response rate was 40% (17/43 patients; 95% CI 25, 56), the majority were \n\nunilineage responses (13/17, 76%) whilst there were 3 bilineage and 1 trilineage responses at week 12. \n\nEltrombopag was discontinued after 16 weeks if no haematological response or transfusion \n\nindependence was observed. Patients who responded continued therapy in an extension phase of the \n\nstudy. A total of 14 patients entered the extension phase of the trial. Nine of these patients achieved a \n\nmulti-lineage response, 4 of the 9 remain on treatment and 5 tapered off treatment with eltrombopag \n\nand maintained the response (median follow up: 20.6 months, range: 5.7 to 22.5 months). The \n\nremaining 5 patients discontinued treatment, three due to relapse at the month 3 extension visit. \n\n \n\nDuring treatment with eltrombopag 59% (23/39) became platelet transfusion independent (28 days \n\nwithout platelet transfusion) and 27% (10/37) became RBC transfusion independent (56 days without \n\nRBC transfusion). The longest platelet transfusion-free period for non-responders was 27 days \n\n(median). The longest platelet transfusion-free period for responders was 287 days (median). The \n\nlongest RBC transfusion-free period for non-responders was 29 days (median). The longest RBC \n\ntransfusion-free period for responders was 266 days (median). \n\n \n\nOver 50% of responders who were transfusion-dependent at baseline, had >80% reduction in both \n\nplatelet and RBC transfusion requirements compared to baseline. \n\n \n\nPreliminary results from a supportive study (Study ELT116826), an ongoing non-randomised, \n\nphase II, single-arm, open-label study in refractory SAA patients, showed consistent results. Data are \n\nlimited to 21 out of the planned 60 patients with haematological responses reported by 52% of patients \n\nat 6 months. Multilineage responses were reported by 45% of patients. \n\n \n\n \n\n\n\n28 \n\n5.2 Pharmacokinetic properties \n \n\nPharmacokinetics \n\n \n\nThe plasma eltrombopag concentration-time data collected in 88 patients with ITP in studies \n\nTRA100773A and TRA100773B were combined with data from 111 healthy adult subjects in a \n\npopulation PK analysis. Plasma eltrombopag AUC(0-) and Cmax estimates for ITP patients are \n\npresented (Table 8). \n\n \n\nTable 8 Geometric mean (95% confidence intervals) of steady-state plasma eltrombopag \n\npharmacokinetic parameters in adults with ITP \n\n \n\nEltrombopag dose, once \n\ndaily \n\nN AUC(0-)a, g.h/ml Cmaxa, g/ml \n\n30 mg 28 47 (39, 58) 3.78 (3.18, 4.49) \n\n50 mg 34 108 (88, 134) 8.01 (6.73, 9.53) \n\n75 mg 26 168 (143, 198) 12.7 (11.0, 14.5) \n\na AUC(0-) and Cmax based on population PK post-hoc estimates. \n\n \n\nPlasma eltrombopag concentration-time data collected in 590 patients with HCV enrolled in phase III \n\nstudies TPL103922/ENABLE 1 and TPL108390/ENABLE 2 were combined with data from patients \n\nwith HCV enrolled in the phase II study TPL102357 and healthy adult patients in a population PK \n\nanalysis. Plasma eltrombopag Cmax and AUC(0-) estimates for patients with HCV enrolled in the \n\nphase III studies are presented for each dose studied in Table 9. \n \n\nTable 9 Geometric mean (95% CI) steady-state plasma eltrombopag pharmacokinetic \n\nparameters in patients with chronic HCV \n\n \n\nEltrombopag dose \n\n(once daily) \n\nN AUC(0-) \n\n(g.h/ml) \n\nCmax \n\n(g/ml) \n\n25 mg 330 118 \n\n(109, 128) \n\n6.40 \n\n(5.97, 6.86) \n\n50 mg 119 166 \n\n(143, 192) \n\n9.08 \n\n(7.96, 10.35) \n\n75 mg 45 301 \n\n(250, 363) \n\n16.71 \n\n(14.26, 19.58) \n\n100 mg 96 354 \n\n(304, 411) \n\n19.19 \n\n(16.81, 21.91) \n\nData presented as geometric mean (95% CI). \n\nAUC (0-) and Cmax based on population PK post-hoc estimates at the highest dose in the data for each \n\npatient. \n\n \n\nAbsorption and bioavailability \n\n \n\nEltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. \n\nAdministration of eltrombopag concomitantly with antacids and other products containing polyvalent \n\ncations such as dairy products and mineral supplements significantly reduces eltrombopag exposure \n\n(see section 4.2). In a relative bioavailability study in adults, the eltrombopag powder for oral \n\nsuspension delivered 22% higher plasma AUC(0-) than the film-coated tablet formulation. The \n\nabsolute oral bioavailability of eltrombopag after administration to humans has not been established. \n\nBased on urinary excretion and metabolites eliminated in faeces, the oral absorption of drug-related \n\nmaterial following administration of a single 75 mg eltrombopag solution dose was estimated to be at \n\nleast 52%. \n\n \n\n\n\n29 \n\nDistribution \n\n \n\nEltrombopag is highly bound to human plasma proteins (>99.9%), predominantly to albumin. \n\nEltrombopag is a substrate for BCRP, but is not a substrate for P-glycoprotein or OATP1B1. \n\n \n\nBiotransformation \n\n \n\nEltrombopag is primarily metabolised through cleavage, oxidation and conjugation with glucuronic \n\nacid, glutathione, or cysteine. In a human radiolabel study, eltrombopag accounted for approximately \n\n64% of plasma radiocarbon AUC0-. Minor metabolites due to glucuronidation and oxidation were \n\nalso detected. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for oxidative \n\nmetabolism of eltrombopag. Uridine diphosphoglucuronyl transferase UGT1A1 and UGT1A3 are \n\nresponsible for glucuronidation, and bacteria in the lower gastrointestinal tract may be responsible for \n\nthe cleavage pathway. \n\n \n\nElimination \n\n \n\nAbsorbed eltrombopag is extensively metabolised. The predominant route of eltrombopag excretion is \n\nvia faeces (59%) with 31% of the dose found in the urine as metabolites. Unchanged parent compound \n\n(eltrombopag) is not detected in urine. Unchanged eltrombopag excreted in faeces accounts for \n\napproximately 20% of the dose. The plasma elimination half-life of eltrombopag is approximately \n\n21-32 hours. \n\n \n\nPharmacokinetic interactions \n\n \n\nBased on a human study with radiolabelled eltrombopag, glucuronidation plays a minor role in the \n\nmetabolism of eltrombopag. Human liver microsome studies identified UGT1A1 and UGT1A3 as the \n\nenzymes responsible for eltrombopag glucuronidation. Eltrombopag was an inhibitor of a number of \n\nUGT enzymes in vitro. Clinically significant drug interactions involving glucuronidation are not \n\nanticipated due to limited contribution of individual UGT enzymes in the glucuronidation of \n\neltrombopag. \n\n \n\nApproximately 21% of an eltrombopag dose could undergo oxidative metabolism. Human liver \n\nmicrosome studies identified CYP1A2 and CYP2C8 as the enzymes responsible for eltrombopag \n\noxidation. Eltrombopag does not inhibit or induce CYP enzymes based on in vitro and in vivo data \n\n(see section 4.5). \n\n \n\nIn vitro studies demonstrate that eltrombopag is an inhibitor of the OATP1B1 transporter and an \n\ninhibitor of the BCRP transporter and eltrombopag increased exposure of the OATP1B1 and BCRP \n\nsubstrate rosuvastatin in a clinical drug interaction study (see section 4.5). In clinical studies with \n\neltrombopag, a dose reduction of statins by 50% was recommended. \n\n \n\nEltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium \n\nand zinc (see sections 4.2 and 4.5). \n\n \n\nIn vitro studies demonstrated that eltrombopag is not a substrate for the organic anion transporter \n\npolypeptide, OATP1B1, but is an inhibitor of this transporter (IC50 value of 2.7 μM (1.2 μg/ml). In \n\nvitro studies also demonstrated that eltrombopag is a breast cancer resistance protein (BCRP) substrate \n\nand inhibitor (IC50 value of 2.7 μM (1.2 μg/ml). \n\n \n\n \n\n\n\n30 \n\nSpecial patient populations \n\n \n\nRenal impairment \n\n \n\nThe pharmacokinetics of eltrombopag have been studied after administration of eltrombopag to adult \n\npatients with renal impairment. Following administration of a single 50 mg dose, the AUC0- of \n\neltrombopag was 32% to 36% lower in patients with mild to moderate renal impairment, and 60% \n\nlower in patients with severe renal impairment compared with healthy volunteers. There was \n\nsubstantial variability and significant overlap in exposures between patients with renal impairment and \n\nhealthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein-bound \n\nmedicinal product were not measured. Patients with impaired renal function should use eltrombopag \n\nwith caution and close monitoring, for example by testing serum creatinine and/or urine analysis (see \n\nsection 4.2). The efficacy and safety of eltrombopag have not been established in patients with both \n\nmoderate to severe renal impairment and hepatic impairment. \n\n \n\nHepatic impairment \n\n \n\nThe pharmacokinetics of eltrombopag have been studied after administration of eltrombopag to adult \n\npatients with hepatic impairment. Following the administration of a single 50 mg dose, the AUC0- of \n\neltrombopag was 41% higher in patients with mild hepatic impairment and 80% to 93% higher in \n\npatients with moderate to severe hepatic impairment compared with healthy volunteers. There was \n\nsubstantial variability and significant overlap in exposures between patients with hepatic impairment \n\nand healthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein-bound \n\nmedicinal product were not measured. \n\n \n\nThe influence of hepatic impairment on the pharmacokinetics of eltrombopag following repeat \n\nadministration was evaluated using a population pharmacokinetic analysis in 28 healthy adults and \n\n714 patients with hepatic impairment (673 patients with HCV and 41 patients with chronic liver \n\ndisease of other aetiology). Of the 714 patients, 642 were with mild hepatic impairment, 67 with \n\nmoderate hepatic impairment, and 2 with severe hepatic impairment. Compared to healthy volunteers, \n\npatients with mild hepatic impairment had approximately 111% (95% CI: 45% to 283%) higher \n\nplasma eltrombopag AUC(0-) values and patients with moderate hepatic impairment had \n\napproximately 183% (95% CI: 90% to 459%) higher plasma eltrombopag AUC(0-) values. \n\n \n\nTherefore, eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score \n\n≥5) unless the expected benefit outweighs the identified risk of portal venous thrombosis (see \n\nsections 4.2 and 4.4). For patients with HCV initiate eltrombopag at a dose of 25 mg once daily (see \n\nsection 4.2). \n\n \n\nRace \n\n \n\nThe influence of Asian ethnicity (such as Japanese, Chinese, Taiwanese and Korean) on the \n\npharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 \n\nhealthy adults (31 Asians) and 88 patients with ITP (18 Asians). Based on estimates from the \n\npopulation pharmacokinetic analysis, Asian ITP patients had approximately 49% higher plasma \n\neltrombopag AUC(0-) values as compared to non-Asian patients who were predominantly Caucasian \n\n(see section 4.2). \n\n \n\nThe influence of Asian ethnicity (such as Chinese, Japanese, Taiwanese, Korean, and Thai) on the \n\npharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in \n\n635 patients with HCV (145 Asians and 69 South Asians). Based on estimates from the population \n\npharmacokinetic analysis, Asian patients had approximately 55% higher plasma eltrombopag AUC(0-) \n\nvalues as compared to patients of other races who were predominantly Caucasian (see section 4.2). \n\n \n\n \n\n\n\n31 \n\nGender \n\n \n\nThe influence of gender on the pharmacokinetics of eltrombopag was evaluated using a population \n\npharmacokinetic analysis in 111 healthy adults (14 females) and 88 patients with ITP (57 females). \n\nBased on estimates from the population pharmacokinetic analysis, female ITP patients had \n\napproximately 23% higher plasma eltrombopag AUC(0-) as compared to male patients, without \n\nadjustment for body weight differences. \n\n \n\nThe influence of gender on eltrombopag pharmacokinetics was evaluated using population \n\npharmacokinetics analysis in 635 patients with HCV (260 females). Based on model estimate, female \n\nHCV patient had approximately 41% higher plasma eltrombopag AUC(0-) as compared to male \n\npatients. \n\n \n\nAge \n\n \n\nThe influence of age on eltrombopag pharmacokinetics was evaluated using population \n\npharmacokinetics analysis in 28 healthy subjects, 673 patients with HCV, and 41 patients with chronic \n\nliver disease of other aetiology ranging from 19 to 74 years old. There are no PK data on the use of \n\neltrombopag in patients ≥75 years. Based on model estimate, elderly (≥65 years) patients had \n\napproximately 41% higher plasma eltrombopag AUC(0-) as compared to younger patients (see \n\nsection 4.2). \n\n \n\nPaediatric population (aged 1 to 17 years) \n\n \n\nThe pharmacokinetics of eltrombopag have been evaluated in 168 paediatric ITP patients dosed once \n\ndaily in two studies, TRA108062/PETIT and TRA115450/PETIT-2. Plasma eltrombopag apparent \n\nclearance following oral administration (CL/F) increased with increasing body weight. The effects of \n\nrace and sex on plasma eltrombopag CL/F estimates were consistent between paediatric and adult \n\npatients. Asian paediatric ITP patients had approximately 43% higher plasma eltrombopag AUC(0-) \n\nvalues as compared to non-Asian patients. Female paediatric ITP patients had approximately 25% \n\nhigher plasma eltrombopag AUC(0-) values as compared to male patients. \n\n \n\nThe pharmacokinetic parameters of eltrombopag in paediatric patients with ITP are shown in \n\nTable 10. \n\n \n\nTable 10 Geometric mean (95% CI) steady-state plasma eltrombopag pharmacokinetic \n\nparameters in paediatric patients with ITP (50 mg once daily dosing regimen) \n\n \n\nAge Cmax \n(µg/ml) \n\nAUC(0-) \n(µg.hr/ml) \n\n12 to 17 years (n=62) 6.80 \n\n(6.17, 7.50) \n\n103 \n\n(91.1, 116) \n\n6 to 11 years (n=68) 10.3 \n\n(9.42, 11.2) \n\n153 \n\n(137, 170) \n\n1 to 5 years (n=38) 11.6 \n\n(10.4, 12.9) \n\n162 \n\n(139, 187) \n\nData presented as geometric mean (95%CI). AUC(0-) and Cmax based on population PK post-hoc \n\nestimates \n\n \n\n \n\n\n\n32 \n\n5.3 Preclinical safety data \n \n\nSafety pharmacology and repeat-dose toxicity \n\n \n\nEltrombopag does not stimulate platelet production in mice, rats or dogs because of unique TPO \n\nreceptor specificity. Therefore, data from these animals do not fully model potential adverse effects \n\nrelated to the pharmacology of eltrombopag in humans, including the reproduction and carcinogenicity \n\nstudies. \n\n \n\nTreatment-related cataracts were detected in rodents and were dose and time-dependent. At ≥6 times \n\nthe human clinical exposure in adult ITP patients at 75 mg/day and 3 times the human clinical \n\nexposure in adult HCV patients at 100 mg/day, based on AUC, cataracts were observed in mice after \n\n6 weeks and rats after 28 weeks of dosing. At 4 times the human clinical exposure in ITP patients at \n\n75 mg/day and 2 times the human exposure in HCV patients at 100 mg/day, based on AUC, cataracts \n\nwere observed in mice after 13 weeks and in rats after 39 weeks of dosing. At non-tolerated doses in \n\npre-weaning juvenile rats dosed from Days 4-32 (approximately equating to a 2-year-old human at the \n\nend of the dosing period), ocular opacities were observed (histology not performed) at 9 times the \n\nmaximum human clinical exposure in paediatric ITP patients at 75 mg/day, based on AUC. However, \n\ncataracts were not observed in juvenile rats given tolerated doses at 5 times the human clinical \n\nexposure in paediatric ITP patients, based on AUC. Cataracts have not been observed in adult dogs \n\nafter 52 weeks of dosing at 2 times the human clinical exposure in adult or paediatric ITP patients at \n\n75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on \n\nAUC). \n\n \n\nRenal tubular toxicity was observed in studies of up to 14 days duration in mice and rats at exposures \n\nthat were generally associated with morbidity and mortality. Tubular toxicity was also observed in a \n\n2-year oral carcinogenicity study in mice at doses of 25, 75 and 150 mg/kg/day. Effects were less \n\nsevere at lower doses and were characterised by a spectrum of regenerative changes. The exposure at \n\nthe lowest dose was 1.2 or 0.8 times the human clinical exposure based on AUC in adult or paediatric \n\nITP patients at 75 mg/day and 0.6 times the human clinical exposure in HCV patients at 100 mg/day, \n\nbased on AUC. Renal effects were not observed in rats after 28 weeks or in dogs after 52 weeks at \n\nexposures 4 and 2 times the human clinical exposure in adult ITP patients and 3 and 2 times the \n\nhuman clinical exposure in paediatric ITP patients at 75 mg/day and 2 times and equivalent to the \n\nhuman clinical exposure in HCV patients at 100 mg/day, based on AUC. \n\n \n\nHepatocyte degeneration and/or necrosis, often accompanied by increased serum liver enzymes, was \n\nobserved in mice, rats and dogs at doses that were associated with morbidity and mortality or were \n\npoorly tolerated. No hepatic effects were observed after chronic dosing in rats (28 weeks) and in dogs \n\n(52 weeks) at 4 or 2 times the human clinical exposure in adult ITP patients and 3 or 2 times the \n\nhuman clinical exposure in paediatric ITP patients at 75 mg/day and 2 times or equivalent to the \n\nhuman clinical exposure in HCV patients at 100 mg/day, based on AUC. \n\n \n\nAt poorly tolerated doses in rats and dogs (>10 or 7 times the human clinical exposure in adult or \n\npaediatric ITP patients at 75 mg/day and>4 times the human clinical exposure in HCV patients at \n\n100 mg/day, based on AUC), decreased reticulocyte counts and regenerative bone marrow erythroid \n\nhyperplasia (rats only) were observed in short-term studies. There were no effects of note on red cell \n\nmass or reticulocyte counts after dosing for up to 28 weeks in rats, 52 weeks in dogs and 2 years in \n\nmice or rats at maximally tolerated doses which were 2 to 4 times human clinical exposure in adult or \n\npaediatric ITP patients at 75 mg/day and ≤2 times the human clinical exposure in HCV patients at \n\n100 mg/day, based on AUC. \n\n \n\nEndosteal hyperostosis was observed in a 28-week toxicity study in rats at a non-tolerated dose of \n\n60 mg/kg/day (6 times or 4 times the human clinical exposure in adult or paediatric ITP patients at \n\n75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). \n\nThere were no bone changes observed in mice or rats after lifetime exposure (2 years) at 4 times or \n\n2 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 2 times the \n\nhuman clinical exposure in HCV patients at 100 mg/day, based on AUC. \n\n\n\n33 \n\n \n\nCarcinogenicity and mutagenicity \n\n \n\nEltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to \n\n40 mg/kg/day (exposures up to 4 or 2 times the human clinical exposure in adult or paediatric ITP \n\npatients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, based \n\non AUC). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in \n\nvivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times or 8 times the human \n\nclinical exposure in adult or paediatric ITP patients at 75 mg/day and 7 times the human clinical \n\nexposure in HCV patients at 100 mg/day, based on Cmax). In the in vitro mouse lymphoma assay, \n\neltrombopag was marginally positive (<3-fold increase in mutation frequency). These in vitro and in \n\nvivo findings suggest that eltrombopag does not pose a genotoxic risk to humans. \n\n \n\nReproductive toxicity \n\n \n\nEltrombopag did not affect female fertility, early embryonic development or embryofoetal \n\ndevelopment in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure in adult or \n\nadolescent (12-17 years old) ITP patients at 75 mg/day and equivalent to the human clinical exposure \n\nin HCV patients at 100 mg/day, based on AUC). Also there was no effect on embryofoetal \n\ndevelopment in rabbits at doses up to 150 mg/kg/day, the highest dose tested (0.3 to 0.5 times the \n\nhuman clinical exposure in ITP patients at 75 mg/day and HCV patients at 100 mg/day, based on \n\nAUC). However, at a maternally toxic dose of 60 mg/kg/day (6 times the human clinical exposure in \n\nITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, \n\nbased on AUC) in rats, eltrombopag treatment was associated with embryo lethality (increased pre- \n\nand post-implantation loss), reduced foetal body weight and gravid uterine weight in the female \n\nfertility study and a low incidence of cervical ribs and reduced foetal body weight in the embryofoetal \n\ndevelopment study. Eltrombopag should be used during pregnancy only if the expected benefit \n\njustifies the potential risk to the foetus (see section 4.6). Eltrombopag did not affect male fertility in \n\nrats at doses up to 40 mg/kg/day, the highest dose tested (3 times the human clinical exposure in ITP \n\npatients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, based \n\non AUC). In the pre- and post-natal development study in rats, there were no undesirable effects on \n\npregnancy, parturition or lactation of F0 female rats at maternally non-toxic doses (10 and \n\n20 mg/kg/day) and no effects on the growth, development, neurobehavioural or reproductive function \n\nof the offspring (F1). Eltrombopag was detected in the plasma of all F1 rat pups for the entire 22 hour \n\nsampling period following administration of medicinal product to the F0 dams, suggesting that rat pup \n\nexposure to eltrombopag was likely via lactation. \n\n \n\nPhototoxicity \n\n \n\nIn vitro studies with eltrombopag suggest a potential phototoxicity risk; however, in rodents there was \n\nno evidence of cutaneous phototoxicity (10 or 7 times the human clinical exposure in adult or \n\npaediatric ITP patients at 75 mg/day and 5 times the human clinical exposure in HCV patients at \n\n100 mg/day, based on AUC) or ocular phototoxicity (4 times the human clinical exposure in adult or \n\npaediatric ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at \n\n100 mg/day, based on AUC). Furthermore, a clinical pharmacology study in 36 subjects showed no \n\nevidence that photosensitivity was increased following administration of eltrombopag 75 mg. This was \n\nmeasured by delayed phototoxic index. Nevertheless, a potential risk of photoallergy cannot be ruled \n\nout since no specific preclinical study could be performed. \n\n \n\nJuvenile animal studies \n\n \n\nAt non-tolerated doses in pre-weaning rats, ocular opacities were observed. At tolerated doses, no \n\nocular opacities were observed (see above subsection ‘Safety pharmacology and repeat-dose toxicity’). \n\nIn conclusion, taking into account the exposure margins based on AUC, a risk of eltrombopag-related \n\ncataracts in paediatric patients cannot be excluded. There are no findings in juvenile rats to suggest a \n\ngreater risk of toxicity with eltrombopag treatment in paediatric vs. adult ITP patients. \n\n \n\n\n\n34 \n\n \n\n6. PHARMACEUTICAL PARTICULARS \n\n \n\n6.1 List of excipients \n\n \n\nRevolade 12.5 mg film-coated tablets \n\nTablet core \n\nMagnesium stearate \n\nMannitol (E421) \n\nMicrocrystalline cellulose \n\nPovidone \n\nSodium starch glycolate \n\n \n\nTablet coating \n\nHypromellose (E464) \n\nMacrogol 400 (E1521) \n\nPolysorbate 80 (E433) \n\nTitanium dioxide (E171) \n\n \n\nRevolade 25 mg film-coated tablets \n\nTablet core \n\nMagnesium stearate \n\nMannitol (E421) \n\nMicrocrystalline cellulose \n\nPovidone \n\nSodium starch glycolate \n\n \n\nTablet coating \n\nHypromellose (E464) \n\nMacrogol 400 (E1521) \n\nPolysorbate 80 (E433) \n\nTitanium dioxide (E171) \n\n \n\nRevolade 50 mg film-coated tablets \n\nTablet core \n\nMagnesium stearate \n\nMannitol (E421) \n\nMicrocrystalline cellulose \n\nPovidone \n\nSodium starch glycolate \n\n \n\nTablet coating \n\nHypromellose (E464) \n\nIron oxide red (E172) \n\nIron oxide yellow (E172) \n\nMacrogol 400 (E1521) \n\nTitanium dioxide (E171) \n\n \n\n \n\n\n\n35 \n\nRevolade 75 mg film-coated tablets \n\nTablet core \n\nMagnesium stearate \n\nMannitol (E421) \n\nMicrocrystalline cellulose \n\nPovidone \n\nSodium starch glycolate \n\n \n\nTablet coating \n\nHypromellose (E464) \n\nIron oxide red (E172) \n\nIron oxide black (E172) \n\nMacrogol 400 (E1521) \n\nTitanium dioxide (E171) \n\n \n\n6.2 Incompatibilities \n \n\nNot applicable. \n\n \n\n6.3 Shelf life \n \n\n4 years. \n\n \n\n6.4 Special precautions for storage \n \n\nThis medicinal product does not require any special storage conditions. \n\n \n\n6.5 Nature and contents of container \n\n \n\nFilm-coated tablets \n\nAluminum blisters (PA/Alu/PVC/Alu) in a carton containing 14 or 28 film-coated tablets and \n\nmultipacks containing 84 (3 packs of 28) film-coated tablets. \n\n \n\nNot all pack sizes may be marketed. \n\n \n\n6.6 Special precautions for disposal \n \n\nAny unused medicinal product or waste material should be disposed of in accordance with local \n\nrequirements. \n\n \n\n \n\n7. MARKETING AUTHORISATION HOLDER \n \n\nNovartis Europharm Limited \n\nVista Building \n\nElm Park, Merrion Road \n\nDublin 4 \n\nIreland \n\n \n\n \n\n\n\n36 \n\n \n\n8. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nRevolade 12.5 mg film-coated tablets \n\nEU/1/10/612/010 \n\nEU/1/10/612/011 \n\nEU/1/10/612/012 \n\n \n\nRevolade 25 mg film-coated tablets \n\nEU/1/10/612/001 \n\nEU/1/10/612/002 \n\nEU/1/10/612/003 \n\n \n\nRevolade 50 mg film-coated tablets \n\nEU/1/10/612/004 \n\nEU/1/10/612/005 \n\nEU/1/10/612/006 \n\n \n\nRevolade 75 mg film-coated tablets \n\nEU/1/10/612/007 \n\nEU/1/10/612/008 \n\nEU/1/10/612/009 \n\n \n\n \n\n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n \n\nDate of first authorisation: 11 March 2010 \n\nDate of latest renewal: 15 January 2015 \n\n \n\n \n\n10. DATE OF REVISION OF THE TEXT \n\n \n\n \n\nDetailed information on this medicinal product is available on the website of the European Medicines \n\nAgency http://www.ema.europa.eu/. \n\n\n\n37 \n\n1. NAME OF THE MEDICINAL PRODUCT \n \n\nRevolade 25 mg powder for oral suspension \n\n \n\n \n\n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \n\nEach sachet contains eltrombopag olamine equivalent to 25 mg of eltrombopag. \n\n \n\nFor the full list of excipients, see section 6.1. \n\n \n\n \n\n3. PHARMACEUTICAL FORM \n\n \n\nPowder for oral suspension \n\n \n\nReddish-brown to yellow powder. \n\n \n\n \n\n4. CLINICAL PARTICULARS \n \n\n4.1 Therapeutic indications \n \n\nRevolade is indicated for the treatment of patients aged 1 year and above with primary immune \n\nthrombocytopenia (ITP) lasting 6 months or longer from diagnosis and who are refractory to other \n\ntreatments (e.g. corticosteroids, immunoglobulins) (see sections 4.2 and 5.1). \n\n \n\nRevolade is indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment \n\nof thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the \n\ninitiation or limiting the ability to maintain optimal interferon-based therapy (see sections 4.4 and 5.1). \n\n \n\nRevolade is indicated in adult patients with acquired severe aplastic anaemia (SAA) who were either \n\nrefractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for \n\nhaematopoietic stem cell transplantation (see section 5.1). \n\n \n\n4.2 Posology and method of administration \n\n \n\nEltrombopag treatment should be initiated by and remain under the supervision of a physician who is \n\nexperienced in the treatment of haematological diseases or the management of chronic hepatitis C and \n\nits complications. \n\n \n\nPosology \n\n \n\nEltrombopag dosing requirements must be individualised based on the patient’s platelet counts. The \n\nobjective of treatment with eltrombopag should not be to normalise platelet counts. \n\n \n\nThe powder for oral suspension may lead to higher eltrombopag exposure than the tablet formulation \n\n(see section 5.2). When switching between the tablet and powder for oral suspension formulations, \n\nplatelet counts should be monitored weekly for 2 weeks. \n\n \n\nImmune (primary) thrombocytopenia \n\n \n\nThe lowest dose of eltrombopag to achieve and maintain a platelet count ≥50,000/µl should be used. \n\nDose adjustments are based upon the platelet count response. Eltrombopag must not be used to \n\nnormalise platelet counts. In clinical studies, platelet counts generally increased within 1 to 2 weeks \n\nafter starting eltrombopag and decreased within 1 to 2 weeks after discontinuation. \n\n \n\n\n\n38 \n\nAdults and paediatric population aged 6 to 17 years \n\nThe recommended starting dose of eltrombopag is 50 mg once daily. For patients of Asian ancestry \n\n(such as Chinese, Japanese, Taiwanese, Korean or Thai), eltrombopag should be initiated at a reduced \n\ndose of 25 mg once daily (see section 5.2). \n\n \n\nPaediatric population aged 1 to 5 years \n\nThe recommended starting dose of eltrombopag is 25 mg once daily. \n\n \n\nMonitoring and dose adjustment \n\nAfter initiating eltrombopag, the dose must be adjusted to achieve and maintain a platelet count \n\n≥50,000/µl as necessary to reduce the risk for bleeding. A daily dose of 75 mg must not be exceeded. \n\n \n\nClinical haematology and liver tests should be monitored regularly throughout therapy with \n\neltrombopag and the dose regimen of eltrombopag modified based on platelet counts as outlined in \n\nTable 1. During therapy with eltrombopag full blood counts (FBCs), including platelet count and \n\nperipheral blood smears, should be assessed weekly until a stable platelet count (≥50,000/µl for at \n\nleast 4 weeks) has been achieved. FBCs including platelet counts and peripheral blood smears should \n\nbe obtained monthly thereafter. \n\n \n\nTable 1 Dose adjustments of eltrombopag in ITP patients \n\n \n\nPlatelet count Dose adjustment or response \n\n<50,000/µl following at least \n\n2 weeks of therapy \n\nIncrease daily dose by 25 mg to a maximum of 75 mg/day*. \n\n50,000/µl to 150,000/µl Use lowest dose of eltrombopag and/or concomitant ITP \n\ntreatment to maintain platelet counts that avoid or reduce \n\nbleeding. \n\n>150,000/µl to 250,000/µl Decrease the daily dose by 25 mg. Wait 2 weeks to assess the \n\neffects of this and any subsequent dose adjustments♦. \n\n>250,000/µl Stop eltrombopag; increase the frequency of platelet monitoring \n\nto twice weekly. \n\n \n\nOnce the platelet count is ≤100,000/µl, reinitiate therapy at a \n\ndaily dose reduced by 25 mg. \n\n* For patients taking 25 mg eltrombopag once every other day, increase dose to 25 mg once daily. \n\n♦ For patients taking 25 mg eltrombopag once daily, consideration should be given to dosing at \n\n12.5 mg once daily or alternatively a dose of 25 mg once every other day. \n\n \n\nEltrombopag can be administered in addition to other ITP medicinal products. The dose regimen of \n\nconcomitant ITP medicinal products should be modified, as medically appropriate, to avoid excessive \n\nincreases in platelet counts during therapy with eltrombopag. \n\n \n\nIt is necessary to wait for at least 2 weeks to see the effect of any dose adjustment on the patient’s \n\nplatelet response prior to considering another dose adjustment. \n\n \n\nThe standard eltrombopag dose adjustment, either decrease or increase, would be 25 mg once daily. \n\n \n\nDiscontinuation \n\nTreatment with eltrombopag should be discontinued if the platelet count does not increase to a level \n\nsufficient to avoid clinically important bleeding after 4 weeks of eltrombopag therapy at 75 mg once \n\ndaily. \n\n \n\nPatients should be clinically evaluated periodically and continuation of treatment should be decided on \n\nan individual basis by the treating physician. In non-splenectomised patients this should include \n\nevaluation relative to splenectomy. The reoccurrence of thrombocytopenia is possible upon \n\ndiscontinuation of treatment (see section 4.4). \n\n \n\n\n\n39 \n\nChronic hepatitis C (HCV) associated thrombocytopenia \n\n \n\nWhen eltrombopag is given in combination with antivirals reference should be made to the full \n\nsummary of product characteristics of the respective coadministered medicinal products for \n\ncomprehensive details of relevant safety information or contraindications. \n\n \n\nIn clinical studies, platelet counts generally began to increase within 1 week of starting eltrombopag. \n\nThe aim of treatment with eltrombopag should be to achieve the minimum level of platelet counts \n\nneeded to initiate antiviral therapy, in adherence to clinical practice recommendations. During antiviral \n\ntherapy, the aim of treatment should be to keep platelet counts at a level that prevents the risk of \n\nbleeding complications, normally around 50,000-75,000/µl. Platelet counts >75,000/µl should be \n\navoided. The lowest dose of eltrombopag needed to achieve the targets should be used. Dose \n\nadjustments are based upon the platelet count response. \n\n \n\nInitial dose regimen \n\nEltrombopag should be initiated at a dose of 25 mg once daily. No dosage adjustment is necessary for \n\nHCV patients of Asian ancestry or patients with mild hepatic impairment (see section 5.2). \n\n \n\nMonitoring and dose adjustment \n\nThe dose of eltrombopag should be adjusted in 25 mg increments every 2 weeks as necessary to \n\nachieve the target platelet count required to initiate antiviral therapy. Platelet counts should be \n\nmonitored every week prior to starting antiviral therapy. On initiation of antiviral therapy the platelet \n\ncount may fall, so immediate eltrombopag dose adjustments should be avoided (see Table 2). \n\n \n\nDuring antiviral therapy, the dose of eltrombopag should be adjusted as necessary to avoid dose \n\nreductions of peginterferon due to decreasing platelet counts that may put patients at risk of bleeding \n\n(see Table 2). Platelet counts should be monitored weekly during antiviral therapy until a stable \n\nplatelet count is achieved, normally around 50,000-75,000/µl. FBCs including platelet counts and \n\nperipheral blood smears should be obtained monthly thereafter. Dose reductions on the daily dose by \n\n25 mg should be considered if platelet counts exceed the required target. It is recommended to wait for \n\n2 weeks to assess the effects of this and any subsequent dose adjustments. \n\n \n\nA dose of 100 mg eltrombopag once daily must not be exceeded. \n\n \n\nTable 2 Dose adjustments of eltrombopag in HCV patients during antiviral therapy \n\n \n\nPlatelet count Dose adjustment or response \n\n<50,000/µl following at least \n\n2 weeks of therapy \n\nIncrease daily dose by 25 mg to a maximum of 100 mg/day. \n\n≥50,000/µl to ≤100,000/µl Use lowest dose of eltrombopag as necessary to avoid dose \n\nreductions of peginterferon. \n\n>100,000/µl to ≤150,000/µl Decrease the daily dose by 25 mg. Wait 2 weeks to assess the \n\neffects of this and any subsequent dose adjustments♦. \n\n>150,000/µl Stop eltrombopag; increase the frequency of platelet monitoring to \n\ntwice weekly. \n\n \n\nOnce the platelet count is ≤100,000/µl, reinitiate therapy at a daily \n\ndose reduced by 25 mg*. \n\n* For patients taking 25 mg eltrombopag once daily, consideration should be given to reinitiating \n\ndosing at 25 mg every other day. \n♦ On initiation of antiviral therapy the platelet count may fall, so immediate eltrombopag dose \n\nreductions should be avoided. \n\n \n\n \n\n\n\n40 \n\nDiscontinuation \n\nIf after 2 weeks of eltrombopag therapy at 100 mg the required platelet level to initiate antiviral \n\ntherapy is not achieved, eltrombopag should be discontinued. \n\n \n\nEltrombopag treatment should be terminated when antiviral therapy is discontinued unless otherwise \n\njustified. Excessive platelet count responses or important liver test abnormalities also necessitate \n\ndiscontinuation. \n\n \n\nSevere aplastic anaemia \n\n \n\nInitial dose regimen \n\nEltrombopag should be initiated at a dose of 50 mg once daily. For patients of Asian ancestry, \n\neltrombopag should be initiated at a reduced dose of 25 mg once daily (see section 5.2). The treatment \n\nshould not be initiated when the patients has existing cytogenetic abnormalities of chromosome 7. \n\n \n\nMonitoring and dose adjustment \n\nHaematological response requires dose titration, generally up to 150 mg, and may take up to 16 weeks \n\nafter starting eltrombopag (see section 5.1). The dose of eltrombopag should be adjusted in 50 mg \n\nincrements every 2 weeks as necessary to achieve the target platelet count ≥50,000/µl. For patients \n\ntaking 25 mg once daily, the dose should be increased to 50 mg daily before increasing the dose \n\namount by 50 mg. A dose of 150 mg daily must not be exceeded. Clinical haematology and liver tests \n\nshould be monitored regularly throughout therapy with eltrombopag and the dosage regimen of \n\neltrombopag modified based on platelet counts as outlined in Table 3. \n\n \n\nTable 3 Dose adjustments of eltrombopag in patients with severe aplastic anaemia \n\n \n\nPlatelet count Dose adjustment or response \n\n<50,000/µl following at least \n\n2 weeks of therapy \n\nIncrease daily dose by 50 mg to a maximum of 150 mg/day. \n\n \n\nFor patients taking 25 mg once daily, increase the dose to \n\n50 mg daily before increasing the dose amount by 50 mg. \n\n50,000/µl to 150,000/µl Use lowest dose of eltrombopag to maintain platelet counts. \n\n>150,000/µl to 250,000/µl Decrease the daily dose by 50 mg. Wait 2 weeks to assess the \n\neffects of this and any subsequent dose adjustments. \n\n>250,000/µl Stop eltrombopag; for at least one week. \n\n \n\nOnce the platelet count is ≤100,000/µl, reinitiate therapy at a \n\ndaily dose reduced by 50 mg. \n\n \n\nTapering for tri-lineage (white blood cells, red blood cells, and platelets) responders \n\nFor patients who achieve tri-lineage response, including transfusion independence, lasting at least \n\n8 weeks: the dose of eltrombopag may be reduced by 50%. \n\n \n\nIf counts remain stable after 8 weeks at the reduced dose, then eltrombopag must be discontinued and \n\nblood counts monitored. If platelet counts drop to <30,000/µl, haemoglobin drops to <9 g/dl or \n\nabsolute neutrophil count (ANC) to <0.5 x 109/l, eltrombopag may be reinitiated at the previous \n\neffective dose. \n\n \n\nDiscontinuation \n\nIf no haematological response has occurred after 16 weeks of therapy with eltrombopag, therapy \n\nshould be discontinued. If new cytogenetic abnormalities are detected, it must be evaluated whether \n\ncontinuation of eltrombopag is appropriate (see sections 4.4 and 4.8). Excessive platelet count \n\nresponses (as outlined in Table 3) or important liver test abnormalities also necessitate discontinuation \n\nof eltrombopag (see section 4.8). \n\n \n\n\n\n41 \n\nSpecial populations \n\n \n\nRenal impairment \n\nNo dose adjustment is necessary in patients with renal impairment. Patients with impaired renal \n\nfunction should use eltrombopag with caution and close monitoring, for example by testing serum \n\ncreatinine and/or performing urine analysis (see section 5.2). \n\n \n\nHepatic impairment \n\nEltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless \n\nthe expected benefit outweighs the identified risk of portal venous thrombosis (see section 4.4). \n\n \n\nIf the use of eltrombopag is deemed necessary for ITP patients with hepatic impairment the starting \n\ndose must be 25 mg once daily. After initiating the dose of eltrombopag in patients with hepatic \n\nimpairment an interval of 3 weeks should be observed before increasing the dose. \n\n \n\nNo dose adjustment is required for thrombocytopenic patients with chronic HCV and mild hepatic \n\nimpairment (Child-Pugh score ≤6). Chronic HCV patients and severe aplastic anaemia patients with \n\nhepatic impairment should initiate eltrombopag at a dose of 25 mg once daily (see section 5.2). After \n\ninitiating the dose of eltrombopag in patients with hepatic impairment an interval of 2 weeks should be \n\nobserved before increasing the dose. \n\n \n\nThere is an increased risk for adverse events, including hepatic decompensation and thromboembolic \n\nevents, in thrombocytopenic patients with advanced chronic liver disease treated with eltrombopag, \n\neither in preparation for invasive procedure or in HCV patients undergoing antiviral therapy (see \n\nsections 4.4 and 4.8). \n\n \n\nElderly \n\nThere are limited data on the use of eltrombopag in ITP patients aged 65 years and older and no \n\nclinical experience in ITP patients aged over 85 years. In the clinical studies of eltrombopag, overall \n\nno clinically significant differences in safety of eltrombopag were observed between patients aged at \n\nleast 65 years and younger patients. Other reported clinical experience has not identified differences in \n\nresponses between the elderly and younger patients, but greater sensitivity of some older individuals \n\ncannot be ruled out (see section 5.2). \n\n \n\nThere are limited data on the use of eltrombopag in HCV and SAA patients aged over 75 years. \n\nCaution should be exercised in these patients (see section 4.4). \n\n \n\nAsian patients \n\nFor patients of Asian ancestry (such as Chinese, Japanese, Taiwanese, Korean or Thai), including \n\nthose with hepatic impairment, eltrombopag should be initiated at a dose of 25 mg once daily (see \n\nsection 5.2). \n\n \n\nPatient platelet count should continue to be monitored and the standard criteria for further dose \n\nmodification followed. \n\n \n\nPaediatric population \n\nRevolade is not recommended for use in children under the age of one year with ITP due to \n\ninsufficient data on safety and efficacy. The safety and efficacy of eltrombopag has not been \n\nestablished in children and adolescents (<18 years) with chronic HCV related thrombocytopenia or \n\nSAA. No data are available. \n\n \n\n \n\n\n\n42 \n\nMethod of administration (see section 6.6) \n\n \n\nOral use. \n\nThe suspension should be taken at least two hours before or four hours after any products such as \n\nantacids, dairy products (or other calcium containing food products), or mineral supplements \n\ncontaining polyvalent cations (e.g. iron, calcium, magnesium, aluminium, selenium and zinc) (see \n\nsections 4.5 and 5.2). \n\n \n\n4.3 Contraindications \n \n\nHypersensitivity to eltrombopag or to any of the excipients listed in section 6.1. \n\n \n\n4.4 Special warnings and precautions for use \n\n \n\nThere is an increased risk for adverse reactions, including potentially fatal hepatic decompensation and \n\nthromboembolic events, in thrombocytopenic HCV patients with advanced chronic liver disease, as \n\ndefined by low albumin levels ≤35 g/l or model for end stage liver disease (MELD) score ≥10, when \n\ntreated with eltrombopag in combination with interferon-based therapy. In addition, the benefits of \n\ntreatment in terms of the proportion achieving sustained virological response (SVR) compared with \n\nplacebo were modest in these patients (especially for those with baseline albumin ≤35 g/l) compared \n\nwith the group overall. Treatment with eltrombopag in these patients should be initiated only by \n\nphysicians experienced in the management of advanced HCV, and only when the risks of \n\nthrombocytopenia or withholding antiviral therapy necessitate intervention. If treatment is considered \n\nclinically indicated, close monitoring of these patients is required. \n\n \n\nCombination with direct-acting antiviral agents \n\n \n\nSafety and efficacy have not been established in combination with direct-acting antiviral agents \n\napproved for treatment of chronic hepatitis C infection. \n\n \n\nRisk of hepatotoxicity \n\n \n\nEltrombopag administration can cause abnormal liver function and severe hepatotoxicity, which might \n\nbe life-threatening (see section 4.8). \n\n \n\nSerum alanine aminotransferase (ALT), aspartate aminotrasferase (AST) and bilirubin should be \n\nmeasured prior to initiation of eltrombopag, every 2 weeks during the dose adjustment phase and \n\nmonthly following establishment of a stable dose. Eltrombopag inhibits UGT1A1 and OATP1B1, \n\nwhich may lead to indirect hyperbilirubinaemia. If bilirubin is elevated fractionation should be \n\nperformed. Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. If \n\nthe abnormalities are confirmed, serum liver tests should be monitored until the abnormalities resolve, \n\nstabilise, or return to baseline levels. Eltrombopag should be discontinued if ALT levels increase \n\n(3 times the upper limit of normal [x ULN] in patients with normal liver function, or ≥3 x baseline or \n\n>5 x ULN, whichever is the lower, in patients with pre-treatment elevations in transaminases) and are: \n\n progressive, or \n\n persistent for ≥4 weeks, or \n\n accompanied by increased direct bilirubin, or \n\n accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation. \n \n\nCaution is required when administering eltrombopag to patients with hepatic disease. In ITP and SAA \n\npatients a lower starting dose of eltrombopag should be used. Close monitoring is required when \n\nadministering to patients with hepatic impairment (see section 4.2). \n\n \n\n \n\n\n\n43 \n\nHepatic decompensation (use with interferon) \n\n \n\nHepatic decompensation in patients with chronic hepatitis C: Monitoring is required in patients with \n\nlow albumin levels (≤35 g/l) or with MELD score ≥10 at baseline. \n\n \n\nChronic HCV patients with cirrhosis may be at risk of hepatic decompensation when receiving alfa \n\ninterferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV, hepatic \n\ndecompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial \n\nperitonitis) occurred more frequently in the eltrombopag arm (11%) than in the placebo arm (6%). In \n\npatients with low albumin levels (≤35 g/l) or with a MELD score ≥10 at baseline, there was a 3-fold \n\ngreater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared to \n\nthose with less advanced liver disease. In addition, the benefits of treatment in terms of the proportion \n\nachieving SVR compared with placebo were modest in these patients (especially for those with \n\nbaseline albumin ≤35 g/l) compared with the group overall. Eltrombopag should only be administered \n\nto such patients after careful consideration of the expected benefits in comparison with the risks. \n\nPatients with these characteristics should be closely monitored for signs and symptoms of hepatic \n\ndecompensation. The respective interferon summary of product characteristics should be referenced \n\nfor discontinuation criteria. Eltrombopag should be terminated if antiviral therapy is discontinued for \n\nhepatic decompensation. \n\n \n\nThrombotic/thromboembolic complications \n\n \n\nIn controlled studies in thrombocytopenic patients with HCV receiving interferon-based therapy \n\n(n=1,439), 38 out of 955 patients (4%) treated with eltrombopag and 6 out of 484 patients (1%) in the \n\nplacebo group experienced thromboembolic events (TEEs). Reported thrombotic/thromboembolic \n\ncomplications included both venous and arterial events. The majority of TEEs were non-serious and \n\nresolved by the end of the study. Portal vein thrombosis was the most common TEE in both treatment \n\ngroups (2% in patients treated with eltrombopag versus <1% for placebo). No specific temporal \n\nrelationship between start of treatment and event of TEE were observed. Patients with low albumin \n\nlevels (≤35 g/l) or MELD ≥10 had a 2-fold greater risk of TEEs than those with higher albumin levels; \n\nthose aged ≥60 years had a 2-fold greater risk of TEEs compared to younger patients. Eltrombopag \n\nshould only be administered to such patients after careful consideration of the expected benefits in \n\ncomparison with the risks. Patients should be closely monitored for signs and symptoms of TEE. \n\n \n\nThe risk of TEEs has been found to be increased in patients with chronic liver disease (CLD) treated \n\nwith 75 mg eltrombopag once daily for 2 weeks in preparation for invasive procedures. Six of 143 \n\n(4%) adult patients with CLD receiving eltrombopag experienced TEEs (all of the portal venous \n\nsystem) and 2 of 145 (1%) patients in the placebo group experienced TEEs (one in the portal venous \n\nsystem and one myocardial infarction). Five of the 6 patients treated with eltrombopag experienced the \n\nthrombotic complication at a platelet count >200,000/µl and within 30 days of the last dose of \n\neltrombopag. Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with \n\nchronic liver disease in preparation for invasive procedures. \n\n \n\nIn eltrombopag clinical studies in ITP thromboembolic events were observed at low and normal \n\nplatelet counts. Caution should be used when administering eltrombopag to patients with known risk \n\nfactors for thromboembolism including but not limited to inherited (e.g. Factor V Leiden) or acquired \n\nrisk factors (e.g. ATIII deficiency, antiphospholipid syndrome), advanced age, patients with prolonged \n\nperiods of immobilisation, malignancies, contraceptives and hormone replacement therapy, \n\nsurgery/trauma, obesity and smoking. Platelet counts should be closely monitored and consideration \n\ngiven to reducing the dose or discontinuing eltrombopag treatment if the platelet count exceeds the \n\ntarget levels (see section 4.2). The risk-benefit balance should be considered in patients at risk of TEEs \n\nof any aetiology. \n\n \n\nNo case of TEE was identified from a clinical study in refractory SAA, however the risk of these \n\nevents cannot be excluded in this patient population due to the limited number of exposed patients. As \n\nthe highest authorised dose is indicated for patients with SAA (150 mg/day) and due to the nature of \n\nthe reaction, TEEs might be expected in this patient population. \n\n\n\n44 \n\n \n\nEltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score ≥5) unless \n\nthe expected benefit outweighs the identified risk of portal venous thrombosis. When treatment is \n\nconsidered appropriate, caution is required when administering eltrombopag to patients with hepatic \n\nimpairment (see sections 4.2 and 4.8). \n\n \n\nBleeding following discontinuation of eltrombopag \n\n \n\nThrombocytopenia is likely to reoccur in ITP patients upon discontinuation of treatment with \n\neltrombopag. Following discontinuation of eltrombopag, platelet counts return to baseline levels \n\nwithin 2 weeks in the majority of patients, which increases the bleeding risk and in some cases may \n\nlead to bleeding. This risk is increased if eltrombopag treatment is discontinued in the presence of \n\nanticoagulants or anti-platelet agents. It is recommended that, if treatment with eltrombopag is \n\ndiscontinued, ITP treatment be restarted according to current treatment guidelines. Additional medical \n\nmanagement may include cessation of anticoagulant and/or anti-platelet therapy, reversal of \n\nanticoagulation, or platelet support. Platelet counts must be monitored weekly for 4 weeks following \n\ndiscontinuation of eltrombopag. \n\n \n\nIn HCV clinical studies, a higher incidence of gastrointestinal bleeding, including serious and fatal \n\ncases, was reported following discontinuation of peginterferon, ribavirin, and eltrombopag. Following \n\ndiscontinuation of therapy, patients should be monitored for any signs or symptoms of gastrointestinal \n\nbleeding. \n\n \n\nBone marrow reticulin formation and risk of bone marrow fibrosis \n\n \n\nEltrombopag may increase the risk for development or progression of reticulin fibres within the bone \n\nmarrow. The relevance of this finding, as with other thrombopoietin receptor (TPO-R) agonists, has \n\nnot been established yet. \n\n \n\nPrior to initiation of eltrombopag, the peripheral blood smear should be examined closely to establish \n\na baseline level of cellular morphologic abnormalities. Following identification of a stable dose of \n\neltrombopag, full blood count (FBC) with white blood cell count (WBC) differential should be \n\nperformed monthly. If immature or dysplastic cells are observed, peripheral blood smears should be \n\nexamined for new or worsening morphological abnormalities (e.g. teardrop and nucleated red blood \n\ncells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening \n\nmorphological abnormalities or cytopenia(s), treatment with eltrombopag should be discontinued and \n\na bone marrow biopsy considered, including staining for fibrosis. \n\n \n\nProgression of existing myelodysplastic syndrome (MDS) \n\n \n\nThere is a theoretical concern that TPO-R agonists may stimulate the progression of existing \n\nhaematological malignancies such as MDS. TPO-R agonists are growth factors that lead to \n\nthrombopoietic progenitor cell expansion, differentiation and platelet production. The TPO-R is \n\npredominantly expressed on the surface of cells of the myeloid lineage. For TPO-R agonists there is a \n\nconcern that they may stimulate the progression of existing haematopoietic malignancies such as \n\nMDS. \n\n \n\nIn clinical studies with a TPO-R agonist in patients with MDS, cases of transient increases in blast cell \n\ncounts were observed and cases of MDS disease progression to acute myeloid leukaemia (AML) were \n\nreported. \n\n \n\nThe diagnosis of ITP or SAA in adults and elderly patients should be confirmed by the exclusion of \n\nother clinical entities presenting with thrombocytopenia, in particular the diagnosis of MDS must be \n\nexcluded. Consideration should be given to performing a bone marrow aspirate and biopsy over the \n\ncourse of the disease and treatment, particularly in patients over 60 years of age, those with systemic \n\nsymptoms, or abnormal signs such as increased peripheral blast cells. \n\n \n\n\n\n45 \n\nThe effectiveness and safety of Revolade have not been established for the treatment of \n\nthrombocytopenia due to MDS. Revolade should not be used outside of clinical studies for the \n\ntreatment of thrombocytopenia due to MDS. \n\n \n\nCytogenetic abnormalities and progression to MDS/AML in patients with SAA \n\n \n\nCytogenetic abnormalities are known to occur in SAA patients. It is not known whether eltrombopag \n\nincreases the risk of cytogenetic abnormalities in patients with SAA. In the phase II refractory SAA \n\nclinical study with eltrombopag with a starting dose of 50 mg/day (escalated every 2 weeks to a \n\nmaximum of 150 mg/day) (ELT112523), the incidence of new cytogenetic abnormalities was \n\nobserved in 17.1% of patients [7/41 (where 4 of them had changes in chromosome 7)]. The median \n\ntime on study to a cytogenetic abnormality was 2.9 months. \n\n \n\nIn the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic or \n\nage related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities \n\nwas observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All \n\n7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of \n\neltrombopag therapy and one patient had cytogenetic abnormality at Month 6. \n \n\nIn clinical studies with eltrombopag in SAA, 4% of patients (5/133) were diagnosed with MDS. The \n\nmedian time to diagnosis was 3 months from the start of eltrombopag treatment. \n\n \n\nFor SAA patients refractory to or heavily pretreated with prior immunosuppressive therapy, bone \n\nmarrow examination with aspirations for cytogenetics is recommended prior to initiation of \n\neltrombopag, at 3 months of treatment and 6 months thereafter. If new cytogenetic abnormalities are \n\ndetected, it must be evaluated whether continuation of eltrombopag is appropriate. \n\n \n\nOcular changes \n\n \n\nCataracts were observed in toxicology studies of eltrombopag in rodents (see section 5.3). In \n\ncontrolled studies in thrombocytopenic patients with HCV receiving interferon therapy (n=1,439), \n\nprogression of pre-existing baseline cataract(s) or incident cataracts was reported in 8% of the \n\neltrombopag group and 5% of the placebo group. Retinal haemorrhages, mostly Grade 1 or 2, have \n\nbeen reported in HCV patients receiving interferon, ribavirin and eltrombopag (2% of the eltrombopag \n\ngroup and 2% of the placebo group. Haemorrhages occurred on the surface of the retina (preretinal), \n\nunder the retina (subretinal), or within the retinal tissue. Routine ophthalmologic monitoring of \n\npatients is recommended. \n\n \n\nQT/QTc prolongation \n\n \n\nA QTc study in healthy volunteers dosed 150 mg eltrombopag per day did not show a clinically \n\nsignificant effect on cardiac repolarisation. QTc interval prolongation has been reported in clinical \n\nstudies of patients with ITP and thrombocytopenic patients with HCV. The clinical significance of \n\nthese QTc prolongation events is unknown. \n\n \n\nLoss of response to eltrombopag \n\n \n\nA loss of response or failure to maintain a platelet response with eltrombopag treatment within the \n\nrecommended dosing range should prompt a search for causative factors, including an increased bone \n\nmarrow reticulin. \n\n \n\n \n\n\n\n46 \n\nPaediatric population \n\n \n\nThe above warnings and precautions for ITP also apply to the paediatric population. \n\n \n\nInterference with laboratory tests \n\n \n\nEltrombopag is highly coloured and so has the potential to interfere with some laboratory tests. Serum \n\ndiscolouration and interference with total bilirubin and creatinine testing have been reported in \n\npatients taking Revolade. If the laboratory results and clinical observations are inconsistent, re-testing \n\nusing another method may help in determining the validity of the result. \n\n \n\n4.5 Interaction with other medicinal products and other forms of interaction \n \n\nEffects of eltrombopag on other medicinal products \n\n \n\nHMG CoA reductase inhibitors \n\n \n\nAdministration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1 \n\nand BCRP substrate rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin Cmax 103% \n\n(90% confidence interval [CI]: 82%, 126%) and AUC0- 55% (90% CI: 42%, 69%). Interactions are \n\nalso expected with other HMG-CoA reductase inhibitors, including atorvastatin, fluvastatin, lovastatin, \n\npravastatin and simvastatin. When co-administered with eltrombopag, a reduced dose of statins should \n\nbe considered and careful monitoring for statin adverse reactions should be undertaken (see \n\nsection 5.2). \n\n \n\nOATP1B1 and BCRP substrates \n\n \n\nConcomitant administration of eltrombopag and OATP1B1 (e.g. methotrexate) and BCRP (e.g. \n\ntopotecan and methotrexate) substrates should be undertaken with caution (see section 5.2). \n\n \n\nCytochrome P450 substrates \n\n \n\nIn studies utilising human liver microsomes, eltrombopag (up to 100 M) showed no in vitro \n\ninhibition of the CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11 and was an \n\ninhibitor of CYP2C8 and CYP2C9 as measured using paclitaxel and diclofenac as the probe \n\nsubstrates. Administration of eltrombopag 75 mg once daily for 7 days to 24 healthy male subjects did \n\nnot inhibit or induce the metabolism of probe substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 \n\n(flurbiprofen), or 3A4 (midazolam) in humans. No clinically significant interactions are expected \n\nwhen eltrombopag and CYP450 substrates are co-administered (see section 5.2). \n\n \n\nHCV protease inhibitors \n\n \n\nDose adjustment is not required when eltrombopag is co-administered with either telaprevir or \n\nboceprevir. Co-administration of a single dose of eltrombopag 200 mg with telaprevir 750 mg every \n\n8 hours did not alter plasma telaprevir exposure. \n\n \n\nCo-administration of a single dose of eltrombopag 200 mg with boceprevir 800 mg every 8 hours did \n\nnot alter plasma boceprevir AUC(0-), but increased Cmax by 20%, and decreased Cmin by 32%. The \n\nclinical relevance of the decrease in Cmin has not been established, increased clinical and laboratory \n\nmonitoring for HCV suppression is recommended. \n\n \n\n \n\n\n\n47 \n\nEffects of other medicinal products on eltrombopag \n\n \n\nCiclosporin \n\n \nA decrease in eltrombopag exposure was observed with co-administration of 200 mg and 600 mg \n\nciclosporin (a BCRP inhibitor). The co-administration of 200 mg ciclosporin decreased the Cmax and \n\nthe AUCinf of eltrombopag by 25% and 18%, respectively. The co-administration of 600 mg \n\nciclosporin decreased the Cmax and the AUCinf of eltrombopag by 39% and 24%, respectively. \n\nEltrombopag dose adjustment is permitted during the course of the treatment based on the patient’s \n\nplatelet count (see section 4.2). Platelet count should be monitored at least weekly for 2 to 3 weeks \n\nwhen eltrombopag is co-administered with ciclosporin. Eltrombopag dose may need to be increased \n\nbased on these platelet counts. \n\n \n\nPolyvalent cations (chelation) \n\n \n\nEltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium \n\nand zinc. Administration of a single dose of eltrombopag 75 mg with a polyvalent cation-containing \n\nantacid (1524 mg aluminium hydroxide and 1425 mg magnesium carbonate) decreased plasma \n\neltrombopag AUC0- by 70% (90% CI: 64%, 76%) and Cmax by 70% (90% CI: 62%, 76%). \n\nEltrombopag should be taken at least two hours before or four hours after any products such as \n\nantacids, dairy products or mineral supplements containing polyvalent cations to avoid significant \n\nreduction in eltrombopag absorption due to chelation (see sections 4.2 and 5.2). \n\n \n\nLopinavir/ritonavir \n\n \n\nCo-administration of eltrombopag with lopinavir/ritonavir may cause a decrease in the concentration \n\nof eltrombopag. A study in 40 healthy volunteers showed that the co-administration of a single 100 mg \n\ndose of eltrombopag with repeat dose lopinavir/ritonavir 400/100 mg twice daily resulted in a \n\nreduction in eltrombopag plasma AUCinf by 17% (90% CI: 6.6%, 26.6%). Therefore, caution should \n\nbe used when co-administration of eltrombopag with lopinavir/ritonavir takes place. Platelet count \n\nshould be closely monitored in order to ensure appropriate medical management of the dose of \n\neltrombopag when lopinavir/ritonavir therapy is initiated or discontinued. \n\n \n\nCYP1A2 and CYP2C8 inhibitors and inducers \n\n \n\nEltrombopag is metabolised through multiple pathways including CYP1A2, CYP2C8, UGT1A1, and \n\nUGT1A3 (see section 5.2). Medicinal products that inhibit or induce a single enzyme are unlikely to \n\nsignificantly affect plasma eltrombopag concentrations, whereas medicinal products that inhibit or \n\ninduce multiple enzymes have the potential to increase (e.g. fluvoxamine) or decrease (e.g. rifampicin) \n\neltrombopag concentrations. \n\n \n\nHCV protease inhibitors \n\n \n\nResults of a drug-drug pharmacokinetic (PK) interaction study show that co-administration of repeat \n\ndoses of boceprevir 800 mg every 8 hours or telaprevir 750 mg every 8 hours with a single dose of \n\neltrombopag 200 mg did not alter plasma eltrombopag exposure to a clinically significant extent. \n\n \n\nMedicinal products for treatment of ITP \n\n \n\nMedicinal products used in the treatment of ITP in combination with eltrombopag in clinical studies \n\nincluded corticosteroids, danazol, and/or azathioprine, intravenous immunoglobulin (IVIG), and \n\nanti-D immunoglobulin. Platelet counts should be monitored when combining eltrombopag with other \n\nmedicinal products for the treatment of ITP in order to avoid platelet counts outside of the \n\nrecommended range (see section 4.2). \n\n \n\n\n\n48 \n\nFood interaction \n\n \n\nThe administration of eltrombopag tablet or powder for oral suspension formulations with a high-\n\ncalcium meal (e.g. a meal that included dairy products) significantly reduced plasma eltrombopag \n\nAUC0-∞ and Cmax. In contrast, the administration of eltrombopag 2 hours before or 4 hours after a high-\n\ncalcium meal or with low-calcium food [<50 mg calcium] did not alter plasma eltrombopag exposure \n\nto a clinically significant extent (see section 4.2). \n\n \n\nAdministration of a single 50 mg dose of eltrombopag in tablet form with a standard high-calorie, \n\nhigh-fat breakfast that included dairy products reduced plasma eltrombopag mean AUC0-∞ by 59% and \n\nmean Cmax by 65%. \n\n \n\nAdministration of a single 25 mg dose of eltrombopag as powder for oral suspension with a high-\n\ncalcium, moderate-fat and moderate-calorie meal reduced plasma eltrombopag mean AUC0-∞ by 75% \n\nand mean Cmax by 79%. This decrease of exposure was attenuated when a single 25 mg dose of \n\neltrombopag powder for oral suspension was administered 2 hours before a high-calcium meal (mean \n\nAUC0-∞ was decreased by 20% and mean Cmax by 14%). \n\n \n\nFood low in calcium (<50 mg calcium), including fruit, lean ham, beef and unfortified (no added \n\ncalcium, magnesium or iron) fruit juice, unfortified soya milk and unfortified grain, did not \n\nsignificantly impact plasma eltrombopag exposure, regardless of calorie and fat content (see \n\nsections 4.2 and 4.5). \n\n \n\n4.6 Fertility, pregnancy and lactation \n \n\nPregnancy \n\n \n\nThere are no or limited amount of data from the use of eltrombopag in pregnant women. Studies in \n\nanimals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. \n\n \n\nRevolade is not recommended during pregnancy. \n\n \n\nWomen of childbearing potential / Contraception in males and females \n\n \n\nRevolade is not recommended in women of childbearing potential not using contraception. \n\n \n\nBreast-feeding \n\n \n\nIt is not known whether eltrombopag/metabolites are excreted in human milk. Studies in animals have \n\nshown that eltrombopag is likely secreted into milk (see section 5.3); therefore a risk to the suckling \n\nchild cannot be excluded. A decision must be made whether to discontinue breast-feeding or to \n\ncontinue/abstain from Revolade therapy, taking into account the benefit of breast-feeding for the child \n\nand the benefit of therapy for the woman. \n\n \n\nFertility \n\n \n\nFertility was not affected in male or female rats at exposures that were comparable to those in humans. \n\nHowever a risk for humans cannot be ruled out (see section 5.3). \n\n \n\n4.7 Effects on ability to drive and use machines \n \n\nEltrombopag has negligible influence on the ability to drive and use machines. The clinical status of \n\nthe patient and the adverse reaction profile of eltrombopag, including dizziness and lack of alertness, \n\nshould be borne in mind when considering the patient’s ability to perform tasks that require \n\njudgement, motor and cognitive skills. \n\n \n\n\n\n49 \n\n4.8 Undesirable effects \n\n \n\nSummary of the safety profile \n\nImmune thrombocytopenia in adult and paediatric patients \n\n \n\nThe safety of Revolade was assessed using the pooled double-blind, placebo-controlled studies \n\nTRA100773A and B, TRA102537 (RAISE) and TRA113765, in which 403 patients were exposed to \n\nRevolade and 179 to placebo, in addition to data from the completed open-label studies TRA108057, \n\nTRA105325 (EXTEND) and TRA112940. Patients received study medication for up to 8 years (in \n\nEXTEND). The most important serious adverse reactions were hepatotoxicity and \n\nthrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of \n\npatients included nausea, diarrhoea and increased alanine aminotransferase. \n\n \n\nThe safety of Revolade in paediatric patients (aged 1 to 17 years) with previously treated ITP has been \n\ndemonstrated in two studies. PETIT2 (TRA115450) was a 2-part, double-blind and open-label, \n\nrandomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=63) or \n\nplacebo (n=29) for up to 13 weeks in the randomised period of the study. PETIT (TRA108062) was a \n\n3-part, staggered-cohort, open-label and double-blind, randomised, placebo-controlled study. Patients \n\nwere randomised 2:1 and received Revolade (n=44) or placebo (n=21), for up to 7 weeks. The profile \n\nof adverse reactions was comparable to that seen in adults with some additional adverse reactions, \n\nmarked ♦ in the table below. The most common adverse reactions in paediatric ITP patients 1 year and \n\nolder (≥3% and greater than placebo) were upper respiratory tract infection, nasopharyngitis, cough, \n\npyrexia, abdominal pain, oropharyngeal pain, toothache and rhinorrhoea. \n\n \n\nThrombocytopenia with HCV infection in adult patients \n\n \n\nENABLE 1 (TPL103922 n=716) and ENABLE 2 (TPL108390 n=805) were randomised, double-\n\nblind, placebo-controlled, multicentre studies to assess the efficacy and safety of Revolade in \n\nthrombocytopenic patients with HCV infection who were otherwise eligible to initiate antiviral \n\ntherapy. In the HCV studies the safety population consisted of all randomised patients who received \n\ndouble-blind study medicinal product during Part 2 of ENABLE 1 (Revolade treatment n=450, \n\nplacebo treatment n=232) and ENABLE 2 (Revolade treatment n=506, placebo treatment n=253). \n\nPatients are analysed according to the treatment received (total safety double-blind population, \n\nRevolade n=955 and placebo n=484). The most important serious adverse reactions identified were \n\nhepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring \n\nin at least 10% of patients included headache, anaemia, decreased appetite, cough, nausea, diarrhoea, \n\nhyperbilirubinaemia, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-like illness, asthenia, \n\nchills and oedema. \n\n \n\nSevere aplastic anaemia in adult patients \n\n \n\nThe safety of eltrombopag in severe aplastic anaemia was assessed in a single-arm, open-label study \n\n(N=43) in which 11 patients (26%) were treated for >6 months and 7 patients (16%) were treated for \n\n>1 year. The most important serious adverse reactions were febrile neutropenia and sepsis/infection. \n\nThe most common adverse reactions occurring in at least 10% of patients included headache, \n\ndizziness, cough, oropharyngeal pain, nausea, diarrhoea, abdominal pain, transaminases increased, \n\narthralgia, pain in extremity, fatigue and pyrexia. \n\n \n\n \n\n\n\n50 \n\nList of adverse reactions \n\n \n\nThe adverse reactions in the adult ITP studies (N=763), paediatric ITP studies (N=171), the HCV \n\nstudies (N=1,520), the SAA studies (N=43) and post-marketing reports are listed below by MedDRA \n\nsystem organ class and by frequency. Within each system organ class, the adverse drug reactions are \n\nranked by frequency, with the most frequent reactions first. The corresponding frequency category for \n\neach adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); \n\ncommon (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known \n\n(cannot be estimated from the available data). \n\n \n\nITP study population \n\n \n\nSystem organ class Frequency Adverse reaction \n\nInfections and infestations Very \n\ncommon \n\nNasopharyngitis♦, upper respiratory tract infection♦ \n\nCommon Pharyngitis, influenza, oral herpes, pneumonia, sinusitis, tonsillitis, \n\nrespiratory tract infection, gingivitis \n\nUncommon Skin infection \n\nNeoplasms benign, malignant \n\nand unspecified (incl cysts \n\nand polyps) \n\nUncommon Rectosigmoid cancer \n\nBlood and lymphatic system \n\ndisorders \n\nCommon Anaemia, eosinophilia, leukocytosis, thrombocytopenia, \n\nhaemoglobin decreased, white blood cell count decreased \n\nUncommon Anisocytosis, haemolytic anaemia, myelocytosis, band neutrophil \n\ncount increased, myelocyte present, platelet count increased, \n\nhaemoglobin increased \n\nImmune system disorders Uncommon Hypersensitivity \n\nMetabolism and nutrition \n\ndisorders \n\nCommon Hypokalaemia, decreased appetite, blood uric acid increased \n\nUncommon Anorexia, gout, hypocalcaemia \n\nPsychiatric disorders Common Sleep disorder, depression \n\nUncommon Apathy, mood altered, tearfulness \n\nNervous system disorders Common Paraesthesia, hypoaesthesia, somnolence, migraine \n\nUncommon Tremor, balance disorder, dysaesthesia, hemiparesis, migraine \n\nwith aura, neuropathy peripheral, peripheral sensory neuropathy, \n\nspeech disorder, toxic neuropathy, vascular headache \n\nEye disorders Common Dry eye, vision blurred, eye pain, visual acuity reduced \n\nUncommon Lenticular opacities, astigmatism, cataract cortical, lacrimation \n\nincreased, retinal haemorrhage, retinal pigment epitheliopathy, \n\nvisual impairment, visual acuity tests abnormal, blepharitis, \n\nkeratoconjunctivitis sicca \n\nEar and labyrinth disorders Common Ear pain, vertigo \n\nCardiac disorders Uncommon Tachycardia, acute myocardial infarction, cardiovascular disorder, \n\ncyanosis, sinus tachycardia, electrocardiogram QT prolonged \n\n\n\n51 \n\nVascular disorders Common Deep vein thrombosis, haematoma, hot flush \n\nUncommon Embolism, hot flush, thrombophlebitis superficial, flushing \n\nRespiratory, thoracic and \n\nmediastinal disorders \n\nVery \n\ncommon \n\nCough♦ \n\nCommon Oropharyngeal pain, rhinorrhoea♦ \n\nUncommon Pulmonary embolism, pulmonary infarction, nasal discomfort, \n\noropharyngeal blistering, sinus disorder, sleep apnoea syndrome \n\nGastrointestinal disorders Very \n\ncommon \n\nNausea, diarrhoea♦ \n\nCommon Mouth ulceration, toothache♦, vomiting, abdominal pain*, mouth \n\nhaemorrhage, flatulence \n\n* Very common in paediatric ITP \n\nUncommon Dry mouth, glossodynia, abdominal tenderness, faeces \n\ndiscoloured, food poisoning, frequent bowel movements, \n\nhaematemesis, oral discomfort \n\nHepatobiliary disorders Very \n\ncommon \n\nAlanine aminotransferase increased† \n\nCommon Aspartate aminotransferase increased†, hyperbilirubinaemia, \n\nhepatic function abnormal \n\nUncommon Cholestasis, hepatic lesion, hepatitis, drug-induced liver injury \n\nSkin and subcutaneous tissue \n\ndisorders \n\nCommon Rash, alopecia, hyperhidrosis, pruritus generalised, petechiae \n\nUncommon Urticaria, dermatosis, cold sweat, erythema, melanosis, \n\npigmentation disorder, skin discolouration, skin exfoliation \n\nMusculoskeletal and \n\nconnective tissue disorders \n\nCommon Myalgia, muscle spasm, musculoskeletal pain, bone pain, back \n\npain \n\nUncommon Muscular weakness \n\nRenal and urinary disorders Common Proteinuria, blood creatinine increased, thrombotic \n\nmicroangiopathy with renal failure‡ \n\nUncommon Renal failure, leukocyturia, lupus nephritis, nocturia, blood urea \n\nincreased, urine protein/creatinine ratio increased \n\nReproductive system and \n\nbreast disorders \n\nCommon Menorrhagia \n\nGeneral disorders and \n\nadministration site conditions \n\nCommon Pyrexia*, chest pain, asthenia \n\n*Very common in paediatric ITP \n\nUncommon Feeling hot, vessel puncture site haemorrhage, feeling jittery, \n\ninflammation of wound, malaise, sensation of foreign body \n\nInvestigations Common Blood alkaline phosphatase increased \n\nUncommon Blood albumin increased, protein total increased, blood albumin \n\ndecreased, pH urine increased \n\nInjury, poisoning and \n\nprocedural complications \n\nUncommon Sunburn \n\n♦ Additional adverse reactions observed in paediatric studies (aged 1to 17 years). \n† Increase of alanine aminotransferase and aspartate aminotransferase may occur simultaneously, \n\nalthough at a lower frequency. \n‡ Grouped term with preferred terms acute kidney injury and renal failure \n\n \n\nHCV study population (in combination with anti-viral interferon and ribavirin therapy) \n\n \n\nSystem organ class Frequency Adverse reaction \n\nInfections and infestations Common Urinary tract infection, upper respiratory tract infection, \n\nbronchitis, nasopharyngitis, influenza, oral herpes \n\nUncommon Gastroenteritis, pharyngitis \n\nNeoplasms benign, malignant \n\nand unspecified (incl cysts and \n\npolyps) \n\nCommon Hepatic neoplasm malignant \n\n\n\n52 \n\nBlood and lymphatic system \n\ndisorders \n\nVery \n\ncommon \n\nAnaemia \n\nCommon Lymphopenia \n\nUncommon Haemolytic anaemia \n\nMetabolism and nutrition \n\ndisorders \n\nVery \n\ncommon \n\nDecreased appetite \n\nCommon Hyperglycaemia, abnormal loss of weight \n\nPsychiatric disorders Common Depression, anxiety, sleep disorder \n\nUncommon Confusional state, agitation \n\nNervous system disorders Very \n\ncommon \n\nHeadache \n\nCommon Dizziness, disturbance in attention, dysgeusia, hepatic \n\nencephalopathy, lethargy, memory impairment, paraesthesia \n\nEye disorders Common Cataract, retinal exudates, dry eye, ocular icterus, retinal \n\nhaemorrhage \n\nEar and labyrinth disorders Common Vertigo \n\nCardiac disorders Common Palpitations \n\nRespiratory, thoracic and \n\nmediastinal disorders \n\nVery \n\ncommon \n\nCough \n\nCommon Dyspnoea, oropharyngeal pain, dyspnoea exertional, productive \n\ncough \n\nGastrointestinal disorders Very \n\ncommon \n\nNausea, diarrhoea \n\nCommon Vomiting, ascites, abdominal pain, abdominal pain upper, \n\ndyspepsia, dry mouth, constipation, abdominal distension, \n\ntoothache, stomatitis, gastrooesophagal reflux disease, \n\nhaemorrhoids, abdominal discomfort, varices oesophageal \n\nUncomon Oesophageal varices haemorrhage, gastritis, aphthous stomatitis \n\nHepatobiliary disorders Common Hyperbilirubinaemia, jaundice, drug-induced liver injury \n\nUncommon Portal vein thrombosis, hepatic failure \n\nSkin and subcutaneous tissue \n\ndisorders \n\nVery \n\ncommon \n\nPruritus \n\nCommon Rash, dry skin, eczema, rash pruritic, erythema, hyperhidrosis, \n\npruritus generalised, alopecia \n\nUncommon Skin lesion, skin discolouration, skin hyperpigmentation, night \n\nsweats \n\nMusculoskeletal and \n\nconnective tissue disorder \n\nVery \n\ncommon \n\nMyalgia \n\nCommon Arthralgia, muscle spasms, back pain, pain in extremity, \n\nmusculoskeletal pain, bone pain \n\nRenal and urinary disorders Uncommon Thrombotic microangiopathy with acute renal failure†, dysuria \n\nGeneral disorders and \n\nadministration site conditions \n\nVery \n\ncommon \n\nPyrexia, fatigue, influenza-like illness, asthenia, chills \n\nCommon Irritability, pain, malaise, injection site reaction, non-cardiac chest \n\npain, oedema, oedema peripheral \n\nUncommon Injection site pruritus, injection site rash, chest discomfort \n\nInvestigations Common Blood bilirubin increased, weight decreased, white blood cell \n\ncount decreased, haemoglobin decreased, neutrophil count \n\ndecreased, international normalised ratio increased, activated \n\npartial thromboplastin time prolonged, blood glucose increased, \n\nblood albumin decreased \n\nUncommon Electrocardiogram QT prolonged \n† Grouped term with preferred terms oliguria, renal failure and renal impairment \n\n \n\n\n\n53 \n\nSAA study population \n\n \n\nSystem organ class Frequency Adverse reaction \n\nBlood and lymphatic system \n\ndisorders \n\nCommon Neutropenia, splenic infarction \n\nMetabolism and nutrition \n\ndisorders \n\nCommon Iron overload, decreased appetite, hypoglycaemia, increased \n\nappetite \n\nPsychiatric disorders Common Anxiety, depression \n\nNervous system disorders Very \n\ncommon \n\nHeadache, dizziness \n\nCommon Syncope \n\nEye disorders Common Dry eye, cataract, ocular icterus, vision blurred, visual \n\nimpairment, vitreous floaters \n\nRespiratory, thoracic and \n\nmediastinal disorders \n\nVery \n\ncommon \n\nCough, oropharyngeal pain, rhinorrhoea \n\nCommon Epistaxis \n\nGastrointestinal disorders Very \n\ncommon \n\nDiarrhoea, nausea, gingival bleeding, abdominal pain \n\nCommon Oral mucosal blistering, oral pain, vomiting, abdominal \n\ndiscomfort, constipation, abdominal distension, dysphagia, faeces \n\ndiscoloured, swollen tongue, gastrointestinal motility disorder, \n\nflatulence \n\nHepatobiliary disorders Very \n\ncommon \n\nTransaminases increased \n\nCommon Blood bilirubin increased (hyperbilirubinemia), jaundice \n\nNot known Drug-induced liver injury* \n\n* Cases of drug-induced liver injury have been reported in \n\npatients with ITP and HCV \n\nSkin and subcutaneous tissue \n\ndisorders \n\nCommon Petechiae, rash, pruritus, urticaria, skin lesion, rash macular \n\nNot known Skin discolouration, skin hyperpigmentation \n\nMusculosketal and connective \n\ntissue disorders \n\nVery \n\ncommon \n\nArthralgia, pain in extremity, muscle spasms \n\nCommon Back pain, myalgia, bone pain \n\nRenal and urinary disorders Common Chromaturia \n\nGeneral disorders and \n\nadministration site conditions \n\nVery \n\ncommon \n\nFatigue, pyrexia, chills \n\nCommon Asthenia, oedema peripheral, malaise \n\nInvestigations Common Blood creatine phosphokinase increased \n\n \n\nDescription of selected adverse reactions \n\n \n\nThrombotic/thromboembolic events (TEEs) \n\n \n\nIn 3 controlled and 2 uncontrolled clinical studies among adult ITP patients receiving eltrombopag \n\n(n=446), 17 patients experienced a total of 19 TEEs, which included (in descending order of \n\noccurrence) deep vein thrombosis (n=6), pulmonary embolism (n=6), acute myocardial infarction \n\n(n=2), cerebral infarction (n=2), embolism (n=1) (see section 4.4). \n\n \n\nIn a placebo-controlled study (n=288, Safety population), following 2 weeks’ treatment in preparation \n\nfor invasive procedures, 6 of 143 (4%) adult patients with chronic liver disease receiving eltrombopag \n\nexperienced 7 TEEs of the portal venous system and 2 of 145 (1%) patients in the placebo group \n\nexperienced 3 TEEs. Five of the 6 patients treated with eltrombopag experienced the TEE at a platelet \n\ncount >200,000/µl. \n\n \n\nNo specific risk factors were identified in those patients who experienced a TEE with the exception of \n\nplatelet counts ≥200,000/µl (see section 4.4). \n\n\n\n54 \n\n \n\nIn controlled studies in thrombocytopenic patients with HCV (n=1439), 38 out of 955 patients (4%) \n\ntreated with eltrombopag experienced a TEE and 6 out of 484 patients (1%) in the placebo group \n\nexperienced TEEs. Portal vein thrombosis was the most common TEE in both treatment groups (2% in \n\npatients treated with eltrombopag versus <1% for placebo) (see section 4.4). Patients with low albumin \n\nlevels (≤35 g/l) or MELD ≥10 had a 2-fold greater risk of TEEs than those with higher albumin levels; \n\nthose aged ≥60 years had a 2-fold greater risk of TEEs compared to younger patients. \n\n \n\nHepatic decompensation (use with interferon) \n\n \n\nChronic HCV patients with cirrhosis may be at risk of hepatic decompensation when receiving alfa \n\ninterferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV, hepatic \n\ndecompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial \n\nperitonitis) was reported more frequently in the eltrombopag arm (11%) than in the placebo arm (6%). \n\nIn patients with low albumin levels (≤35 g/l) or MELD score ≥10 at baseline, there was a 3-fold \n\ngreater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared to \n\nthose with less advanced liver disease. Eltrombopag should only be administered to such patients after \n\ncareful consideration of the expected benefits in comparison with the risks. Patients with these \n\ncharacteristics should be closely monitored for signs and symptoms of hepatic decompensation (see \n\nsection 4.4). \n\n \n\nHepatotoxixity \n\n \n\nIn the controlled clinical studies in chronic ITP with eltrombopag, increases in serum ALT, AST and \n\nbilirubin were observed (see section 4.4). \n\n \n\nThese findings were mostly mild (Grade 1-2), reversible and not accompanied by clinically significant \n\nsymptoms that would indicate an impaired liver function. Across the 3 placebo-controlled studies in \n\nadults with chronic ITP, 1 patient in the placebo group and 1 patient in the eltrombopag group \n\nexperienced a Grade 4 liver test abnormality. In two placebo-controlled studies in paediatric patients \n\n(aged 1 to 17 years) with chronic ITP, ALT 3 x ULN was reported in 4.7% and 0% of the \n\neltrombopag and placebo groups, respectively. \n\n \n\nIn 2 controlled clinical studies in patients with HCV, ALT or AST 3 x ULN was reported in 34% and \n\n38% of the eltrombopag and placebo groups, respectively. Most patients receiving eltrombopag in \n\ncombination with peginterferon / ribavirin therapy will experience indirect hyperbilirubinaemia. \n\nOverall, total bilirubin ≥1.5 x ULN was reported in 76% and 50% of the eltrombopag and placebo \n\ngroups, respectively. \n\n \n\nIn the single-arm phase II monotherapy refractory SAA study, concurrent ALT or AST >3 x ULN \n\nwith total (indirect) bilirubin >1.5 x ULN were reported in 5% of patients. Total bilirubin >1.5 x ULN \n\noccurred in 14% of patients. \n\n \n\nThrombocytopenia following discontinuation of treatment \n\n \n\nIn the 3 controlled clinical ITP studies, transient decreases in platelet counts to levels lower than \n\nbaseline were observed following discontinuation of treatment in 8% and 8% of the eltrombopag and \n\nplacebo groups, respectively (see section 4.4). \n\n \n\nIncreased bone marrow reticulin \n\n \n\nAcross the programme, no patients had evidence of clinically relevant bone marrow abnormalities or \n\nclinical findings that would indicate bone marrow dysfunction. In a small number of ITP patients, \n\neltrombopag treatment was discontinued due to bone marrow reticulin (see section 4.4). \n\n \n\n\n\n55 \n\nCytogenetic abnormalities \n\n \n\nIn the phase II refractory SAA clinical study with eltrombopag with a starting dose of 50 mg/day \n\n(escalated every 2 weeks to a maximum of 150 mg/day) (ELT112523), the incidence of new \n\ncytogenetic abnormalities was observed in 17.1% of adult patients [7/41 (where 4 of them had changes \n\nin chromosome 7)]. The median time on study to a cytogenetic abnormality was 2.9 months. \n\n \n\nIn the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic or \n\nage related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities \n\nwas observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All \n\n7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of \n\neltrombopag therapy and one patient had cytogenetic abnormality at Month 6. \n\n \n\nHaematologic malignancies \n\n \n\nIn the single-arm, open-label study in SAA, three (7%) patients were diagnosed with MDS following \n\ntreatment with eltrombopag, in the two ongoing studies (ELT116826 and ELT116643), 1/28 (4%) and \n\n1/62 (2%) patient has been diagnosed with MDS or AML in each study. \n\n \n\nReporting of suspected adverse reactions \n\n \n\nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \n\nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \n\nprofessionals are asked to report any suspected adverse reactions via the national reporting system \n\nlisted in Appendix V. \n\n \n\n4.9 Overdose \n \n\nIn the event of overdose, platelet counts may increase excessively and result in \n\nthrombotic/thromboembolic complications. In case of an overdose, consideration should be given to \n\noral administration of a metal cation-containing preparation, such as calcium, aluminium, or \n\nmagnesium preparations to chelate eltrombopag and thus limit absorption. Platelet counts should be \n\nclosely monitored. Treatment with eltrombopag should be reinitiated in accordance with dosing and \n\nadministration recommendations (see section 4.2). \n\n \n\nIn the clinical studies there was one report of overdose where the patient ingested 5000 mg of \n\neltrombopag. Reported adverse reactions included mild rash, transient bradycardia, ALT and AST \n\nelevation, and fatigue. Liver enzymes measured between Days 2 and 18 after ingestion peaked at a \n\n1.6-fold ULN in AST, a 3.9-fold ULN in ALT, and a 2.4-fold ULN in total bilirubin, The platelet \n\ncounts were 672,000/µl on Day 18 after ingestion and the maximum platelet count was 929,000/µl. All \n\nevents were resolved without sequelae following treatment. \n\n \n\nBecause eltrombopag is not significantly renally excreted and is highly bound to plasma proteins, \n\nhaemodialysis would not be expected to be an effective method to enhance the elimination of \n\neltrombopag. \n\n \n\n \n\n \n\n\n\n56 \n\n5. PHARMACOLOGICAL PROPERTIES \n \n\n5.1 Pharmacodynamic properties \n \n\nPharmacotherapeutic group: Antihemorrhagics, other systemic hemostatics. ATC code: B02BX 05. \n\n \n\nMechanism of action \n\n \n\nTPO is the main cytokine involved in regulation of megakaryopoiesis and platelet production, and is \n\nthe endogenous ligand for the TPO-R. Eltrombopag interacts with the transmembrane domain of the \n\nhuman TPO-R and initiates signalling cascades similar but not identical to that of endogenous \n\nthrombopoietin (TPO), inducing proliferation and differentiation from bone marrow progenitor cells. \n\n \n\nClinical efficacy and safety \n\n \n\nImmune (primary) thrombocytopenia (ITP) studies \n\n \n\nTwo phase III, randomised, double-blind, placebo-controlled studies RAISE (TRA102537) and \n\nTRA100773B and two open-label studies REPEAT (TRA108057) and EXTEND (TRA105325) \n\nevaluated the safety and efficacy of eltrombopag in adult patients with previously treated ITP. Overall, \n\neltrombopag was administered to 277 ITP patients for at least 6 months and 202 patients for at least \n\n1 year. \n\n \n\nDouble-blind placebo-controlled studies \n\nRAISE: 197 ITP patients were randomised 2:1, eltrombopag (n=135) to placebo (n=62), and \n\nrandomisation was stratified based upon splenectomy status, use of ITP medicinal products at baseline \n\nand baseline platelet count. The dose of eltrombopag was adjusted during the 6 month treatment \n\nperiod based on individual platelet counts. All patients initiated treatment with eltrombopag 50 mg. \n\nFrom Day 29 to the end of treatment, 15 to 28% of eltrombopag treated patients were maintained on \n\n≤25 mg and 29 to 53% received 75 mg. \n\n \n\nIn addition, patients could taper off concomitant ITP medicinal products and receive rescue treatments \n\nas dictated by local standard of care. More than half of all patients in each treatment group had ≥3 \n\nprior ITP therapies and 36% had a prior splenectomy. \n\n \n\nMedian platelet counts at baseline were 16,000/l for both treatment groups and in the eltrombopag \n\ngroup were maintained above 50,000/µl at all on-therapy visits starting at Day 15; in contrast, median \n\nplatelet counts in the placebo group remained <30,000/µl throughout the study. \n\n \n\nPlatelet count response between 50,000-400,000/l in the absence of rescue treatment was achieved by \n\nsignificantly more patients in the eltrombopag treated group during the 6 month treatment period, \n\np <0.001. Fifty-four percent of the eltrombopag-treated patients and 13% of placebo-treated patients \n\nachieved this level of response after 6 weeks of treatment. A similar platelet response was maintained \n\nthroughout the study, with 52% and 16% of patients responding at the end of the 6-month treatment \n\nperiod. \n\n \n\n\n\n57 \n\nTable 4 Secondary efficacy results from RAISE \n\n \n\n \n\nEltrombopag \n\nN=135 \n\nPlacebo \n\nN=62 \n\nKey secondary endpoints \n\nNumber of cumulative weeks with platelet counts \n\n50,000-400,000/µl, Mean (SD) \n11.3 (9.46) 2.4 (5.95) \n\nPatients with ≥75% of assessments in the target range (50,000 to \n\n400,000/l), n (%) \n\np-value a \n\n51 (38) 4 (7) \n\n<0.001 \n\nPatients with bleeding (WHO Grades 1-4) at any time during \n\n6 months, n (%) \n\n p-value a \n\n106 (79) 56 (93) \n\n0.012 \n\nPatients with bleeding (WHO Grades 2-4) at any time during \n\n6 months, n (%) \n\n p-value a \n\n44 (33) 32 (53) \n\n0.002 \n\nRequiring rescue therapy, n (%) \n\n p-value a \n\n24 (18) 25 (40) \n\n0.001 \n\nPatients receiving ITP therapy at baseline (n) 63 31 \n\nPatients who attempted to reduce or discontinue baseline \n\ntherapy, n (%)b \n\n p-value a \n\n37 (59) 10 (32) \n\n0.016 \n\na Logistic regression model adjusted for randomisation stratification variables \n\nb 21 out of 63 (33%) patients treated with eltrombopag who were taking an ITP medicinal product \n\nat baseline permanently discontinued all baseline ITP medicinal products. \n\n \n\nAt baseline, more than 70% of ITP patients in each treatment group reported any bleeding (WHO \n\nGrades 1-4) and more than 20% reported clinically significant bleeding (WHO Grades 2-4), \n\nrespectively. The proportion of eltrombopag-treated patients with any bleeding (Grades 1-4) and \n\nclinically significant bleeding (Grades 2-4) was reduced from baseline by approximately 50% from \n\nDay 15 to the end of treatment throughout the 6-month treatment period. \n\n \n\nTRA100773B: The primary efficacy endpoint was the proportion of responders, defined as ITP \n\npatients who had an increase in platelet counts to 50,000/l at Day 43 from a baseline of <30,000/l; \n\npatients who withdrew prematurely due to a platelet count 200,000/l were considered responders, \n\nthose that discontinued for any other reason were considered non-responders irrespective of platelet \n\ncount. A total of 114 patients with previously treated ITP were randomised 2:1 eltrombopag (n=76) to \n\nplacebo (n=38). \n\n \n\nTable 5 Efficacy results from TRA100773B \n\n \n\n \n\nEltrombopag \n\nN=74 \n\nPlacebo \n\nN=38 \n\nKey primary endpoints \n\nEligible for efficacy analysis, n 73 37 \n\nPatients with platelet count 50,000/l after up to 42 days \n\nof dosing (compared to a baseline count of <30,000/l), n \n\n(%) \n\n \n\np-valuea \n\n43 (59) 6 (16) \n\n<0.001 \n\nKey secondary endpoints \n\nPatients with a Day 43 bleeding assessment, n 51 30 \n\nBleeding (WHO Grades 1-4) n (%) \n\n \n\np-valuea \n\n20 (39) 18 (60) \n\n0.029 \n\na Logistic regression model adjusted for randomisation stratification variables \n\n\n\n58 \n\n \n\nIn both RAISE and TRA100773B the response to eltrombopag relative to placebo was similar \n\nirrespective of ITP medicinal product use, splenectomy status and baseline platelet count (≤15,000/µl, \n\n>15,000/µl) at randomisation. \n\n \n\nIn RAISE and TRA100773B studies, in the subgroup of ITP patients with baseline platelet count \n\n≤15,000/μl the median platelet counts did not reach the target level (>50,000/l), although in both \n\nstudies 43% of these patients treated with eltrombopag responded after 6 weeks of treatment. In \n\naddition, in the RAISE study, 42% of patients with baseline platelet count ≤15,000/μl treated with \n\neltrombopag responded at the end of the 6 month treatment period. Forty-two to 60% of the \n\neltrombopag-treated patients in the RAISE study were receiving 75 mg from Day 29 to the end of \n\ntreatment. \n\n \n\nAn open-label, repeat-dose study (3 cycles of 6 weeks of treatment, followed by 4 weeks off \n\ntreatment) showed that episodic use with multiple courses of eltrombopag has demonstrated no loss of \n\nresponse. \n\n \n\nEltrombopag was administered to 302 ITP patients in the open-label extension study EXTEND \n\n(TRA105325), 218 patients completed 1 year, 180 completed 2 years, 107 completed 3 years, 75 \n\ncompleted 4 years, 34 completed 5 years and 18 completed 6 years. The median baseline platelet count \n\nwas 19,000/l prior to eltrombopag administration. Median platelet counts at 1, 2, 3, 4, 5, 6 and \n\n7 years on study were 85,000/l, 85,000/l, 105,000/l, 64,000/l, 75,000/l, 119,000/l and \n\n76,000/l, respectively. \n\n \n\nClinical studies comparing eltrombopag to other treatment options (e.g. splenectomy) have not been \n\nconducted. The long-term safety of eltrombopag should be considered prior to starting therapy. \n\n \n\nPaediatric population (aged 1 to 17 years) \n\nThe safety and efficacy of eltrombopag in paediatric patients have been investigated two studies. \n\n \n\nTRA115450 (PETIT2): The primary endpoint was a sustained response, defined as the proportion of \n\npatients receiving eltrombopag, compared to placebo, achieving platelet counts ≥50,000/µl for at least \n\n6 out of 8 weeks (in the absence of rescue therapy), between weeks 5 to 12 during the double-blind \n\nrandomised period. Patients were diagnosed with chronic ITP for at least 1 year and were refractory or \n\nrelapsed to at least one prior ITP therapy or unable to continue other ITP treatments for a medical \n\nreason and had platelet count <30,000/µl. Ninety-two patients were randomised by three age cohort \n\nstrata (2:1) to eltrombopag (n=63) or placebo (n=29). The dose of eltrombopag could be adjusted \n\nbased on individual platelet counts. \n\n \n\nOverall, a significantly greater proportion of eltrombopag patients (40%) compared with placebo \n\npatients (3%) achieved the primary endpoint (Odds Ratio: 18.0 [95% CI: 2.3, 140.9] p <0.001) which \n\nwas similar across the three age cohorts (Table 6). \n\n \n\nTable 6 Sustained platelet response rates by age cohort in paediatric patients with chronic \n\nITP \n\n \n\n Eltrombopag \n\nn/N (%) \n\n[95% CI] \n\nPlacebo \n\nn/N (%) \n\n[95% CI] \n\nCohort 1 (12 to 17 years) \n\n \n\nCohort 2 (6 to 11 years) \n\n \n\nCohort 3 (1 to 5 years) \n\n9/23 (39%) \n\n[20%, 61%] \n\n11/26 (42%) \n\n[23%, 63%] \n\n5/14 (36%) \n\n[13%, 65%] \n\n1/10 (10%) \n\n[0%, 45%] \n\n0/13 (0%) \n\n[N/A] \n\n0/6 (0%) \n\n[N/A] \n\n \n\n\n\n59 \n\nStatistically fewer eltrombopag patients required rescue treatment during the randomised period \n\ncompared to placebo patients (19% [12/63] vs. 24% [7/29], p=0.032). \n\n \n\nAt baseline, 71% of patients in the eltrombopag group and 69% in the placebo group reported any \n\nbleeding (WHO Grades 1-4). At Week 12, the proportion of eltrombopag patients reporting any \n\nbleeding was decreased to half of baseline (36%). In comparison, at Week 12, 55% of placebo patients \n\nreported any bleeding. \n\n \n\nPatients were permitted to reduce or discontinue baseline ITP therapy only during the open-label phase \n\nof the study and 53% (8/15) of patients were able to reduce (n=1) or discontinue (n=7) baseline ITP \n\ntherapy, mainly corticosteroids, without needing rescue therapy. \n\n \n\nTRA108062 (PETIT): The primary endpoint was the proportion of patients achieving platelet counts \n\n≥50,000/µl at least once between weeks 1 and 6 of the randomised period. Patients were diagnosed \n\nwith ITP for at least 6 months and were refractory or relapsed to at least one prior ITP therapy with a \n\nplatelet count <30,000/µl (n=67). During the randomised period of the study, patients were \n\nrandomised by three age cohort strata (2:1) to eltrombopag (n=45) or placebo (n=22). The dose of \n\neltrombopag could be adjusted based on individual platelet counts. \n\n \n\nOverall, a significantly greater proportion of eltrombopag patients (62%) compared with placebo \n\npatients (32%) met the primary endpoint (Odds Ratio: 4.3 [95% CI: 1.4, 13.3] p=0.011). \n\n \n\nSustained response was seen in 50% of the initial responders during 20 out of 24 weeks in the \n\nPETIT 2 study and 15 out of 24 weeks in the PETIT Study. \n\n \n\nChronic hepatitis C associated thrombocytopenia studies \n\n \n\nThe efficacy and safety of eltrombopag for the treatment of thrombocytopenia in patients with HCV \n\ninfection were evaluated in two randomised, double-blind, placebo-controlled studies. ENABLE 1 \n\nutilised peginterferon alfa-2a plus ribavirin for antiviral treatment and ENABLE 2 utilised \n\npeginterferon alfa-2b plus ribavirin. Patients did not receive direct acting antiviral agents. In both \n\nstudies, patients with a platelet count of <75,000/µl were enrolled and stratified by platelet count \n\n(<50,000/µl and ≥50,000/µl to <75,000/µl), screening HCV RNA (<800,000 IU/ml and \n\n≥800,000 IU/ml), and HCV genotype (genotype 2/3, and genotype 1/4/6). \n\n \n\nBaseline disease characteristics were similar in both studies and were consistent with compensated \n\ncirrhotic HCV patient population. The majority of patients were HCV genotype 1 (64%) and had \n\nbridging fibrosis/cirrhosis. Thirty-one percent of patients had been treated with prior HCV therapies, \n\nprimarily pegylated interferon plus ribavirin. The median baseline platelet count was 59,500/µl in both \n\ntreatment groups: 0.8%, 28% and 72% of the patients recruited had platelet counts <20,000/µl, \n\n<50.000/µl and ≥50,000/µl respectively. \n\n \n\nThe studies consisted of two phases – a pre-antiviral treatment phase and an antiviral treatment phase. \n\nIn the pre-antiviral treatment phase, patients received open-label eltrombopag to increase the platelet \n\ncount to ≥90,000/µl for ENABLE 1 and ≥100,000/µl for ENABLE 2. The median time to achieve the \n\ntarget platelet count ≥90,000/µl (ENABLE 1) or ≥100,000/µl (ENABLE 2) was 2 weeks. \n\n \n\nThe primary efficacy endpoint for both studies was sustained virologic response (SVR), defined as the \n\npercentage of patients with no detectable HCV-RNA at 24 weeks after completion of the planned \n\ntreatment period. \n\n \n\nIn both HCV studies, a significantly greater proportion of patients treated with eltrombopag (n=201, \n\n21%) achieved SVR compared to those treated with placebo (n=65, 13%) (see Table 7). The \n\nimprovement in the proportion of patients who achieved SVR was consistent across all subgroups in \n\nthe randomisation strata (baseline platelet counts (<50,000 vs. >50,000), viral load (<800,000 IU/ml \n\nvs. ≥800,000 IU/ml) and genotype (2/3 vs. 1/4/6)). \n\n \n\n\n\n60 \n\nTable 7 Virologic response in HCV patients in ENABLE 1 and ENABLE 2 \n\n \n\n Pooled data ENABLE 1a ENABLE 2b \n\nPatients achieving \n\ntarget platelet counts \n\nand initiating antiviral \n\ntherapy c \n\n \n\n1,439/1,520 (95%) \n\n \n\n680/715 (95%) \n\n \n\n759/805 (94%) \n\n Eltrombopag Placebo Eltrombopag Placebo Eltrombopag Placebo \n\nTotal number of \n\npatients entering \n\nantiviral treatment \n\nphase \n\nn=956 n=485 n=450 n=232 n=506 n=253 \n\n % patients achieving virologic response \n\nOverall SVR d 21 13 23 14 19 13 \n\nHCV RNA Genotype \n\nGenotype 2/3 35 25 35 24 34 25 \n\nGenotype 1/4/6e 15 8 18 10 13 7 \n\nAlbumin levels f \n\n≤35g/l 11 8 \n\n>35g/l 25 16 \n\nMELD scoref \n\n≥10 18 10 \n\n<10 23 17 \n\na Eltrombopag given in combination with peginterferon alfa-2a (180 μg once weekly for \n\n48 weeks for genotypes 1/4/6; 24 weeks for genotype 2/3) plus ribavirin (800 to 1200 mg daily \n\nin 2 divided doses orally) \n\nb Eltrombopag given in combination with peginterferon alfa-2b (1.5 μg/kg once weekly for \n\n48 weeks for genotype 1/4/6; 24 weeks for genotype 2/3) plus ribavirin (800 to 1400 mg orally \n\nin 2 divided doses) \n\nc Target platelet count was 90,000/µl for ENABLE 1 and 100,000/µl for ENABLE 2. For \n\nENABLE 1, 682 patients were randomised to the antiviral treatment phase; however 2 patients \n\nthen withdrew consent prior to receiving antiviral therapy. \n\nd p-value <0.05 for eltrombopag versus placebo \n\ne 64% patients participating in ENABLE 1 and ENABLE 2 were genotype 1 \n\nf Post-hoc analyses \n\n \n\nOther secondary findings of the studies included the following: significantly fewer patients treated \n\nwith eltrombopag prematurely discontinued antiviral therapy compared to placebo (45% vs. 60%, \n\np=<0.0001). A greater proportion of patients on eltrombopag did not require any antiviral dose \n\nreduction as compared to placebo (45% vs. 27%). Eltrombopag treatment delayed and reduced the \n\nnumber of peginterferon dose reductions. \n\n \n\nSevere aplastic anaemia \n\n \n\nEltrombopag was studied in a single-arm, single-centre open-label study in 43 patients with severe \n\naplastic anaemia with refractory thrombocytopenia following at least one prior immunosuppressive \n\ntherapy (IST) and who had a platelet count ≤30,000/µl. \n\n \n\nThe majority of patients, 33 (77%), were considered to have ‘primary refractory disease’, defined as \n\nhaving no prior adequate response to IST in any lineage. The remaining 10 patients had insufficient \n\nplatelet response to prior therapies. All 10 had received at least 2 prior IST regimens and 50% had \n\nreceived at least 3 prior IST regimens. Patients with diagnosis of Fanconi anaemia, infection not \n\nresponding to appropriate therapy, PNH clone size in neutrophils of ≥50%, where excluded from \n\nparticipation. \n\n \n\n \n\n\n\n61 \n\nAt baseline the median platelet count was 20,000/µl, haemoglobin was 8.4 g/dl, ANC was 0.58 x 109/l \n\nand absolute reticulocyte count was 24.3 x109/l. Eighty-six percent of patients were RBC transfusion \n\ndependent, and 91% were platelet transfusion dependent. The majority of patients (84%) had received \n\nat least 2 prior immunosuppressive therapies. Three patients had cytogenetic abnormalities at baseline. \n\n \n\nThe primary endpoint was haematological response assessed after 12 weeks of eltrombopag treatment. \n\nHaematological response was defined as meeting one or more of the following criteria: 1) platelet \n\ncount increases to 20,000/µl above baseline or stable platelet counts with transfusion independence for \n\na minimum of 8 weeks; 2) haemoglobin increase by >1.5g/dl, or a reduction in ≥4 units of red blood \n\ncell (RBC) transfusions for 8 consecutive weeks; 3) absolute neutrophil count (ANC) increase of \n\n100% or an ANC increase >0.5 x 109/l. \n\n \n\nThe haematological response rate was 40% (17/43 patients; 95 % CI 25, 56), the majority were \n\nunilineage responses (13/17, 76%) whilst there were 3 bilineage and 1 trilineage responses at week 12. \n\nEltrombopag was discontinued after 16 weeks if no haematological response or transfusion \n\nindependence was observed. Patients who responded continued therapy in an extension phase of the \n\nstudy. A total of 14 patients entered the extension phase of the trial. Nine of these patients achieved a \n\nmulti-lineage response, 4 of the 9 remain on treatment and 5 tapered off treatment with eltrombopag \n\nand maintained the response (median follow up: 20.6 months, range: 5.7 to 22.5 months). The \n\nremaining 5 patients discontinued treatment, three due to relapse at the month 3 extension visit. \n\n \n\nDuring treatment with eltrombopag 59% (23/39) became platelet transfusion independent (28 days \n\nwithout platelet transfusion) and 27% (10/37) became RBC transfusion independent (56 days without \n\nRBC transfusion). The longest platelet transfusion-free period for non-responders was 27 days \n\n(median). The longest platelet transfusion-free period for responders was 287 days (median). The \n\nlongest RBC transfusion-free period for non-responders was 29 days (median). The longest RBC \n\ntransfusion-free period for responders was 266 days (median). \n\n \n\nOver 50% of responders who were transfusion-dependent at baseline, had >80% reduction in both \n\nplatelet and RBC transfusion requirements compared to baseline. \n\n \n\nPreliminary results from a supportive study (Study ELT116826), an ongoing non-randomised, \n\nphase II, single-arm, open-label study in refractory SAA patients, showed consistent results. Data are \n\nlimited to 21 out of the planned 60 patients with haematological responses reported by 52% of patients \n\nat 6 months. Multilineage responses were reported by 45% of patients. \n\n \n\n5.2 Pharmacokinetic properties \n \n\nPharmacokinetics \n\n \n\nThe plasma eltrombopag concentration-time data collected in 88 patients with ITP in studies \n\nTRA100773A and TRA100773B were combined with data from 111 healthy adult subjects in a \n\npopulation PK analysis. Plasma eltrombopag AUC(0-) and Cmax estimates for ITP patients are \n\npresented (Table 8). \n\n \n\nTable 8 Geometric mean (95% confidence intervals) of steady-state plasma eltrombopag \n\npharmacokinetic parameters in adults with ITP \n\n \n\nEltrombopag dose, once \n\ndaily \n\nN AUC(0-)a, g.h/ml Cmaxa, g/ml \n\n30 mg 28 47 (39, 58) 3.78 (3.18, 4.49) \n\n50 mg 34 108 (88, 134) 8.01 (6.73, 9.53) \n\n75 mg 26 168 (143, 198) 12.7 (11.0, 14.5) \n\na AUC(0-) and Cmax based on population PK post-hoc estimates. \n\n \n\n \n\n\n\n62 \n\nPlasma eltrombopag concentration-time data collected in 590 patients with HCV enrolled in phase III \n\nstudies TPL103922/ENABLE 1 and TPL108390/ENABLE 2 were combined with data from patients \n\nwith HCV enrolled in the phase II study TPL102357 and healthy adult subjects in a population PK \n\nanalysis. Plasma eltrombopag Cmax and AUC(0-) estimates for patients with HCV enrolled in the \n\nphase III studies are presented for each dose studied in Table 9. \n\n \n\nTable 9 Geometric mean (95% CI) steady-state plasma eltrombopag pharmacokinetic \n\nparameters in patients with chronic HCV \n\n \n\nEltrombopag dose \n\n(once daily) \n\nN AUC(0-) \n\n(g.h/ml) \n\nCmax \n\n(g/ml) \n\n25 mg 330 118 \n\n(109, 128) \n\n6.40 \n\n(5.97, 6.86) \n\n50 mg 119 166 \n\n(143, 192) \n\n9.08 \n\n(7.96, 10.35) \n\n75 mg 45 301 \n\n(250, 363) \n\n16.71 \n\n(14.26, 19.58) \n\n100 mg 96 354 \n\n(304, 411) \n\n19.19 \n\n(16.81, 21.91) \n\nData presented as geometric mean (95% CI). \n\nAUC (0-) and Cmax based on population PK post-hoc estimates at the highest dose in the data for each \n\npatient. \n\n \n\nAbsorption and bioavailability \n\n \n\nEltrombopag is absorbed with a peak concentration occurring 2 to 6 hours after oral administration. \n\nAdministration of eltrombopag concomitantly with antacids and other products containing polyvalent \n\ncations such as dairy products and mineral supplements significantly reduces eltrombopag exposure \n\n(see section 4.2). In a relative bioavailability study in adults, the eltrombopag powder for oral \n\nsuspension delivered 22% higher plasma AUC(0-) than the film-coated tablet formulation. The \n\nabsolute oral bioavailability of eltrombopag after administration to humans has not been established. \n\nBased on urinary excretion and metabolites eliminated in faeces, the oral absorption of drug-related \n\nmaterial following administration of a single 75 mg eltrombopag solution dose was estimated to be at \n\nleast 52%. \n\n \n\nDistribution \n\n \n\nEltrombopag is highly bound to human plasma proteins (>99.9%), predominantly to albumin. \n\nEltrombopag is a substrate for BCRP, but is not a substrate for P-glycoprotein or OATP1B1. \n\n \n\nBiotransformation \n\n \n\nEltrombopag is primarily metabolised through cleavage, oxidation and conjugation with glucuronic \n\nacid, glutathione, or cysteine. In a human radiolabel study, eltrombopag accounted for approximately \n\n64% of plasma radiocarbon AUC0-. Minor metabolites due to glucuronidation and oxidation were \n\nalso detected. In vitro studies suggest that CYP1A2 and CYP2C8 are responsible for oxidative \n\nmetabolism of eltrombopag. Uridine diphosphoglucuronyl transferase UGT1A1 and UGT1A3 are \n\nresponsible for glucuronidation, and bacteria in the lower gastrointestinal tract may be responsible for \n\nthe cleavage pathway. \n\n \n\n \n\n\n\n63 \n\nElimination \n\n \n\nAbsorbed eltrombopag is extensively metabolised. The predominant route of eltrombopag excretion is \n\nvia faeces (59%) with 31% of the dose found in the urine as metabolites. Unchanged parent compound \n\n(eltrombopag) is not detected in urine. Unchanged eltrombopag excreted in faeces accounts for \n\napproximately 20% of the dose. The plasma elimination half-life of eltrombopag is approximately \n\n21-32 hours. \n\n \n\nPharmacokinetic interactions \n\n \n\nBased on a human study with radiolabelled eltrombopag, glucuronidation plays a minor role in the \n\nmetabolism of eltrombopag. Human liver microsome studies identified UGT1A1 and UGT1A3 as the \n\nenzymes responsible for eltrombopag glucuronidation. Eltrombopag was an inhibitor of a number of \n\nUGT enzymes in vitro. Clinically significant drug interactions involving glucuronidation are not \n\nanticipated due to limited contribution of individual UGT enzymes in the glucuronidation of \n\neltrombopag. \n\n \n\nApproximately 21% of an eltrombopag dose could undergo oxidative metabolism. Human liver \n\nmicrosome studies identified CYP1A2 and CYP2C8 as the enzymes responsible for eltrombopag \n\noxidation. Eltrombopag does not inhibit or induce CYP enzymes based on in vitro and in vivo data \n\n(see section 4.5). \n\n \n\nIn vitro studies demonstrate that eltrombopag is an inhibitor of the OATP1B1 transporter and an \n\ninhibitor of the BCRP transporter and eltrombopag increased exposure of the OATP1B1 and BCRP \n\nsubstrate rosuvastatin in a clinical drug interaction study (see section 4.5). In clinical studies with \n\neltrombopag, a dose reduction of statins by 50% was recommended. \n\n \n\nEltrombopag chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium \n\nand zinc (see sections 4.2 and 4.5). \n\n \n\nIn vitro studies demonstrated that eltrombopag is not a substrate for the organic anion transporter \n\npolypeptide, OATP1B1, but is an inhibitor of this transporter (IC50 value of 2.7 μM (1.2 μg/ml). In \n\nvitro studies also demonstrated that eltrombopag is a breast cancer resistance protein (BCRP) substrate \n\nand inhibitor (IC50 value of 2.7 μM (1.2 μg/ml). \n\n \n\nSpecial patient populations \n\n \n\nRenal impairment \n\n \n\nThe pharmacokinetics of eltrombopag have been studied after administration of eltrombopag to adult \n\npatients with renal impairment. Following administration of a single 50 mg dose, the AUC0- of \n\neltrombopag was 32% to 36% lower in patients with mild to moderate renal impairment, and 60% \n\nlower in patients with severe renal impairment compared with healthy volunteers. There was \n\nsubstantial variability and significant overlap in exposures between patients with renal impairment and \n\nhealthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein-bound \n\nmedicinal product were not measured. Patients with impaired renal function should use eltrombopag \n\nwith caution and close monitoring, for example by testing serum creatinine and/or urine analysis (see \n\nsection 4.2). The efficacy and safety of eltrombopag have not been established in patients with both \n\nmoderate to severe renal impairment and hepatic impairment. \n\n \n\n \n\n\n\n64 \n\nHepatic impairment \n\n \n\nThe pharmacokinetics of eltrombopag have been studied after administration of eltrombopag to adult \n\npatients with hepatic impairment. Following the administration of a single 50 mg dose, the AUC0- of \n\neltrombopag was 41% higher in patients with mild hepatic impairment and 80% to 93% higher in \n\npatients with moderate to severe hepatic impairment compared with healthy volunteers. There was \n\nsubstantial variability and significant overlap in exposures between patients with hepatic impairment \n\nand healthy volunteers. Unbound eltrombopag (active) concentrations for this highly protein-bound \n\nmedicinal product were not measured. \n\n \n\nThe influence of hepatic impairment on the pharmacokinetics of eltrombopag following repeat \n\nadministration was evaluated using a population pharmacokinetic analysis in 28 healthy adults and \n\n714 patients with hepatic impairment (673 patients with HCV and 41 patients with chronic liver \n\ndisease of other aetiology). Of the 714 patients, 642 were with mild hepatic impairment, 67 with \n\nmoderate hepatic impairment, and 2 with severe hepatic impairment. Compared to healthy volunteers, \n\npatients with mild hepatic impairment had approximately 111% (95% CI: 45% to 283%) higher \n\nplasma eltrombopag AUC(0-) values and patients with moderate hepatic impairment had \n\napproximately 183% (95% CI: 90% to 459%) higher plasma eltrombopag AUC(0-) values. \n\n \n\nTherefore, eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score \n\n≥5) unless the expected benefit outweighs the identified risk of portal venous thrombosis (see \n\nsections 4.2 and 4.4). For patients with HCV initiate eltrombopag at a dose of 25 mg once daily (see \n\nsection 4.2). \n\n \n\nRace \n\n \n\nThe influence of Asian ethnicity (such as Japanese, Chinese, Taiwanese and Korean) on the \n\npharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in 111 \n\nhealthy adults (31 Asians) and 88 patients with ITP (18 Asians). Based on estimates from the \n\npopulation pharmacokinetic analysis, Asian ITP patients had approximately 49% higher plasma \n\neltrombopag AUC(0-) values as compared to non-Asian patients who were predominantly Caucasian \n\n(see section 4.2). \n\n \n\nThe influence of Asian ethnicity (such as Chinese, Japanese, Taiwanese, Korean, and Thai) on the \n\npharmacokinetics of eltrombopag was evaluated using a population pharmacokinetic analysis in \n\n635 patients with HCV (145 Asians and 69 South Asians). Based on estimates from the population \n\npharmacokinetic analysis, Asian patients had approximately 55% higher plasma eltrombopag AUC(0-) \n\nvalues as compared to patients of other races who were predominantly Caucasian (see section 4.2). \n\n \n\nGender \n\n \n\nThe influence of gender on the pharmacokinetics of eltrombopag was evaluated using a population \n\npharmacokinetic analysis in 111 healthy adults (14 females) and 88 patients with ITP (57 females). \n\nBased on estimates from the population pharmacokinetic analysis, female ITP patients had \n\napproximately 23% higher plasma eltrombopag AUC(0-) as compared to male patients, without \n\nadjustment for body weight differences. \n\n \n\nThe influence of gender on eltrombopag pharmacokinetics was evaluated using population \n\npharmacokinetics analysis in 635 patients with HCV (260 females). Based on model estimate, female \n\nHCV patient had approximately 41% higher plasma eltrombopag AUC(0-) as compared to male \n\npatients. \n\n \n\n \n\n\n\n65 \n\nAge \n\n \n\nThe influence of age on eltrombopag pharmacokinetics was evaluated using population \n\npharmacokinetics analysis in 28 healthy subjects, 673 patients with HCV, and 41 patients with chronic \n\nliver disease of other aetiology ranging from 19 to 74 years old. There are no PK data on the use of \n\neltrombopag in patients ≥75 years. Based on model estimate, elderly (≥65 years) patients had \n\napproximately 41% higher plasma eltrombopag AUC(0-) as compared to younger patients (see \n\nsection 4.2). \n\n \n\nPaediatric Population (aged 1 to 17 years) \n\n \n\nThe pharmacokinetics of eltrombopag have been evaluated in 168 paediatric ITP patients dosed once \n\ndaily in two studies, TRA108062/PETIT and TRA115450/PETIT-2. Plasma eltrombopag apparent \n\nclearance following oral administration (CL/F) increased with increasing body weight. The effects of \n\nrace and sex on plasma eltrombopag CL/F estimates were consistent between paediatric and adult \n\npatients. Asian paediatric ITP patients had approximately 43% higher plasma eltrombopag AUC(0-) \n\nvalues as compared to non-Asian patients. Female paediatric ITP patients had approximately 25% \n\nhigher plasma eltrombopag AUC(0-) values as compared to male patients. \n\n \n\nThe pharmacokinetic parameters of eltrombopag in paediatric patients with ITP are shown in \n\nTable 10. \n\n \n\nTable 10 Geometric mean (95% CI) steady-state plasma eltrombopag pharmacokinetic \n\nparameters in paediatric patients with ITP (50 mg once daily dosing regimen) \n\n \n\nAge Cmax \n(µg/ml) \n\nAUC(0-) \n(µg.hr/ml) \n\n12 to 17 years (n=62) 6.80 \n\n(6.17, 7.50) \n\n103 \n\n(91.1, 116) \n\n6 to 11 years (n=68) 10.3 \n\n(9.42, 11.2) \n\n153 \n\n(137, 170) \n\n1 to 5 years (n=38) 11.6 \n\n(10.4, 12.9) \n\n162 \n\n(139, 187) \n\nData presented as geometric mean (95% CI). AUC(0-) and Cmax based on population PK post-hoc \n\nestimates \n\n \n\n5.3 Preclinical safety data \n \n\nSafety pharmacology and repeat-dose toxicity \n\n \n\nEltrombopag does not stimulate platelet production in mice, rats or dogs because of unique TPO \n\nreceptor specificity. Therefore, data from these animals do not fully model potential adverse effects \n\nrelated to the pharmacology of eltrombopag in humans, including the reproduction and carcinogenicity \n\nstudies. \n\n \n\nTreatment-related cataracts were detected in rodents and were dose and time-dependent. At ≥6 times \n\nthe human clinical exposure in adult ITP patients at 75 mg/day and 3 times the human clinical \n\nexposure in adult HCV patients at 100 mg/day, based on AUC, cataracts were observed in mice after \n\n6 weeks and rats after 28 weeks of dosing. At 4 times the human clinical exposure in ITP patients at \n\n75 mg/day and 2 times the human exposure in HCV patients at 100 mg/day, based on AUC, cataracts \n\nwere observed in mice after 13 weeks and in rats after 39 weeks of dosing. At non-tolerated doses in \n\npre-weaning juvenile rats dosed from days 4-32 (approximately equating to a 2-year-old human at the \n\nend of the dosing period), ocular opacities were observed (histology not performed) at 9 times the \n\nmaximum human clinical exposure in paediatric ITP patients at 75 mg/day, based on AUC. However, \n\ncataracts were not observed in juvenile rats given tolerated doses at 5 times the human clinical \n\nexposure in paediatric ITP patients, based on AUC. Cataracts have not been observed in adult dogs \n\nafter 52 weeks of dosing at 2 times the human clinical exposure in adult or paediatric ITP patients at \n\n\n\n66 \n\n75 mg/day and equivalent to the human clinical exposure in HCV patients at 100 mg/day, based on \n\nAUC). \n\n \n\nRenal tubular toxicity was observed in studies of up to 14 days duration in mice and rats at exposures \n\nthat were generally associated with morbidity and mortality. Tubular toxicity was also observed in a \n\n2-year oral carcinogenicity study in mice at doses of 25, 75 and 150 mg/kg/day. Effects were less \n\nsevere at lower doses and were characterised by a spectrum of regenerative changes. The exposure at \n\nthe lowest dose was 1.2 or 0.8 times the human clinical exposure based on AUC in adult or paediatric \n\nITP patients at 75 mg/day and 0.6 times the human clinical exposure in HCV patients at 100 mg/day, \n\nbased on AUC. Renal effects were not observed in rats after 28 weeks or in dogs after 52 weeks at \n\nexposures 4 and 2 times the human clinical exposure in adult ITP patients and 3 and 2 times the \n\nhuman clinical exposure in paediatric ITP patients at 75 mg/day and 2 times and equivalent to the \n\nhuman clinical exposure in HCV patients at 100 mg/day, based on AUC. \n\n \n\nHepatocyte degeneration and/or necrosis, often accompanied by increased serum liver enzymes, was \n\nobserved in mice, rats and dogs at doses that were associated with morbidity and mortality or were \n\npoorly tolerated. No hepatic effects were observed after chronic dosing in rats (28 weeks) and in dogs \n\n(52 weeks) at 4 or 2 times the human clinical exposure in adult ITP and 3 or 2 times the human \n\nclinical exposure in paediatric ITP patients at 75 mg/day and 2 times and equivalent to the human \n\nclinical exposure in HCV patients at 100 mg/day, based on AUC. \n\n \n\nAt poorly tolerated doses in rats and dogs (>10 or 7 times the human clinical exposure in adult or \n\npaediatric ITP patients at 75 mg/day and>4 times the human clinical exposure in HCV patients at \n\n100 mg/day, based on AUC), decreased reticulocyte counts and regenerative bone marrow erythroid \n\nhyperplasia (rats only) were observed in short-term studies. There were no effects of note on red cell \n\nmass or reticulocyte counts after dosing for up to 28 weeks in rats, 52 weeks in dogs and 2 years in \n\nmice or rats at maximally tolerated doses which were 2 to 4 times human clinical exposure in adult or \n\npaediatric ITP patients at 75 mg/day and ≤2 times the human clinical exposure in HCV patients at \n\n100 mg/day, based on AUC. \n\n \n\nEndosteal hyperostosis was observed in a 28-week toxicity study in rats at a non-tolerated dose of \n\n60 mg/kg/day (6 times or 4 times the human clinical exposure in adult or paediatric ITP patients at \n\n75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). \n\nThere were no bone changes observed in mice or rats after lifetime exposure (2 years) at 4 times or \n\n2 times the human clinical exposure in adult or paediatric ITP patients at 75 mg/day and 2 times the \n\nhuman clinical exposure in HCV patients at 100 mg/day, based on AUC. \n\n \n\nCarcinogenicity and mutagenicity \n\n \n\nEltrombopag was not carcinogenic in mice at doses up to 75 mg/kg/day or in rats at doses up to \n\n40 mg/kg/day (exposures up to 4 or 2 times the human clinical exposure in adult or paediatric ITP \n\npatients at 75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, based \n\non AUC). Eltrombopag was not mutagenic or clastogenic in a bacterial mutation assay or in two in \n\nvivo assays in rats (micronucleus and unscheduled DNA synthesis, 10 times or 8 times the human \n\nclinical exposure in adult or paediatric ITP patients at 75 mg/day and 7 times the human clinical \n\nexposure in HCV patients at 100 mg/day, based on Cmax). In the in vitro mouse lymphoma assay, \n\neltrombopag was marginally positive (<3-fold increase in mutation frequency). These in vitro and in \n\nvivo findings suggest that eltrombopag does not pose a genotoxic risk to humans. \n\n \n\n \n\n\n\n67 \n\nReproductive toxicity \n\n \n\nEltrombopag did not affect female fertility, early embryonic development or embryofoetal \n\ndevelopment in rats at doses up to 20 mg/kg/day (2 times the human clinical exposure in adult or \n\nadolescent (12-17 years) ITP patients at 75 mg/day and equivalent to the human clinical exposure in \n\nHCV patients at 100 mg/day, based on AUC). Also there was no effect on embryofoetal development \n\nin rabbits at doses up to 150 mg/kg/day, the highest dose tested (0.3 to 0.5 times the human clinical \n\nexposure in ITP patients at 75 mg/day and HCV patients at 100 mg/day, based on AUC). However, at \n\na maternally toxic dose of 60 mg/kg/day (6 times the human clinical exposure in ITP patients at \n\n75 mg/day and 3 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC) in \n\nrats, eltrombopag treatment was associated with embryo lethality (increased pre- and post-\n\nimplantation loss), reduced foetal body weight and gravid uterine weight in the female fertility study \n\nand a low incidence of cervical ribs and reduced foetal body weight in the embryofoetal development \n\nstudy. Eltrombopag should be used during pregnancy only if the expected benefit justifies the potential \n\nrisk to the foetus (see section 4.6). Eltrombopag did not affect male fertility in rats at doses up to \n\n40 mg/kg/day, the highest dose tested (3 times the human clinical exposure in ITP patients at \n\n75 mg/day and 2 times the human clinical exposure in HCV patients at 100 mg/day, based on AUC). \n\nIn the pre- and post-natal development study in rats, there were no undesirable effects on pregnancy, \n\nparturition or lactation of F0 female rats at maternally non-toxic doses (10 and 20 mg/kg/day) and no \n\neffects on the growth, development, neurobehavioural or reproductive function of the offspring (F1). \n\nEltrombopag was detected in the plasma of all F1 rat pups for the entire 22 hour sampling period \n\nfollowing administration of medicinal product to the F0 dams, suggesting that rat pup exposure to \n\neltrombopag was likely via lactation. \n\n \n\nPhototoxicity \n\n \n\nIn vitro studies with eltrombopag suggest a potential phototoxicity risk; however, in rodents there was \n\nno evidence of cutaneous phototoxicity (10 or 7 times the human clinical exposure in adult or \n\npaediatric ITP patients at 75 mg/day and 5 times the human clinical exposure in HCV patients at \n\n100 mg/day, based on AUC) or ocular phototoxicity (4 times the human clinical exposure in adult or \n\npaediatric ITP patients at 75 mg/day and 3 times the human clinical exposure in HCV patients at \n\n100 mg/day, based on AUC). Furthermore, a clinical pharmacology study in 36 subjects showed no \n\nevidence that photosensitivity was increased following administration of eltrombopag 75 mg. This was \n\nmeasured by delayed phototoxic index. Nevertheless, a potential risk of photoallergy cannot be ruled \n\nout since no specific preclinical study could be performed. \n\n \n\nJuvenile animal studies \n\n \n\nAt non-tolerated doses in pre-weaning rats, ocular opacities were observed. At tolerated doses, no \n\nocular opacities were observed (see above subsection ‘Safety pharmacology and repeat-dose toxicity’). \n\nIn conclusion, taking into account the exposure margins based on AUC, a risk of eltrombopag-related \n\ncataracts in paediatric patients cannot be excluded. There are no findings in juvenile rats to suggest a \n\ngreater risk of toxicity with eltrombopag treatment in paediatric vs. adult ITP patients. \n\n \n\n \n\n6. PHARMACEUTICAL PARTICULARS \n\n \n\n6.1 List of excipients \n\n \n\nMannitol (E421) \n\nSucralose \n\nXanthan gum \n\n \n\n6.2 Incompatibilities \n \n\nNot applicable. \n\n \n\n\n\n68 \n\n6.3 Shelf life \n \n\n2 years. \n\n \n\nFollowing reconstitution, the medicinal product should be administered immediately but may be \n\nstored for a maximum period of 30 minutes. \n\n \n\n6.4 Special precautions for storage \n \n\nThis medicinal product does not require any special storage conditions. \n\n \n\nFor storage conditions after reconstitution of the medicinal product, see section 6.3. \n\n \n\n6.5 Nature and contents of container \n\n \n\nHeat-sealed foil laminate sachets. The laminate material is comprised of polyester (PET) / orientated \n\npolyamide (OPA) / 9 µm aluminium foil (AL) / low density polyethylene heat seal layer (LDPE). The \n\nproduct contact material is the polyethylene heat seal layer. The sachets are co-packaged in a kit with a \n\n40 ml HDPE mixing bottle, and 30 single-use 20 ml oral dosing syringes (polypropylene/silicon \n\nrubber) with 1 ml graduations. In addition, a screw cap (ethylene vinyl acetate / LDPE) with syringe-\n\nport capability is provided. \n\n \n\nPack size of 30 sachets. \n\n \n\n6.6 Special precautions for disposal \n \n\nInstructions for use \n\n \n\nAvoid direct contact with the medicine. Wash any exposed area immediately with soap and water. \n\n \n\nPreparation and administration of the powder for oral suspension: \n\n Administer the oral suspension immediately after preparation. Discard suspension if not \nadministered within 30 minutes after preparation. \n\n Prepare the suspension with water only. \n\n Add 20 ml of water and the contents of the prescribed number of sachets (depending on the \nrecommended dose) to the provided mixing bottle and mix gently. \n\n Give the entire contents of the bottle to the patient using one of the accompanying oral syringes. \n\n IMPORTANT: Because some medicine will remain in the mixing bottle, complete the \nfollowing steps. \n\n Add 10 ml of water to the mixing bottle and mix gently. \n\n Give the entire contents of the bottle to the patient using the same oral syringe. \n \n\nCleaning of the mixing equipment: \n\n Discard the used oral syringe. \n\n Rinse the mixing bottle and lid, under running water. (The mixing bottle may become stained \nfrom the medicine. This is normal.) \n\n Let all the equipment dry in the air. \n\n Wash your hands with soap and water. \n \n\nDo not re-use the oral dosing syringe. A new single-use oral dosing syringe should be used to prepare \n\neach dose of Revolade for oral suspension. \n\n \n\nFor more details on preparation and administration of the suspension, see Instructions for Use in the \n\npackage leaflet. \n\n \n\n\n\n69 \n\nDisposal \n\nAny unused medicinal product or waste material should be disposed of in accordance with local \n\nrequirements. \n\n \n\n \n\n7. MARKETING AUTHORISATION HOLDER \n \n\nNovartis Europharm Limited \n\nVista Building \n\nElm Park, Merrion Road \n\nDublin 4 \n\nIreland \n\n \n\n \n\n8. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/10/612/013 \n\n \n\n \n\n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n \n\nDate of first authorisation: 11 March 2010 \n\nDate of latest renewal: 15 January 2015 \n\n \n\n \n\n10. DATE OF REVISION OF THE TEXT \n\n \n\n \n\nDetailed information on this medicinal product is available on the website of the European Medicines \n\nAgency http://www.ema.europa.eu/. \n \n\n\n\n70 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX II \n \n\nA. MANUFACTURERS RESPONSIBLE FOR BATCH \n\nRELEASE \n\n \n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY \n\nAND USE \n\n \n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE \n\nMARKETING AUTHORISATION \n\n \n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO \n\nTHE SAFE AND EFFECTIVE USE OF THE MEDICINAL \n\nPRODUCT \n\n \n\n\n\n71 \n\nA. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE \n\n \n\nName and address of the manufacturers responsible for batch release \n\n \n\nRevolade 12.5 mg, 25 mg, 50 mg and 75 mg film-coated tablets: \n\n \n\nNovartis Farmacéutica SA \n\nRonda de Santa Maria 158 \n\n08210 Barberà del Vallès (Barcelona) \n\nSpain \n\n \n\nNovartis Pharma GmbH \n\nRoonstraße 25 \n\nD-90429 Nuremberg \n\nGermany \n\n \n\nGlaxo Wellcome S.A. \n\nAvenida de Extremadura 3 \n\n09400 Aranda de Duero \n\nBurgos \n\nSpain \n\n \n\nRevolade 25 mg powder for oral suspension: \n\n \n\nLek d.d \n\nVerovskova Ulica 57 \n\nLjubljana 1526 \n\nSlovenia \n\n \n\nNovartis Pharma GmbH \n\nRoonstraße 25 \n\nD-90429 Nuremberg \n\nGermany \n\n \n\nThe printed package leaflet of the medicinal product must state the name and address of the \n\nmanufacturer responsible for the release of the concerned batch. \n\n \n\n \n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n\n \n\nMedicinal product subject to restricted medical prescription. (see Annex I: Summary of Product \n\nCharacteristics, section 4.2). \n\n \n\n \n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n \n\n Periodic Safety Update Reports \n \n\nThe requirements for submission of periodic safety update reports for this medicinal product are set \n\nout in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive \n\n2001/83/EC and any subsequent updates published on the European medicines web-portal. \n\n \n\n \n\n\n\n72 \n\n \n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n\n \n\n Risk Management Plan (RMP) \n \n\nThe MAH shall perform the required pharmacovigilance activities and interventions detailed in \n\nthe agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed \n\nsubsequent updates of the RMP. \n\n \n\nAn updated RMP should be submitted: \n\n At the request of the European Medicines Agency; \n\n Whenever the risk management system is modified, especially as the result of new information \nbeing received that may lead to a significant change to the benefit/risk profile or as the result of \n\nan important (pharmacovigilance or risk minimisation) milestone being reached. \n\n \n\n \n\n\n\n73 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX III \n\n \n\nLABELLING AND PACKAGE LEAFLET \n\n \n\n\n\n74 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nA. LABELLING \n\n \n\n\n\n75 \n\n \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n\n \n\nCARTON OF 12.5 mg – 14, 28, 84 (3 PACKS of 28) TABLETS \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nRevolade 12.5 mg film-coated tablets \n\n \n\neltrombopag \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 12.5 mg eltrombopag. \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\n14 film-coated tablets \n\n28 film-coated tablets \n\nMultipack containing 84 (3 packs of 28) film-coated tablets \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nRead the package leaflet before use. Oral use. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE REACH AND SIGHT OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\n \n\n\n\n76 \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\nVista Building \n\nElm Park, Merrion Road \n\nDublin 4 \n\nIreland \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/10/612/010 (14 film-coated tablets) \n\nEU/1/10/612/011 (28 film-coated tablets) \n\nEU/1/10/612/012 84 film-coated tablets (3 packs of 28) \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nrevolade 12.5 mg \n\n \n\n \n\n17. UNIQUE IDENTIFIER – 2D BARCODE \n\n \n\n2D barcode carrying the unique identifier included. \n\n \n\n \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n\n \n\nPC: \n\nSN: \n\nNN: \n \n\n \n\n\n\n77 \n\n \n\nPARTICULARS TO APPEAR ON INTERMEDIATE CARTON \n\n \n\nMultipacks of 84 (3 packs of 28 film-coated tablets) – without blue box – 12.5 mg film-coated \n\ntablets \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nRevolade 12.5 mg film-coated tablets \n\n \n\neltrombopag \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 12.5 mg eltrombopag. \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\n28 film-coated tablets. Component of a multipack, can’t be sold separately. \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nRead the package leaflet before use. Oral use. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE REACH AND SIGHT OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n \n\n\n\n78 \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\nVista Building \n\nElm Park, Merrion Road \n\nDublin 4 \n\nIreland \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/10/612/012 \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nrevolade 12.5 mg \n\n \n\n \n\n\n\n79 \n\n \n\nMINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS \n\n \n\nBlister \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nRevolade 12.5 mg film-coated tablets \n\n \n\neltrombopag \n\n \n\n \n\n2. NAME OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\n \n\n \n\n3. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n4. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n5. OTHER \n\n \n\n \n\n\n\n80 \n\n \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n\n \n\nCARTON OF 25 mg – 14, 28, 84 (3 PACKS of 28) TABLETS \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nRevolade 25 mg film-coated tablets \n\n \n\neltrombopag \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 25 mg eltrombopag. \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\n14 film-coated tablets \n\n28 film-coated tablets \n\nMultipack containing 84 (3 packs of 28) film-coated tablets \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nRead the package leaflet before use. Oral use. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE REACH AND SIGHT OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n\n\n81 \n\n \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\nVista Building \n\nElm Park, Merrion Road \n\nDublin 4 \n\nIreland \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/10/612/001 (14 film-coated tablets) \n\nEU/1/10/612/002 (28 film-coated tablets) \n\nEU/1/10/612/003 84 film-coated tablets (3 packs of 28) \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nrevolade 25 mg \n\n \n\n \n\n17. UNIQUE IDENTIFIER – 2D BARCODE \n\n \n\n2D barcode carrying the unique identifier included. \n\n \n\n \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n\n \n\nPC: \n\nSN: \n\nNN: \n\n \n\n \n\n\n\n82 \n\n \n\nPARTICULARS TO APPEAR ON INTERMEDIATE CARTON \n\n \n\nMultipacks of 84 (3 packs of 28 film-coated tablets) – without blue box – 25 mg film-coated \n\ntablets \n\n \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nRevolade 25 mg film-coated tablets \n\n \n\neltrombopag \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 25 mg eltrombopag. \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\n28 film-coated tablets. Component of a multipack, can’t be sold separately. \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nRead the package leaflet before use. Oral use. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE REACH AND SIGHT OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n\n\n83 \n\n \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\nVista Building \n\nElm Park, Merrion Road \n\nDublin 4 \n\nIreland \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/10/612/003 \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nrevolade 25 mg \n\n \n\n \n\n\n\n84 \n\n \n\nMINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS \n\n \n\nBlister \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nRevolade 25 mg film-coated tablets \n\n \n\neltrombopag \n\n \n\n \n\n2. NAME OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\n \n\n \n\n3. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n4. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n5. OTHER \n\n \n\n \n\n\n\n85 \n\n \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n\n \n\nCARTON OF 50 mg – 14, 28, 84 (3 PACKS of 28) TABLETS \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nRevolade 50 mg film-coated tablets \n\n \n\neltrombopag \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 50 mg eltrombopag \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\n14 film-coated tablets \n\n28 film-coated tablets \n\nMultipack containing 84 (3 packs of 28) film-coated tablets \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nRead the package leaflet before use. Oral use. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE REACH AND SIGHT OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n\n\n86 \n\n \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\nVista Building \n\nElm Park, Merrion Road \n\nDublin 4 \n\nIreland \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/10/612/004 (14 film-coated tablets) \n\nEU/1/10/612/005 (28 film-coated tablets) \n\nEU/1/10/612/006 84 film-coated tablets (3 packs of 28) \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nrevolade 50 mg \n\n \n\n \n\n17. UNIQUE IDENTIFIER – 2D BARCODE \n\n \n\n2D barcode carrying the unique identifier included. \n\n \n\n \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n\n \n\nPC: \n\nSN: \n\nNN: \n\n \n\n \n\n\n\n87 \n\n \n\nPARTICULARS TO APPEAR ON INTERMEDIATE CARTON \n\n \n\nMultipacks of 84 (3 packs of 28 film-coated tablets) – without blue box – 50 mg film-coated \n\ntablets \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nRevolade 50 mg film-coated tablets \n\n \n\neltrombopag \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 50 mg eltrombopag \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\n28 film-coated tablets. Component of a multipack, can’t be sold separately. \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nRead the package leaflet before use. Oral use. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE REACH AND SIGHT OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n \n\n\n\n88 \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\nVista Building \n\nElm Park, Merrion Road \n\nDublin 4 \n\nIreland \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/10/612/006 \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nrevolade 50 mg \n\n \n\n \n\n \n\n\n\n89 \n\n \n\nMINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS \n\n \n\nBlister \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nRevolade 50 mg film-coated tablets \n\n \n\neltrombopag \n\n \n\n \n\n2. NAME OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\n \n\n \n\n3. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n4. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n5. OTHER \n\n \n\n \n\n\n\n90 \n\n \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n\n \n\nCARTON OF 75 mg – 14, 28, 84 (3 PACKS of 28) TABLETS \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nRevolade 75 mg film-coated tablets \n\n \n\neltrombopag \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 75 mg eltrombopag \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\n14 film-coated tablets \n\n28 film-coated tablets \n\nMultipack containing 84 (3 packs of 28) film-coated tablets \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nRead the package leaflet before use. Oral use. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE REACH AND SIGHT OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\n \n\n\n\n91 \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\nVista Building \n\nElm Park, Merrion Road \n\nDublin 4 \n\nIreland \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/10/612/007 (14 film-coated tablets) \n\nEU/1/10/612/008 (28 film-coated tablets) \n\nEU/1/10/612/009 84 film-coated tablets (3 packs of 28) \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nrevolade 75 mg \n\n \n\n \n\n17. UNIQUE IDENTIFIER – 2D BARCODE \n\n \n\n2D barcode carrying the unique identifier included. \n\n \n\n \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n\n \n\nPC: \n\nSN: \n\nNN: \n \n\n \n\n\n\n92 \n\n \n\nPARTICULARS TO APPEAR ON INTERMEDIATE CARTON \n\n \n\nMultipacks of 84 (3 packs of 28 film-coated tablets) – without blue box –75 mg film-coated \n\ntablets \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nRevolade 75 mg film-coated tablets \n\n \n\neltrombopag \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 75 mg eltrombopag \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\n28 film-coated tablets. Component of a multipack, can’t be sold separately. \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nRead the package leaflet before use. Oral use. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE REACH AND SIGHT OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n \n\n\n\n93 \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\nVista Building \n\nElm Park, Merrion Road \n\nDublin 4 \n\nIreland \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/10/612/009 \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nrevolade 75 mg \n\n \n\n \n\n \n\n\n\n94 \n\n \n\nMINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS \n\n \n\nBlister \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nRevolade 75 mg film-coated tablets \n\n \n\neltrombopag \n\n \n\n \n\n2. NAME OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\n \n\n \n\n3. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n4. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n5. OTHER \n\n \n\n \n\n\n\n95 \n\n \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n\n \n\nCarton of 25 mg powder for oral suspension \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nRevolade 25 mg powder for oral suspension \n\n \n\neltrombopag \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nEach sachet contains eltrombopag olamine equivalent to 25 mg of eltrombopag. \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\n30 sachets and 1 mixing bottle + 30 single-use oral syringes \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nRead the package leaflet before use. \n\nOral use \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\nUse within 30 minutes of reconstitution. \n\n \n\n \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\n \n\n\n\n96 \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\nVista Building \n\nElm Park, Merrion Road \n\nDublin 4 \n\nIreland \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/10/612/013 (30 sachets of powder for oral suspension) \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nrevolade 25 mg sachets \n\n \n\n \n\n17. UNIQUE IDENTIFIER – 2D BARCODE \n\n \n\n2D barcode carrying the unique identifier included. \n\n \n\n \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n\n \n\nPC: \n\nSN: \n\nNN: \n \n\n \n\n\n\n97 \n\n \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n\n \n\nCarton of 25 mg powder for oral suspension – without blue box – 30 sachets \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nRevolade 25 mg powder for oral suspension \n\n \n\neltrombopag \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nEach sachet contains eltrombopag olamine equivalent to 25 mg of eltrombopag. \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\n30 sachets. \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nRead the package leaflet before use. \n\nOral use \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\nUse within 30 minutes of reconstitution. \n\n \n\n \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\n \n\n\n\n98 \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\nVista Building \n\nElm Park, Merrion Road \n\nDublin 4 \n\nIreland \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/10/612/013 \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nrevolade 25 mg sachets \n\n \n\n \n\n\n\n99 \n\n \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n\n \n\nSACHET \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n\n \n\nRevolade 25 mg powder for oral suspension \n\n \n\neltrombopag \n\n \n\nOral use \n\n \n\n \n\n2. NAME OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nNovartis Europharm Limited \n\n \n\n \n\n3. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n4. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n5. OTHER \n\n \n\n \n\n\n\n100 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nB. PACKAGE LEAFLET \n\n\n\n101 \n\nPackage Leaflet: Information for the patient \n\n \n\nRevolade 12.5 mg film-coated tablets \n\nRevolade 25 mg film-coated tablets \n\nRevolade 50 mg film-coated tablets \n\nRevolade 75 mg film-coated tablets \n\n \n\neltrombopag \n\n \n\nRead all of this leaflet carefully before you start taking this medicine because it contains \n\nimportant information for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor or pharmacist. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n\n- If you get any of the side effects talk to your doctor or pharmacist. This includes any possible \nside effects not listed in this leaflet. See section 4 \n\n \n\nWhat is in this leaflet: \n\n1. What Revolade is and what it is used for \n\n2. What you need to know before you take Revolade \n\n3. How to take Revolade \n\n4. Possible side effects \n\n5. How to store Revolade \n\n6. Contents of the pack and other information \n\n \n\n \n\n1. What Revolade is and what it is used for \n\n \n\nRevolade contains eltrombopag, which belongs to a group of medicines called thrombopoietin \n\nreceptor agonists. It is used to help increase the number of platelets in your blood. Platelets are blood \n\ncells that help to reduce or prevent bleeding. \n\n \n\n Revolade is used to treat a bleeding disorder called immune (primary) thrombocytopenia (ITP) \nin patients aged 1 year and above who have already taken other medicines (corticosteroids or \n\nimmunoglobulins), which have not worked. \n\n \n\nITP is caused by a low blood platelet count (thrombocytopenia). People with ITP have an \n\nincreased risk of bleeding. Symptoms patients with ITP may notice include petechiae (pinpoint-\n\nsized flat round red spots under the skin), bruising, nosebleeds, bleeding gums and not being \n\nable to control bleeding if they are cut or injured. \n\n \n\n Revolade can also be used to treat low platelet count (thrombocytopenia) in adults with \nhepatitis C virus (HCV) infections, if they have had problems with side effects while on \n\ninterferon treatment. Many people with hepatitis C have low platelet counts, not only as a result \n\nof the disease, but also due to some of the antiviral medicines that are used to treat it. Taking \n\nRevolade may make it easier for you to complete a full course of antiviral medicine \n\n(peginterferon and ribavirin). \n\n \n\n Revolade may also be used to treat adult patients with low blood counts caused by severe \naplastic anaemia (SAA). SAA is a disease in which the bone marrow is damaged, causing a \n\ndeficiency of the red blood cells (anaemia), white blood cells (leukopenia) and platelets \n\n(thrombocytopenia). \n\n \n\n\n\n102 \n\n \n\n2. What you need to know before you take Revolade \n\n \n\nDo not take Revolade \n\n if you are allergic to eltrombopag or any of the other ingredients of this medicine (listed in \nsection 6 under ‘What Revolade contains’). \n\n Check with your doctor if you think this applies to you. \n \n\nWarnings and precautions \n\nTalk to your doctor before taking Revolade: \n\n if you have liver problems. People who have low platelet counts as well as advanced chronic \n(long-term) liver disease are more at risk of side effects, including life-threatening liver damage \n\nand blood clots. If your doctor considers that the benefits of taking Revolade outweigh the risks, \n\nyou will be closely monitored during treatment. \n\n if you are at risk of blood clots in your veins or arteries, or you know that blood clots are \ncommon in your family. \n\nYou may be at higher risk of blood clots: \n\n- as you get older \n- if you have had to stay in bed for a long time \n- if you have cancer \n- if you are taking the contraceptive birth control pill or hormone replacement therapy \n- if you have recently had surgery or received a physical injury \n- if you are very overweight (obese) \n- if you are a smoker \n- if you have advanced chronic liver disease \n If any of these apply to you, tell your doctor before starting treatment. You should not \n\ntake Revolade unless your doctor considers that the expected benefits outweigh the risk of \n\nblood clots. \n\n if you have cataracts (the lens of the eye getting cloudy) \n\n if you have another blood condition, such as myelodysplastic syndrome (MDS). Your doctor \nwill carry out tests to check that you do not have this blood condition before you start Revolade. \n\nIf you have MDS and take Revolade, your MDS may get worse. \n\n Tell your doctor if any of these apply to you. \n \n\nEye examinations \nYour doctor will recommend that you are checked for cataracts. If you do not have routine eye-tests \n\nyour doctor should arrange regular testing. You may also be checked for the occurrence of any \n\nbleeding in or around your retina (the light-sensitive layer of cells at the back of the eye). \n\n \n\nYou will need regular tests \n\nBefore you start taking Revolade, your doctor will carry out blood tests to check your blood cells, \n\nincluding platelets. These tests will be repeated at intervals while you are taking it. \n\n \n\nBlood tests for liver function \n\nRevolade can cause blood test results that may be signs of liver damage - an increase of some liver \n\nenzymes, especially bilirubin and alanine / aspartate transaminases. If you are taking interferon-based \n\ntreatments together with Revolade to treat low platelet count due to hepatitis C, some liver problems \n\ncan get worse. \n\n \n\nYou will have blood tests to check your liver function before you start taking Revolade and at \n\nintervals while you are taking it. You may need to stop taking Revolade if the amount of these \n\nsubstances increases too much, or if you get other signs of liver damage. \n\n Read the information ‘Liver problems’ in section 4 of this leaflet. \n \n\n \n\n\n\n103 \n\nBlood tests for platelet count \n\nIf you stop taking Revolade, your blood platelet count is likely to become low again within several \n\ndays. The platelet count will be monitored, and your doctor will discuss appropriate precautions with \n\nyou. \n\n \n\nA very high blood platelet count may increase the risk of blood clotting. However blood clots can also \n\nform with normal or even low platelet counts. Your doctor will adjust your dose of Revolade to ensure \n\nthat your platelet count does not become too high. \n\n \n\n Get medical help immediately if you have any of these signs of a blood clot: \n\n swelling, pain or tenderness in one leg \n\n sudden shortness of breath especially together with sharp pain in the chest or rapid breathing \n\n abdominal (stomach) pain, enlarged abdomen, blood in your stools \n \n\nTests to check your bone marrow \n\nIn people who have problems with their bone marrow, medicines like Revolade could make the \n\nproblems worse. Signs of bone marrow changes may show up as abnormal results in your blood tests. \n\nYour doctor may also carry out tests to directly check your bone marrow during treatment with \n\nRevolade. \n\n \n\nChecks for digestive bleeding \n\nIf you are taking interferon-based treatments together with Revolade you will be monitored for any \n\nsigns of bleeding in your stomach or intestine after you stop taking Revolade. \n\n \n\nHeart monitoring \n\nYour doctor may consider it necessary to monitor your heart during treatment with Revolade and carry \n\nout an electrocardiogram (ECG) test. \n\n \n\nOlder people (65 years and above) \n\nThere are limited data on the use of Revolade in patients aged 65 years and older. Care should be \n\ntaken when using Revolade if you are aged 65 years or above. \n\n \n\nChildren and adolescents \n\nRevolade is not recommended for children aged under 1 year who have ITP. It is also not \n\nrecommended for people under 18 years with low platelet counts due to hepatitis C or severe aplastic \n\nanaemia. \n\n \n\nOther medicines and Revolade \nTell your doctor or pharmacist if you are taking, have recently taken or might take any other \n\nmedicines. This includes medicines obtained without prescription and vitamins. \n\n \n\nSome everyday medicines interact with Revolade – including prescription and non-prescription \n\nmedicines and minerals. These include: \n\n antacid medicines to treat indigestion, heartburn or stomach ulcers (see also ‘When to take it’ \nin section 3) \n\n medicines called statins, to lower cholesterol \n\n some medicines to treat HIV infection, such as lopinavir and/or ritonavir \n\n ciclosporin used in the context of transplantations or immune diseases \n\n minerals such as iron, calcium, magnesium, aluminium, selenium and zinc which may be found \nin vitamin and mineral supplements (see also ‘When to take it’ in section 3) \n\n medicines such as methotrexate and topotecan, to treat cancer \n Talk to your doctor if you take any of these. Some of them are not to be taken with Revolade, \n\nor the dose may need adjusting, or you may need to alter the timing of when you take them. \n\nYour doctor will review the medicines you are taking, and suggest suitable replacements if \n\nnecessary. \n\n \n\n\n\n104 \n\nIf you are also taking medicines to prevent blood clots there is a greater risk of bleeding. Your doctor \n\nwill discuss this with you. \n\n \n\nIf you are taking corticosteroids, danazol, and/or azathioprine you may need to take a lower dose or \n\nto stop taking them while you are taking Revolade. \n\n \n\nRevolade with food and drink \n\nDo not take Revolade with dairy foods or drinks as the calcium in dairy products affects the absorption \n\nof the medicine. For more information, see ‘When to take it’ in section 3. \n\n \n\nPregnancy and breast-feeding \n\nDon’t use Revolade if you are pregnant unless your doctor specifically recommends it. The effect of \n\nRevolade during pregnancy is not known. \n\n Tell your doctor if you are pregnant, think you may be pregnant, or are planning to have a \nbaby. \n\n Use a reliable method of contraception while you’re taking Revolade, to prevent pregnancy \n\n If you do become pregnant during treatment with Revolade, tell your doctor. \n \n\nDon’t breast-feed while you are taking Revolade. It is not known whether Revolade passes into \n\nbreast-milk. \n\n If you are breast-feeding or planning to breast-feed, tell your doctor. \n \n\nDriving and using machines \n\nRevolade can make you dizzy and have other side effects that make you less alert. \n\n Don’t drive or use machines unless you are sure you’re not affected. \n \n\n \n\n3. How to take Revolade \n\n \n\nAlways take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist \n\nif you are not sure. Do not change the dose or schedule for taking Revolade unless your doctor or \n\npharmacist advises you to. While you are taking Revolade, you will be under the care of a doctor with \n\nspecialist experience in treating your condition. \n\n \n\nHow much to take \n\nFor ITP \n\nAdults and children (6 to 17 years) – the usual starting dose for ITP is one 50 mg tablet of Revolade \n\na day. If you are of Asian origin (Chinese, Japanese, Taiwanese, Thai or Korean) you may need to \n\nstart at a lower dose of 25 mg. \n\n \n\nChildren (1 to 5 years) — the usual starting dose for ITP is one 25 mg tablet of Revolade a day. \n\n \n\nFor hepatitis C \n\nAdults - the usual starting dose for hepatitis C is one 25 mg tablet of Revolade a day. If you are of \n\nAsian origin (Chinese, Japanese, Taiwanese, Thai or Korean) you will start on the same 25 mg dose. \n\n \n\nFor SAA \n\nAdults - the usual starting dose for SAA is one 50 mg tablet of Revolade a day. If you are of Asian \n\norigin (Chinese, Japanese, Taiwanese, Thai or Korean) you may need to start at a lower dose of \n\n25 mg. \n\n \n\nRevolade may take 1 to 2 weeks to work. Based on your response to Revolade your doctor may \n\nrecommend that your daily dose is changed. \n\n \n\n \n\n\n\n105 \n\nHow to take the tablets \nSwallow the tablet whole, with some water. \n\n \n\nWhen to take it \n\n \n\nMake sure that – \n\n in the 4 hours before you take Revolade \n\n and the 2 hours after you take Revolade \n\n \n\nyou don’t consume any of the following: \n\n dairy foods such as cheese, butter, yoghurt or ice cream \n\n milk or milk shakes, drinks containing milk, yoghurt or cream \n\n antacids, a type of medicine for indigestion and heartburn \n\n some mineral and vitamin supplements including iron, calcium, magnesium, aluminium, \nselenium and zinc \n\n \n\nIf you do, the medicine will not be properly absorbed into your body. \n\n \n\n \n \n\nFor more advice about suitable foods and drinks, talk to your doctor. \n\n \n\nIf you take more Revolade than you should \n\nContact a doctor or pharmacist immediately. If possible show them the pack, or this leaflet. \n\nYouwill be monitored for any signs or symptoms of side effects and given appropriate treatment \n\nimmediately. \n\n \n\nIf you forget to take Revolade \n\nTake the next dose at the usual time. Do not take more than one dose of Revolade in one day. \n\n \n\nIf you stop taking Revolade \n\nDon’t stop taking Revolade without talking to your doctor. If your doctor advises you to stop \n\ntreatment, your platelet count will then be checked each week for four weeks. See also ‘Bleeding or \n\nbruising after you stop treatment’ in section 4. \n\n \n\nIf you have any further questions on the use of this medicine, ask your doctor or pharmacist. \n\n \n\n \n\n \n\nNO dairy products, antacids \nor mineral supplements \n\nTake Revolade \n\nFor 4 hours \nbefore you \ntake \n\nRevolade... \n\n ... and for \n\n2 hours after \n\n\n\n106 \n\n4. Possible side effects \n \n\nLike all medicines, this medicine can cause side effects, although not everybody gets them. \n\n \n\nSymptoms needing attention: see a doctor \n\nPeople taking Revolade for either ITP or low blood platelet counts due to hepatitis C could develop \n\nsigns of potentially serious side effects. It is important to tell a doctor if you develop these \n\nsymptoms. \n\n \n\nHigher risk of blood clots \n\nCertain people may have a higher risk of blood clots, and medicines like Revolade could make this \n\nproblem worse. The sudden blocking of a blood vessel by a blood clot is an uncommon side effect and \n\nmay affect up to 1 in 100 people. \n\n \n\nGet medical help immediately if you develop signs and symptoms of a blood clot, such as: \n\n swelling, pain, heat, redness, or tenderness in one leg \n\n sudden shortness of breath, especially together with sharp pain in the chest or rapid breathing \n\n abdominal (stomach) pain, enlarged abdomen, blood in your stools. \n \n\nLiver problems \n\nRevolade can cause changes that show up in blood tests, and may be signs of liver damage. Liver \n\nproblems (increased enzymes showing up in blood tests) are common and may affect up to 1 in \n\n10 people. Other liver problems (bile not flowing properly) are uncommon and may affect up to 1 in \n\n100 people. \n\n \n\nIf you have either of these signs of liver problems: \n\n yellowing of the skin or the whites of the eyes (jaundice) \n\n unusually dark-coloured urine \n tell your doctor immediately. \n \n\nBleeding or bruising after you stop treatment \n\nWithin two weeks of stopping Revolade, your blood platelet count will usually drop back down to \n\nwhat it was before starting Revolade. The lower platelet count may increase the risk of bleeding or \n\nbruising. Your doctor will check your platelet count for at least 4 weeks after you stop taking \n\nRevolade. \n\n Tell your doctor if you have any bleeding or bruising after stopping Revolade. \n \n\nSome people have bleeding in the digestive system after they stop taking peginterferon, ribavirin, and \n\nRevolade. Symptoms include: \n\n black tarry stools (discoloured bowel movements are a uncommon side effect that may affect up \nto 1 in 100 people) \n\n blood in your stools \n\n vomiting blood or something that looks like coffee grounds \n Tell your doctor immediately if you have any of these symptoms. \n \n\nThe following side effects have been reported to be associated with treatment with Revolade in \n\nadult patients with ITP: \n\n \n\nVery common side effects \n\nThese may affect more than 1 in 10 people: \n\n common cold \n\n feeling sick (nausea) \n\n diarrhoea \n\n cough \n\n infection in the nose, sinuses, throat and upper airways, common cold (upper respiratory tract \ninfection) \n\n\n\n107 \n\n \n\nVery common side effects that may show up in blood tests: \n\n increased of liver enzymes (alanine aminotransferase (ALT)) \n \n\nCommon side effects \n\nThese may affect up to 1 in 10 people: \n\n muscle pain, muscle spasm, muscle weakness \n\n back pain \n\n bone pain \n\n heavy menstrual period \n\n sore throat and discomfort when swallowing \n\n eye problems including abnormal eye test, dry eye, eye pain and blurred vision \n\n vomiting \n\n flu (influenza) \n\n cold sore \n\n pneumonia \n\n irritation and inflammation (swelling) of the sinuses \n\n inflammation (swelling) and infection of the tonsils infection of the lungs, sinuses, tonsils, nose \nand throat \n\n inflammation of the gum tissue \n\n loss of appetite \n\n feeling of tingling, prickling or numbness, commonly called “pins and needles” \n\n feeling drowsy \n\n ear pain \n\n pain, swelling and tenderness in one of your legs (usually the calf) with warm skin in the \naffected area (signs of a blood clot in a deep vein) \n\n localised swelling filled with blood from a break in a blood vessel (haematoma) \n\n mouth problems including dry mouth, sore mouth, sensitive tongue, bleeding gums, mouth \nulcers \n\n runny nose \n\n toothache \n\n stomach pain and tenderness \n\n liver problems \n\n skin changes including excessive sweating, itching bumpy rash, red spots, changes in \nappearance of the skin \n\n hair loss \n\n foamy, frothy or bubbly-looking urine (signs of protein in urine) \n\n generally feeling unwell, high temperature, feeling hot \n\n chest pain \n\n problems sleeping, depression \n\n migraine \n\n decreased vision \n\n spinning sensation (vertigo) \n\n digestive wind/gas \n \n\nCommon side effects that may show up in blood test: \n\n decreased number of red blood cells (anaemia) \n\n decreased number of platelets (thrombocytopenia) \n\n decreased number of white blood cells \n\n decreased haemaglobin level \n\n decreased number of eosinophils \n\n increased number of white blood cells (leukocytosis) \n\n increased levels of uric acid \n\n decreased levels of potassium \n\n\n\n108 \n\n increased levels of creatinine \n\n increased levels of alkaline phosphatase \n\n increase of liver enzymes (aspartate aminotransferase (AST)) \n\n increase in bilirubin (a substance produced by the liver) \n\n increased levels of some proteins \n \n\nUncommon side effects \n\nThese may affect up to 1 in 100 people: \n\n interruption of blood supply to part of the heart \n\n sudden shortness of breath, especially when accompanied with sharp pain in the chest and /or \nrapid breathing, which could be signs of a blood clot in the lungs (see ‘Higher risk of blood \n\nclots’ earlier in section 4) \n\n the loss of function of part of the lung caused by a blockage in the lung artery \n\n including yellowing of the eyes and skin (see ‘Liver problems’ earlier in section 4) \n\n liver injury due to medication \n\n heart beating faster, irregular heartbeat, bluish discolouration of the skin \n\n disturbances of heart rhythm (QT prolongation) \n\n blood clot \n\n painful swollen joints caused by uric acid (gout) \n\n lack of interest, mood changes \n\n problems with balance, speech and nerve function, shaking \n\n eye problems including increased production of tears, cloudy lens in the eye (cataract), bleeding \nof the retina \n\n problems with the nose, throat and sinuses, breathing problems when sleeping \n\n digestive system problems including frequent bowel movements, food poisoning, blood in stool \n\n rectal bleeding, blood in your stool, abdominal bloating, constipation \n\n mouth problems, including dry or sore mouth, sensitive tongue, bleeding gums \n\n sunburn \n\n redness or swelling around, a woundbleeding around a catheter (if present) into the \nskinsensation of a foreign body \n\n kidney problems including inflammation of the kidney, excessive urination at night, kidney \nfailure, white cells in urine \n\n cold sweat \n\n infection of the skin \n\n skin changes including change in colour, peeling, redness, itching and sweating \n \n\nUncommon side effects that may show up in laboratory tests: \n\n changes in the shape of red blood cells \n\n increased number of platelets \n\n decreased levels of calcium \n\n decreased number of red blood cells (anaemia) cause by excessive destruction of red blood cells \n(haemolytic anaemia) \n\n increased number of myelocytes \n\n increased band neutrophils \n\n increased blood urea \n\n increased levels of blood albumin \n\n increased levels of total protein \n\n decreased levels of blood albumin \n\n increased pH of urine \n\n increased haemaglobin level \n \n\n\n\n109 \n\nThe following additional side effects have been reported to be associated with treatment with \n\nRevolade in children (aged 1 to 17 years) with ITP: \n\nIf these side effects become severe, please tell your doctor, pharmacist or nurse. \n\n \n\nVery common side effects \n\nThese may affect more than 1 in 10 children: \n\n infection in the nose, sinuses, throat and upper airways, common cold (upper respiratory tract \ninfection) \n\n diarrhoea \n\n abdominal pain \n\n cough \n\n high temperature \n\n feeling sick (nausea) \n \n\nCommon side effects \n\nThese may affect up to 1 in 10 children: \n\n difficulty in sleeping (insomnia) \n\n toothache \n\n pain in the nose and throat \n\n itchy, runny or blocked nose \n\n sore throat, runny nose, nasal congestion and sneezing \n\n mouth problems including dry mouth, sore mouth, sensitive tongue, bleeding gums, mouth \nulcers \n\n \n\nThe following side effects have been reported to be associated with treatment with Revolade in \n\ncombination with peginterferon and ribavirin in patients with HCV: \n\n \n\nVery common side effects \n\nThese may affect more than 1 in 10 people: \n\n headache \n\n decreased appetite \n\n cough \n\n feeling sick (nausea), diarrhoea \n\n muscle pain, muscle weakness \n\n itching \n\n lack of energy \n\n high temperature \n\n unusual hair loss \n\n feeling weak \n\n flu-like illness \n\n swelling in the hands or feet \n\n chills \n \n\nVery common side effects that may show up in blood tests: \n\n decreased number of red blood cells (anaemia) \n \n\nCommon side effects \n\nThese may affect up to 1 in 10 people: \n\n infection of the urinary system \n\n inflammation of the nasal passages, throat and mouth, flu-like symptoms, dry mouth, sore or \ninflamed mouth, toothache \n\n weight loss \n\n sleep disorders, abnormal drowsiness, depression, anxiety \n\n dizziness, problems with attention and memory, change in mood \n\n tingling or numbness of the hands or feet \n\n\n\n110 \n\n fever, headache \n\n eye problems, including cloudy lens in the eye (cataract), dry eye, small yellow deposits in the \nretina, yellowing of the whites of the eye \n\n bleeding of the retina \n\n spinning sensation (vertigo) \n\n fast or irregular heartbeat (palpitations), shortness of breath \n\n cough bringing up phlegm, runny nose, flu, cold sore, sore throat and discomfort when \nswallowing \n\n digestive system problems, including being sick (vomiting), stomach pain, indigestion, \nconstipation, swollen stomach, taste disturbances, inflammation of the stomach, piles \n\n(haemorrhoids), irritation of the gut \n\n toothache \n\n liver problems, including blood clot, tumour in the liver (see ‘Liver problems’ earlier in \nsection 4) \n\n skin changes, including rash, dry skin, eczema, redness of the skin, itching, excessive sweating, \nunusual skin growths \n\n joint pain, back pain, bone pain, pain in the hands or feet, muscle spasms \n\n irritability, generally feeling unwell, chest pain and discomfort \n\n infection in the nose, sinuses, throat and upper airways, common cold (upper respiratory tract \ninfection) \n\n depression, anxiety, sleep problems, nervousness \n \n\nCommon side effects that may show up in blood tests: \n\n increased blood sugar (glucose) \n\n decreased number of white blood cells \n\n decreased level of blood proteins \n\n increased levels of blood bilirubin (a substance produced by the liver) \n\n changes in the enzymes that control blood clotting \n \n\nUncommon side effects \n\nThese may affect up to 1 in 100 people: \n\n painful urination \n\n disturbances of heart rhythm (QT prolongation) \n\n stomach flu (gastroenteritis) \n\n skin changes including change in colour, peeling, redness, itching and sweating. \n\n yellowing of the whites of the eyes or skin (jaundice) \n\n swollen blood vessels and bleeding in the gullet (oesophagus) \n\n rash, bruising at the injection site \n\n decreased number of red blood cells (anaemia) caused by excessive destruction of red blood \ncells (haemolytic anaemia) \n\n confusion, agitation \n\n liver injury due to medication \n \n\nThe following side effects have been reported to be associated with treatment with Revolade in \n\npatients with severe aplastic anaemia (SAA): \n\nIf these side effects become severe, please tell your doctor, pharmacist or nurse. \n\n \n\nVery common side effects \n\nThese may affect more than 1 in 10 people. \n\n cough \n\n headache \n\n pain in the nose and throat \n\n diarrhoea \n\n nausea \n\n joint pain (arthralgia) \n\n\n\n111 \n\n pain in extremities (arms, legs, hands and feet) \n\n dizziness \n\n feeling very tired (fatigue) \n\n fever \n\n chills \n\n itchy eyes \n\n blisters in the mouth \n\n abdominal pain \n\n muscle spasms \n \n\nVery common side effects that may show up in the blood tests \n\n abnormal changes to the cells in your bone marrow \n \n\nCommon side effects \n\nThese may affect up to 1 in 10 people. \n\n anxiety \n\n depression \n\n feeling cold \n\n feeling unwell \n\n eye problems including blurred vision, cloudy lens in the eye (cataract), spots or deposits in eye \n(vitreous floaters), dry eye, itchy eye, yellowing of the whites of the eyes or skin \n\n nose bleed \n\n bleeding of the gums \n\n digestive system problems including being sick (vomiting), change in appetite (increased or \ndecreased), stomach pain/discomfort, swollen stomach, passing wind, change in stool colour \n\n fainting \n\n skin problems including small red or purple spots caused by bleeding into the skin (petechiae) \nrash, itching, skin lesion \n\n back pain \n\n muscle pain \n\n bone pain \n\n weakness (asthenia) \n\n swelling of the lower limbs due to the accumulation of fluids \n\n abnormal colored urine \n\n interruption in blood supply to spleen (splenic infarction) \n\n runny nose \n \n\nCommon side effects that may show up in the blood tests \n\n increase in enzymes due to muscle breakdown (creatine phosphokinase) \n\n accumulation of iron in the body (iron overload) \n\n decrease in blood sugar levels (hypoglycaemia) \n\n increased levels of bilirubin (a substance produced by the liver) \n\n increased levels of liver enzymes (aspartate aminotransferase (AST)) \n\n decreased levels of white blood cells \n \n\nSide effects with frequency not known \n\nFrequency cannot be estimated from the available data \n\n skin discolouration \n\n darkening of the skin \n\n yellowing of the skin and eyes, tenderness around the liver \n \n\n \n\n\n\n112 \n\nReporting of side effects \n\nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \n\neffects not listed in this leaflet. You can also report side effects directly via the national reporting \n\nsystem listed in Appendix V. By reporting side effects you can help provide more information on the \n\nsafety of this medicine. \n\n \n\n \n\n5. How to store Revolade \n \n\nKeep this medicine out of the sight and reach of children. \n\n \n\nDo not use this medicine after the expiry date which is stated on the carton and the blister. \n\n \n\nThis medicine does not require any special storage conditions. \n\n \n\nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \n\nthrow away medicines you no longer use. These measures will help protect the environment. \n\n \n\n \n\n6. Contents of the pack and other information \n\n \n\nWhat Revolade contains \n\nThe active substance in Revolade is eltrombopag. \n\n \n\n12.5 mg film-coated tablets \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 12.5 mg eltrombopag. \n\n \n\n25 mg film-coated tablets \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 25 mg eltrombopag. \n\n \n\n50 mg film-coated tablets \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 50 mg eltrombopag. \n\n \n75 mg film-coated tablets \n\nEach film-coated tablet contains eltrombopag olamine equivalent to 75 mg eltrombopag. \n\n \nThe other ingredients are: hypromellose, macrogol 400, magnesium stearate, mannitol (E421), \n\nmicrocrystalline cellulose, povidone, sodium starch glycolate, titanium dioxide (E171). \n\n \n\nRevolade 12.5 mg and 25 mg film-coated tablets also contain polysorbate 80 (E433). \n\n \n\nRevolade 50 mg film-coated tablets also contain iron oxide red (E172) and iron oxide yellow (E172). \n\n \n\nRevolade 75 mg film-coated tablets also contain iron oxide red (E172) and iron oxide black (E172). \n\n \n\nWhat Revolade looks like and contents of the pack \n\nRevolade 12.5 mg film-coated tablets are round, biconvex, white, debossed with ‘GS MZ1’ and ‘12.5’ \n\non one side. \n\n \n\nRevolade 25 mg film-coated tablets are round, biconvex, white, debossed with ‘GS NX3’ and ‘25’ on \n\none side. \n\n \n\nRevolade 50 mg film-coated tablets are round, biconvex, brown, debossed with ‘GS UFU’ and ‘50’ on \n\none side. \n\n \n\nRevolade 75 mg film-coated tablets are round, biconvex, pink, debossed with ‘GS FFS’ and ‘75’ on \n\none side. \n\n\n\n113 \n\n \n\nThey are supplied in aluminum blisters in a carton containing 14 or 28 film-coated tablets and \n\nmultipacks containg 84 (3 packs of 28) film-coated tablets). \n\n \n\nNot all pack sizes may be available in your country. \n\n \n\nMarketing authorisation holder \nNovartis Europharm Limited \n\nVista Building \n\nElm Park, Merrion Road \n\nDublin 4 \n\nIreland \n\n \n\nManufacturer \nNovartis Farmacéutica SA \n\nRonda de Santa Maria 158 \n\n08210 Barberà del Vallès (Barcelona) \n\nSpain \n\n \n\nNovartis Pharma GmbH \n\nRoonstraße 25 \n\nD-90429 Nuremberg \n\nGermany \n\n \n\nGlaxo Wellcome S.A. \n\nAvenida de Extremadura 3 \n\n09400 Aranda de Duero \n\nBurgos \n\nSpain \n\n \n\nFor any information about this medicine, please contact the local representative of the Marketing \n\nAuthorisation Holder: \n\n \n\nBelgië/Belgique/Belgien \n\nNovartis Pharma N.V. \n\nTél/Tel: +32 2 246 16 11 \n\n \n\nLietuva \n\nSIA “Novartis Baltics” Lietuvos filialas \n\nTel: +370 5 269 16 50 \n\n \n\nБългария \n\nNovartis Bulgaria EOOD \n\nТел: +359 2 489 98 28 \n\n \n\nLuxembourg/Luxemburg \n\nNovartis Pharma N.V. \n\nTél/Tel: +32 2 246 16 11 \n\n \n\nČeská republika \n\nNovartis s.r.o. \n\nTel: +420 225 775 111 \n\n \n\nMagyarország \n\nNovartis Hungária Kft. \n\nTel.: +36 1 457 65 00 \n\nDanmark \n\nNovartis Healthcare A/S \n\nTlf: +45 39 16 84 00 \n\n \n\nMalta \n\nNovartis Pharma Services Inc. \n\nTel: +356 2122 2872 \n\nDeutschland \n\nNovartis Pharma GmbH \n\nTel: +49 911 273 0 \n\n \n\nNederland \n\nNovartis Pharma B.V. \n\nTel: +31 26 37 82 555 \n\nEesti \n\nSIA Novartis Baltics Eesti filiaal \n\nTel: +372 66 30 810 \n\n \n\nNorge \n\nNovartis Norge AS \n\nTlf: +47 23 05 20 00 \n\n\n\n114 \n\nΕλλάδα \n\nNovartis (Hellas) A.E.B.E. \n\nΤηλ: +30 210 281 17 12 \n\n \n\nÖsterreich \n\nNovartis Pharma GmbH \n\nTel: +43 1 86 6570 \n\nEspaña \n\nNovartis Farmacéutica, S.A. \n\nTel: +34 93 306 42 00 \n\n \n\nPolska \n\nNovartis Poland Sp. z o.o. \n\nTel.: +48 22 375 4888 \n\nFrance \n\nNovartis Pharma S.A.S. \n\nTél: +33 1 55 47 66 00 \n\n \n\nPortugal \n\nNovartis Farma - Produtos Farmacêuticos, S.A. \n\nTel: +351 21 000 8600 \n\nHrvatska \n\nNovartis Hrvatska d.o.o. \n\nTel. +385 1 6274 220 \n\n \n\nRomânia \n\nNovartis Pharma Services Romania SRL \n\nTel: +40 21 31299 01 \n\nIreland \n\nNovartis Ireland Limited \n\nTel: +353 1 260 12 55 \n\n \n\nSlovenija \n\nNovartis Pharma Services Inc. \n\nTel: +386 1 300 75 50 \n\nÍsland \n\nVistor hf. \n\nSími: +354 535 7000 \n\n \n\nSlovenská republika \n\nNovartis Slovakia s.r.o. \n\nTel: +421 2 5542 5439 \n\n \n\nItalia \n\nNovartis Farma S.p.A. \n\nTel: +39 02 96 54 1 \n\nSuomi/Finland \n\nNovartis Finland Oy \n\nPuh/Tel: +358 (0)10 6133 200 \n\n \n\nΚύπρος \n\nNovartis Pharma Services Inc. \n\nΤηλ: +357 22 690 690 \n\n \n\nSverige \n\nNovartis Sverige AB \n\nTel: +46 8 732 32 00 \n\n \n\nLatvija \n\nSIA “Novartis Baltics” \n\nTel: +371 67 887 070 \n\n \n\nUnited Kingdom \n\nNovartis Pharmaceuticals UK Ltd. \n\nTel: +44 1276 698370 \n\n \n\n \n\nThis leaflet was last revised in \n \n\nDetailed information on this medicine is available on the European Medicines Agency web site: \n\nhttp://www.ema.europa.eu./ \n\n\n\n115 \n\nPackage Leaflet: Information for the patient \n\n \n\nRevolade 25 mg powder for oral suspension \n\n \n\neltrombopag \n\n \n\nRead all of this leaflet carefully before you start taking this medicine because it contains \n\nimportant information for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor or pharmacist. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n\n- If you get any of the side effects talk to your doctor or pharmacist. This includes any possible \nside effects not listed in this leaflet. See section 4 \n\n \n\nWhat is in this leaflet: \n\n1. What Revolade is and what it is used for \n\n2. What you need to know before you take Revolade \n\n3. How to take Revolade \n\n4. Possible side effects \n\n5. How to store Revolade \n\n6. Contents of the pack and other information \n\n Instructions for use \n\n \n\n \n\n1. What Revolade is and what it is used for \n\n \n\nRevolade contains eltrombopag, which belongs to a group of medicines called thrombopoietin \n\nreceptor agonists. It is used to help increase the number of platelets in your blood. Platelets are blood \n\ncells that help to reduce or prevent bleeding. \n\n \n\n Revolade is used to treat a bleeding disorder called immune (primary) thrombocytopenia (ITP) \nin patients aged 1 year and above who have already taken other medicines (corticosteroids or \n\nimmunoglobulins), which have not worked. \n\n \n\nITP is caused by a low blood platelet count (thrombocytopenia). People with ITP have an \n\nincreased risk of bleeding. Symptoms patients with ITP may notice include petechiae (pinpoint-\n\nsized flat round red spots under the skin), bruising, nosebleeds, bleeding gums and not being \n\nable to control bleeding if they are cut or injured. \n\n \n\n Revolade can also be used to treat low platelet count (thrombocytopenia) in adults with \nhepatitis C virus (HCV) infections, if they have had problems with side effects while on \n\ninterferon treatment. Many people with hepatitis C have low platelet counts, not only as a result \n\nof the disease, but also due to some of the antiviral medicines that are used to treat it. Taking \n\nRevolade may make it easier for you to complete a full course of antiviral medicine \n\n(peginterferon and ribavirin). \n\n \n\n Revolade may also be used to treat adult patients with low blood counts caused by severe \naplastic anaemia (SAA). SAA is a disease in which the bone marrow is damaged, causing a \n\ndeficiency of the red blood cells (anaemia), white blood cells (leukopenia) and platelets \n\n(thrombocytopenia). \n\n \n\n \n\n\n\n116 \n\n \n\n2. What you need to know before you take Revolade \n\n \n\nDo not take Revolade \n\n if you are allergic to eltrombopag or any of the other ingredients of this medicine (listed in \nsection 6 under ‘What Revolade contains’). \n\n Check with your doctor if you think this applies to you. \n \n\nWarnings and precautions \n\nTalk to your doctor before taking Revolade: \n\n if you have liver problems. People who have low platelet counts as well as advanced chronic \n(long-term) liver disease are more at risk of side effects, including life-threatening liver damage \n\nand blood clots. If your doctor considers that the benefits of taking Revolade outweigh the risks, \n\nyou will be closely monitored during treatment. \n\n if you are at risk of blood clots in your veins or arteries, or you know that blood clots are \ncommon in your family. \n\nYou may be at higher risk of blood clots: \n\n- as you get older \n- if you have had to stay in bed for a long time \n- if you have cancer \n- if you are taking the contraceptive birth control pill or hormone replacement therapy \n- if you have recently had surgery or received a physical injury \n- if you are very overweight (obese) \n- if you are a smoker \n- if you have advanced chronic liver disease \n If any of these apply to you tell your doctor before starting treatment. You should not \n\ntake Revolade unless your doctor considers that the expected benefits outweigh the risk of \n\nblood clots. \n\n if you have cataracts (the lens of the eye getting cloudy) \n\n if you have another blood condition, such as myelodysplastic syndrome (MDS). Your doctor \nwill carry out tests to check that you do not have this blood condition before you start Revolade. \n\nIf you have MDS and take Revolade, your MDS may get worse. \n\n Tell your doctor if any of these apply to you. \n \n\nEye examinations \nYour doctor will recommend that you are checked for cataracts. If you do not have routine eye-tests, \n\nyour doctor should arrange regular testing. You may also be checked for the occurrence of any \n\nbleeding in or around your retina (the light-sensitive layer of cells at the back of the eye). \n\n \n\nYou will need regular tests \n\nBefore you start taking Revolade, your doctor will carry out blood tests to check your blood cells, \n\nincluding platelets. These tests will be repeated at intervals while you are taking it. \n\n \n\nBlood tests for liver function \n\nRevolade can cause blood test results that may be signs of liver damage - an increase of some liver \n\nenzymes, especially bilirubin and alanine / aspartate transaminases. If you are taking interferon-based \n\ntreatments together with Revolade to treat low platelet count due to hepatitis C, some liver problems \n\ncan get worse. \n\n \n\nYou will have blood tests to check your liver function before you start taking Revolade and at \n\nintervals while you are taking it. You may need to stop taking Revolade if the amount of these \n\nsubstances increases too much, or if you get other signs of liver damage. \n\n Read the information ‘Liver problems’ in section 4 of this leaflet. \n \n\n\n\n117 \n\n \n\nBlood tests for platelet count \n\nIf you stop taking Revolade, your blood platelet count is likely to become low again within several \n\ndays. The platelet count will be monitored, and your doctor will discuss appropriate precautions with \n\nyou. \n\n \n\nA very high blood platelet count may increase the risk of blood clotting. However blood clots can also \n\nform with normal or even low platelet counts. Your doctor will adjust your dose of Revolade to ensure \n\nthat your platelet count does not become too high. \n\n \n\n Get medical help immediately if you have any of these signs of a blood clot: \n\n swelling, pain or tenderness in one leg \n\n sudden shortness of breath especially together with sharp pain in the chest or rapid breathing \n\n abdominal (stomach) pain, enlarged abdomen, blood in your stools \n \n\nTests to check your bone marrow \n\nIn people who have problems with their bone marrow, medicines like Revolade could make the \n\nproblems worse. Signs of bone marrow changes may show up as abnormal results in your blood tests. \n\nYour doctor may also carry out tests to directly check your bone marrow during treatment with \n\nRevolade. \n\n \n\nChecks for digestive bleeding \n\nIf you are taking interferon-based treatments together with Revolade you will be monitored for any \n\nsigns of bleeding in your stomach or intestine after you stop taking Revolade. \n\n \n\nHeart monitoring \n\nYour doctor may consider it necessary to monitor your heart during treatment with Revolade and carry \n\nout an electrocardiogram (ECG) test. \n\n \n\nOlder people (65 years and above) \n\nThere are limited data on the use of Revolade in patients aged 65 years and older. Care should be \n\ntaken when using Revolade if you are aged 65 years or above. \n\n \n\nChildren and adolescents \n\nRevolade is not recommended for children aged under 1 year who have ITP. It is also not \n\nrecommended for people under 18 years with low platelet counts due to hepatitis C or severe aplastic \n\nanaemia. \n\n \n\nOther medicines and Revolade \nTell your doctor or pharmacist if you are taking, have recently taken or might take any other \n\nmedicines. This includes medicines obtained without prescription and vitamins. \n\n \n\nSome everyday medicines interact with Revolade – including prescription and non-prescription \n\nmedicines and minerals. These include: \n\n antacid medicines to treat indigestion, heartburn or stomach ulcers (see also ‘When to take it’ \nin section 3) \n\n medicines called statins, to lower cholesterol \n\n some medicines to treat HIV infection, such as lopinavir and/or ritonavir \n\n ciclosporin used in the context of transplantations or immune diseases \n minerals such as iron, calcium, magnesium, aluminium, selenium and zinc which may be found \n\nin vitamin and mineral supplements (see also ‘When to take it’ in section 3) \n\n medicines such as methotrexate and topotecan, to treat cancer \n Talk to your doctor if you take any of these. Some of them are not to be taken with Revolade, \n\nor the dose may need adjusting, or you may need to alter the timing of when you take them. \n\nYour doctor will review the medicines you are taking, and suggest suitable replacements if \n\nnecessary. \n\n\n\n118 \n\n \n\nIf you are also taking medicines to prevent blood clots, there is a greater risk of bleeding. Your doctor \n\nwill discuss this with you. \n\n \n\nIf you are taking corticosteroids, danazol, and/or azathioprine you may need to take a lower dose or \n\nto stop taking them while you are taking Revolade. \n\n \n\nRevolade with food and drink \n\nDo not take Revolade with dairy foods or drinks as the calcium in dairy products affects the absorption \n\nof the medicine. For more information, see ‘When to take it’ in section 3. \n\n \n\nPregnancy and breast-feeding \n\nDon’t use Revolade if you are pregnant unless your doctor specifically recommends it. The effect of \n\nRevolade during pregnancy is not known. \n\n Tell your doctor if you are pregnant, think you may be pregnant, or are planning to have a \nbaby. \n\n Use a reliable method of contraception while you’re taking Revolade, to prevent pregnancy \n\n If you do become pregnant during treatment with Revolade, tell your doctor. \n \n\nDon’t breast-feed while you are taking Revolade. It is not known whether Revolade passes into \n\nbreast-milk. \n\n If you are breast-feeding or planning to breast-feed, tell your doctor. \n \n\nDriving and using machines \n\nRevolade can make you dizzy and have other side effects that make you less alert. \n\n Don’t drive or use machines unless you are sure you’re not affected. \n \n\n \n\n3. How to take Revolade \n\n \n\nAlways take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist \n\nif you are not sure. Do not change the dose or schedule for taking Revolade unless your doctor or \n\npharmacist advises you to. While you are taking Revolade, you will be under the care of a doctor with \n\nspecialist experience in treating your condition. \n\n \n\nHow much to take \n\nFor ITP \n\nAdults and children (6 to 17 years) - the usual starting dose for ITP is two 25 mg sachets of \n\nRevolade a day. If you are of Asian origin (Chinese, Japanese, Taiwanese, Thai or Korean) you may \n\nneed to start at a lower dose of 25 mg. \n\n \n\nChildren (1 to 5 years) — the usual starting dose for ITP is one 25 mg sachet of Revolade a day. \n\n \n\nFor hepatitis C \n\nAdults - the usual starting dose for hepatitis C is one 25 mg sachet of Revolade a day. If you are of \n\nAsian origin (Chinese, Japanese, Taiwanese, Thai or Korean) you will start on the same 25 mg dose. \n\n \n\nFor SAA \n\nAdults - the usual starting dose for SAA is two 25 mg sachets of Revolade a day. If you are of Asian \n\norigin (Chinese, Japanese, Taiwanese, Thai or Korean) you may need to start at a lower dose of \n\n25 mg. \n \n\nRevolade may take 1 to 2 weeks to work. Based on your response to Revolade your doctor may \n\nrecommend that your daily dose is changed. \n\n \n\n\n\n119 \n\nHow to give a dose of medicine \n\nThe powder for oral suspension is in sachets, the contents of which will need to mixed before you can \n\ntake the medicine. After section 6 of this leaflet there are Instructions For Use on how to mix and \n\nadminister the medicine. If you have questions or do not understand the Instructions For Use, talk to \n\nyour doctor, nurse or pharmacist. \n\n \n\nIMPORTANT — Use the medicine immediately after you have mixed the powder with water. If \n\nyou do not use it within 30 minutes of mixing it, you will need to mix a new dose. Do not re-use the \n\noral dosing syringe. A new single-use oral dosing syringe should be used to prepare each dose of \n\nRevolade for oral suspension. \n\n \n\nWhen to take it \n\n \n\nMake sure – \n\n in the 4 hours before you take Revolade \n\n and the 2 hours after you take Revolade \n\n \n\nyou don’t consume any of the following: \n\n dairy foods such as cheese, butter, yoghurt or ice cream \n\n milk or milk shakes, drinks containing milk, yoghurt or cream \n\n antacids, a type of medicine for indigestion and heartburn \n\n some mineral and vitamin supplements including iron, calcium, magnesium, aluminium, \n\nselenium and zinc \n\n \n\nIf you do, the medicine will not be properly absorbed into your body. \n\n \n\n \n \n\nFor more advice about suitable foods and drinks, talk to your doctor. \n\n \n\nIf you take more Revolade than you should \n\nContact a doctor or pharmacist immediately. If possible show them the pack, or this leaflet. \n\nYou will be monitored for any signs or symptoms of side effects and given appropriate treatment \n\nimmediately. \n\n \n\nIf you forget to take Revolade \n\nTake your next dose at the usual time. Do not take more than one dose of Revolade in one day. \n\n \n\nIf you stop taking Revolade \n\nDon’t stop taking Revolade without talking to your doctor. If your doctor advises you to stop \n\ntreatment, your platelet count will then be checked each week for four weeks. See also ‘Bleeding or \n\nbruising after you stop treatment’ in section 4. \n\n \n\nIf you have any further questions on the use of this medicine, ask your doctor or pharmacist. \n\n \n\n \n\nNO dairy products, antacids \n\nor mineral supplements \n\nTake Revolade \n\nFor 4 hours \nbefore you \ntake \n\nRevolade... \n\n ... and for \n\n2 hours after \n\n\n\n120 \n\n4. Possible side effects \n \n\nLike all medicines, this medicine can cause side effects, although not everybody gets them. \n\n \n\nSymptoms needing attention: see a doctor \n\nPeople taking Revolade for either ITP or low blood platelet counts due to hepatitis C could develop \n\nsigns of potentially serious side effects. It is important to tell a doctor if you develop these \n\nsymptoms. \n\n \n\nHigher risk of blood clots \n\nCertain people may have a higher risk of blood clots, and medicines like Revolade could make this \n\nproblem worse. The sudden blocking of a blood vessel by a blood clot is an uncommon side effect and \n\nmay affect up to 1 in 100 people. \n\n \n\n Get medical help immediately if you develop signs and symptoms of a blood clot, such as: \n\n swelling, pain, heat, redness or tenderness in one leg \n\n sudden shortness of breath, especially together with sharp pain in the chest or rapid breathing \n\n abdominal (stomach) pain, enlarged abdomen, blood in your stools. \n \n\nLiver problems \n\nRevolade can cause changes that show up in blood tests, and may be signs of liver damage. Liver \n\nproblems (increased enzymes showing up in blood tests) are common and may affect up to 1 in \n\n10 people. Other liver problems (bile not flowing properly) are uncommon and may affect up to 1 in \n\n100 people. \n\n \n\nIf you have either of these signs of liver problems: \n\n yellowing of the skin or the whites of the eyes (jaundice) \n\n unusually dark-coloured urine \n tell your doctor immediately. \n \n\nBleeding or bruising after you stop treatment \n\nWithin two weeks of stopping Revolade, your blood platelet count will usually drop back down to \n\nwhat it was before starting Revolade. The lower platelet count may increase the risk of bleeding or \n\nbruising. Your doctor will check your platelet count for at least 4 weeks after you stop taking \n\nRevolade. \n\n Tell your doctor if you have any bleeding or bruising after stopping Revolade. \n \n\nSome people have bleeding in the digestive system after they stop taking peginterferon, ribavirin, and \n\nRevolade. Symptoms include: \n\n- black tarry stools (discoloured bowel movements are a uncommon side effect that may affect up \nto 1 in 100 people) \n\n- blood in your stools \n- vomiting blood or something that looks like coffee grounds \n Tell your doctor immediately if you have any of these symptoms. \n \n\nThe following side effects have been reported to be associated with treatment with Revolade in \n\nadult patients with ITP: \n\n \n\nVery common side effects \n\nThese may affect more than 1 in 10 people: \n\n common cold \n\n feeling sick (nausea) \n\n diarrhoea \n\n cough \n\n infection in the nose, sinuses, throat and upper airways, common cold (upper respiratory tract \ninfection) \n\n\n\n121 \n\n \n\nVery common side effects that may show up in blood tests: \n\n increased of liver enzymes (alanine aminotransferase (ALT)) \n \n\nCommon side effects \n\nThese may affect up to 1 in 10 people: \n\n muscle pain, muscle spasm, muscle weakness \n\n back pain \n\n bone pain \n\n heavy menstrual period \n\n sore throat and discomfort when swallowing \n\n eye problems including abnormal eye test, dry eye, eye pain and blurred vision \n\n vomiting \n\n flu (influenza) \n\n cold sore \n\n pneumonia \n\n irritation and inflammation (swelling) of the sinuses \n\n inflammation (swelling) and infection of the tonsils infection of the lungs, sinuses, tonsils, nose \nand throat \n\n inflammation of the gum tissue \n\n loss of appetite \n\n feeling of tingling, prickling or numbness, commonly called “pins and needles” \n\n feeling drowsy \n\n ear pain \n\n pain, swelling and tenderness in one of your legs (usually the calf) with warm skin in the \naffected area (signs of a blood clot in a deep vein) \n\n localised swelling filled with blood from a break in a blood vessel (haematoma) \n\n mouth problems including dry mouth, sore mouth, sensitive tongue, bleeding gums, mouth \nulcers \n\n runny nose \n\n toothache \n\n stomach pain and tenderness \n\n liver problems \n\n skin changes including excessive sweating, itching bumpy rash, red spots, changes in \nappearance of the skin \n\n hair loss \n\n foamy, frothy or bubbly-looking urine (signs of protein in urine) \n\n generally feeling unwell, high temperature, feeling hot \n\n chest pain \n\n problems sleeping, depression \n\n migraine \n\n decreased vision \n\n spinning sensation (vertigo) \n\n digestive wind/gas \n \n\nCommon side effects that may show up in blood test: \n\n decreased number of red blood cells (anaemia) \n\n decreased number of platelets (thrombocytopenia) \n\n decreased number of white blood cells \n\n decreased haemaglobin level \n\n decreased number of eosinophils \n\n increased number of white blood cells (leukocytosis) \n\n increased levels of uric acid \n\n decreased levels of potassium \n\n\n\n122 \n\n increased levels of creatinine \n\n increased levels of alkaline phosphatase \n\n increase of liver enzymes (aspartate aminotransferase (AST)) \n\n increase in bilirubin (a substance produced by the liver) \n\n increased levels of some proteins \n \n\nUncommon side effects \n\nThese may affect up to 1 in 100 people: \n\n interruption of blood supply to part of the heart \n\n sudden shortness of breath, especially when accompanied with sharp pain in the chest and /or \nrapid breathing, which could be signs of a blood clot in the lungs (see ‘Higher risk of blood \n\nclots’ earlier in section 4) \n\n the loss of function of part of the lung caused by a blockage in the lung artery \n\n including yellowing of the eyes and skin (see ‘Liver problems’ earlier in section 4) \n\n liver injury due to medication \n\n heart beating faster, irregular heartbeat, bluish discolouration of the skin \n\n disturbances of heart rhythm (QT prolongation) \n\n blood clot \n\n painful swollen joints caused by uric acid (gout) \n\n lack of interest, mood changes \n\n problems with balance, speech and nerve function, shaking \n\n eye problems including increased production of tears, cloudy lens in the eye (cataract), bleeding \nof the retina \n\n problems with the nose, throat and sinuses, breathing problems when sleeping \n\n digestive system problems including frequent bowel movements, food poisoning, blood in stool \n\n rectal bleeding, blood in your stool, abdominal bloating, constipation \n\n mouth problems, including dry or sore mouth, sensitive tongue, bleeding gums \n\n sunburn \n\n redness or swelling around, a woundbleeding around a catheter (if present) into the \nskinsensation of a foreign body \n\n kidney problems including inflammation of the kidney, excessive urination at night, kidney \nfailure, white cells in urine \n\n cold sweat \n\n infection of the skin \n\n skin changes including change in colour, peeling, redness, itching and sweating \n \n\nUncommon side effects that may show up in laboratory tests: \n\n changes in the shape of red blood cells \n\n increased number of platelets \n\n decreased levels of calcium \n\n decreased number of red blood cells (anaemia) cause by excessive destruction of red blood cells \n(haemolytic anaemia) \n\n increased number of myelocytes \n\n increased band neutrophils \n\n increased blood urea \n\n increased levels of blood albumin \n\n increased levels of total protein \n\n decreased levels of blood albumin \n\n increased pH of urine \n\n increased haemaglobin level \n \n\n\n\n123 \n\nThe following additional side effects have been reported to be associated with treatment with \n\nRevolade in children (aged 1 to 17 years) with ITP: \n\nIf these side effects become severe, please tell your doctor, pharmacist or nurse. \n\n \n\nVery common side effects \n\nThese may affect more than 1 in 10 children: \n\n infection in the nose, sinuses, throat and upper airways, common cold (upper respiratory tract \ninfection) \n\n diarrhoea \n\n abdominal pain \n\n cough \n\n high temperature \n\n feeling sick (nausea) \n \n\nCommon side effects \n\nThese may affect up to 1 in 10 children: \n\n difficulty in sleeping (insomnia) \n\n toothache \n\n pain in the nose and throat \n\n itchy, runny or blocked nose \n\n sore throat, runny nose, nasal congestion and sneezing \n\n mouth problems including dry mouth, sore mouth, sensitive tongue, bleeding gums, mouth \nulcers \n\n \n\nThe following side effects have been reported to be associated with treatment with Revolade in \n\ncombination with peginterferon and ribavirin in patients with HCV: \n\n \n\nVery common side effects \n\nThese may affect more than 1 in 10 people: \n\n headache \n\n decreased appetite \n\n cough \n\n feeling sick (nausea), diarrhoea \n\n muscle pain, muscle weakness \n\n itching \n\n lack of energy \n\n high temperature \n\n unusual hair loss \n\n feeling weak \n\n flu-like illness \n\n swelling in the hands or feet \n\n chills \n \n\nVery common side effects that may show up in blood tests: \n\n decreased number of red blood cells (anaemia) \n \n\nCommon side effects \n\nThese may affect up to 1 in 10 people: \n\n infection of the urinary system \n\n inflammation of the nasal passages, throat and mouth, flu-like symptoms, dry mouth, sore or \ninflamed mouth, toothache \n\n weight loss \n\n sleep disorders, abnormal drowsiness, depression, anxiety \n\n dizziness, problems with attention and memory, change in mood \n\n tingling or numbness of the hands or feet \n\n\n\n124 \n\n fever, headache \n\n eye problems, including cloudy lens in the eye (cataract), dry eye, small yellow deposits in the \nretina, yellowing of the whites of the eye \n\n bleeding of the retina \n\n spinning sensation (vertigo) \n\n fast or irregular heartbeat (palpitations), shortness of breath \n\n cough bringing up phlegm, runny nose, flu, cold sore, sore throat and discomfort when \nswallowing \n\n digestive system problems, including being sick (vomiting), stomach pain, indigestion, \nconstipation, swollen stomach, taste disturbances, inflammation of the stomach, piles \n\n(haemorrhoids), irritation of the gut \n\n toothache \n\n liver problems, including blood clot, tumour in the liver (see ‘Liver problems’ earlier in \nsection 4) \n\n skin changes, including rash, dry skin, eczema, redness of the skin, itching, excessive sweating, \nunusual skin growths \n\n joint pain, back pain, bone pain, pain in the hands or feet, muscle spasms \n\n irritability, generally feeling unwell, chest pain and discomfort \n\n infection in the nose, sinuses, throat and upper airways, common cold (upper respiratory tract \ninfection) \n\n depression, anxiety, sleep problems, nervousness \n \n\nCommon side effects that may show up in blood tests: \n\n increased blood sugar (glucose) \n\n decreased number of white blood cells \n\n decreased level of blood proteins \n\n increased levels of blood bilirubin (a substance produced by the liver) \n\n changes in the enzymes that control blood clotting \n \n\nUncommon side effects \n\nThese may affect up to 1 in 100 people: \n\n painful urination \n\n disturbances of heart rhythm (QT prolongation) \n\n stomach flu (gastroenteritis) \n\n skin changes including change in colour, peeling, redness, itching and sweating. \n\n yellowing of the whites of the eyes or skin (jaundice) \n\n swollen blood vessels and bleeding in the gullet (oesophagus) \n\n rash, bruising at the injection site \n\n decreased number of red blood cells (anaemia) caused by excessive destruction of red blood \ncells (haemolytic anaemia) \n\n confusion, agitation \n\n liver injury due to medication \n \n\nThe following side effects have been reported to be associated with treatment with Revolade in \n\npatients with severe aplastic anaemia (SAA): \n\nIf these side effects become severe, please tell your doctor, pharmacist or nurse. \n\n \n\nVery common side effects \n\nThese may affect more than 1 in 10 people. \n\n cough \n\n headache \n\n pain in the nose and throat \n\n diarrhoea \n\n nausea \n\n joint pain (arthralgia) \n\n\n\n125 \n\n pain in extremities (arms, legs, hands and feet) \n\n dizziness \n\n feeling very tired (fatigue) \n\n fever \n\n chills \n\n itchy eyes \n\n blisters in the mouth \n\n abdominal pain \n\n muscle spasms \n \n\nVery common side effects that may show up in the blood tests \n\n abnormal changes to the cells in your bone marrow \n \n\nCommon side effects \n\nThese may affect up to 1 in 10 people. \n\n anxiety \n\n depression \n\n feeling cold \n\n feeling unwell \n\n eye problems including blurred vision, cloudy lens in the eye (cataract), spots or deposits in eye \n(vitreous floaters), dry eye, itchy eye, yellowing of the whites of the eyes or skin \n\n nose bleed \n\n bleeding of the gums \n\n digestive system problems including being sick (vomiting), change in appetite (increased or \ndecreased), stomach pain/discomfort, swollen stomach, passing wind, change in stool colour \n\n fainting \n\n skin problems including small red or purple spots caused by bleeding into the skin (petechiae) \nrash, itching, skin lesion \n\n back pain \n\n muscle pain \n\n bone pain \n\n weakness (asthenia) \n\n swelling of the lower limbs due to the accumulation of fluids \n\n abnormal colored urine \n\n interruption in blood supply to spleen (splenic infarction) \n\n runny nose \n \n\nCommon side effects that may show up in the blood tests \n\n increase in enzymes due to muscle breakdown (creatine phosphokinase) \n\n accumulation of iron in the body (iron overload) \n\n decrease in blood sugar levels (hypoglycaemia) \n\n increased levels of bilirubin (a substance produced by the liver) \n\n increased levels of liver enzymes (aspartate aminotransferase (AST)) \n\n decreased levels of white blood cells \n \n\nSide effects with frequency not known \n\nFrequency cannot be estimated from the available data \n\n skin discolouration \n\n darkening of the skin \n\n yellowing of the skin and eyes, tenderness around the liver \n \n\n \n\n\n\n126 \n\nReporting of side effects \n\nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \n\neffects not listed in this leaflet. You can also report side effects directly via the national reporting \n\nsystem listed in Appendix V. By reporting side effects you can help provide more information on the \n\nsafety of this medicine. \n\n \n\n \n\n5. How to store Revolade \n \n\nKeep this medicine out of the sight and reach of children. \n\n \n\nDo not use this medicine after the expiry date which is stated on the carton and the sachet. \n\n \n\nThis medicine does not require any special storage conditions. \n\n \n\nDo not open the foil sachets until ready for use. After mixing, Revolade oral suspension should be \n\nadministered immediately, but may be stored for no more than 30 minutes at room temperature. \n\n \n\nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \n\nthrow away medicines you no longer use. These measures will help protect the environment. \n\n \n\n \n\n6. Contents of the pack and other information \n\n \n\nWhat Revolade contains \n\n25 mg powder for oral suspension \n\nThe active substance in Revolade is eltrombopag. Each sachet contains a powder for reconstitution \n\nthat delivers 32 mg eltrombopag olamine, equivalent to 25 mg of eltrombopag free acid. \n\n \n\nThe other ingredients are: mannitol, sucralose and xanthan gum. \n\n \n\nWhat Revolade looks like and contents of the pack \n\nRevolade 25 mg powder for oral suspension is available in kits containing 30 sachets; each sachet \n\ncontains a reddish-brown to yellow powder. Each pack contains 30 sachets, one 40 ml reusable mixing \n\nbottle with lid and cap, and 30 single-use oral dosing syringes. \n\n \n\nMarketing authorisation holder \nNovartis Europharm Limited \n\nVista Building \n\nElm Park, Merrion Road \n\nDublin 4 \n\nIreland \n\n \n\nManufacturer \nLek d.d \n\nVerovskova Ulica 57 \n\nLjubljana 1526 \n\nSlovenia \n\n \n\nNovartis Pharma GmbH \n\nRoonstraße 25 \n\nD-90429 Nuremberg \n\nGermany \n\n \n\n \n\n\n\n127 \n\nFor any information about this medicine, please contact the local representative of the Marketing \n\nAuthorisation Holder: \n\n \n\nBelgië/Belgique/Belgien \n\nNovartis Pharma N.V. \n\nTél/Tel: +32 2 246 16 11 \n\n \n\nLietuva \n\nSIA “Novartis Baltics” Lietuvos filialas \n\nTel: +370 5 269 16 50 \n\n \n\nБългария \n\nNovartis Bulgaria EOOD \n\nТел: +359 2 489 98 28 \n\n \n\nLuxembourg/Luxemburg \n\nNovartis Pharma N.V. \n\nTél/Tel: +32 2 246 16 11 \n\n \n\nČeská republika \n\nNovartis s.r.o. \n\nTel: +420 225 775 111 \n\n \n\nMagyarország \n\nNovartis Hungária Kft. \n\nTel.: +36 1 457 65 00 \n\nDanmark \n\nNovartis Healthcare A/S \n\nTlf: +45 39 16 84 00 \n\n \n\nMalta \n\nNovartis Pharma Services Inc. \n\nTel: +356 2122 2872 \n\nDeutschland \n\nNovartis Pharma GmbH \n\nTel: +49 911 273 0 \n\n \n\nNederland \n\nNovartis Pharma B.V. \n\nTel: +31 26 37 82 555 \n\nEesti \n\nSIA Novartis Baltics Eesti filiaal \n\nTel: +372 66 30 810 \n\n \n\nNorge \n\nNovartis Norge AS \n\nTlf: +47 23 05 20 00 \n\nΕλλάδα \n\nNovartis (Hellas) A.E.B.E. \n\nΤηλ: +30 210 281 17 12 \n\n \n\nÖsterreich \n\nNovartis Pharma GmbH \n\nTel: +43 1 86 6570 \n\nEspaña \n\nNovartis Farmacéutica, S.A. \n\nTel: +34 93 306 42 00 \n\n \n\nPolska \n\nNovartis Poland Sp. z o.o. \n\nTel.: +48 22 375 4888 \n\nFrance \n\nNovartis Pharma S.A.S. \n\nTél: +33 1 55 47 66 00 \n\n \n\nPortugal \n\nNovartis Farma - Produtos Farmacêuticos, S.A. \n\nTel: +351 21 000 8600 \n\nHrvatska \n\nNovartis Hrvatska d.o.o. \n\nTel. +385 1 6274 220 \n\n \n\nRomânia \n\nNovartis Pharma Services Romania SRL \n\nTel: +40 21 31299 01 \n\nIreland \n\nNovartis Ireland Limited \n\nTel: +353 1 260 12 55 \n\n \n\nSlovenija \n\nNovartis Pharma Services Inc. \n\nTel: +386 1 300 75 50 \n\nÍsland \n\nVistor hf. \n\nSími: +354 535 7000 \n\n \n\nSlovenská republika \n\nNovartis Slovakia s.r.o. \n\nTel: +421 2 5542 5439 \n\n \n\nItalia \n\nNovartis Farma S.p.A. \n\nTel: +39 02 96 54 1 \n\nSuomi/Finland \n\nNovartis Finland Oy \n\nPuh/Tel: +358 (0)10 6133 200 \n\n \n\n\n\n128 \n\nΚύπρος \n\nNovartis Pharma Services Inc. \n\nΤηλ: +357 22 690 690 \n\n \n\nSverige \n\nNovartis Sverige AB \n\nTel: +46 8 732 32 00 \n\n \n\nLatvija \n\nSIA “Novartis Baltics” \n\nTel: +371 67 887 070 \n\n \n\nUnited Kingdom \n\nNovartis Pharmaceuticals UK Ltd. \n\nTel: +44 1276 698370 \n\n \n\n \n\nThis leaflet was last revised in. \n\n \n\nDetailed information on this medicine is available on the European Medicines Agency web site: \n\nhttp://www.ema.europa.eu./ \n\n\n\n129 \n\nINSTRUCTIONS FOR USE \n\n \n\nRevolade 25 mg powder for oral suspension \n\n \n\n(eltrombopag) \n\n \n\nRead and follow these instructions to prepare a dose of Revolade and give it to the child. If you have \n\nany questions, or if you damage or lose any of the supplies in your kit, ask your doctor, nurse or \n\npharmacist for advice \n\n \n\nBefore you start \n\nRead these messages first \n \n\n Revolade powder must be mixed only with water at room temperature. \n\n Give the medicine to the child immediately after you have mixed the powder with water. If you \n\ndon’t use the medicine within 30 minutes of mixing it, you will need to mix a new dose. \n\nDispose of the unused mixture in your household waste; don’t pour it down the drain. \n\n \n\n Try not to let the medicine touch your skin. If this happens, wash the area immediately with \nsoap and water. If you get a skin reaction, or if you have any questions, contact the doctor. \n\n If you spill any powder or liquid, clean it up with a damp cloth (see step 14 of the instructions). \n\n Take care that the child does not play with the bottle, cap, lid or syringes — there is a risk of \nchoking if the child puts them in their mouth. \n\n \n\nWhat you need \n\nEach Revolade powder for oral suspension kit contains: \n\n \n\n30 sachets of powder \n \n\n1 reusable mixing bottle with lid and cap (note — \n\nthe mixing bottle may become stained) \n\n \n30 single-use oral dosing syringes \n\n \n \n\nTo prepare and give a dose of Revolade, you need: \n\n \n\n The correct number of sachets your doctor has prescribed (supplied in the kit) \n\n 1 reusable mixing bottle with lid and cap (supplied in the kit) \n\n 1 single-use oral dosing syringe (supplied in the kit) \n\n 1 clean glass or cup filled with drinking water (not supplied) \n\n scissors to cut sachet (not supplied) \n \n\nCap \n\nLid \n\nPlunger Syringe tip \n\n\n\n130 \n\nMake sure that the bottle, cap and lid are dry before you use them. \n\nTo prepare the dose \n\n1. Make sure the lid is not on the mixing bottle. \n\n2. Fill the syringe with 20 ml drinking water from the glass or cup. \n\nA new single-use oral dosing syringe should be used to prepare each \n\ndose of Revolade for oral suspension. \n\n Start with the plunger pushed all the way into the syringe. \n\n Put the tip of the syringe all the way into the water \n\n Pull back on the plunger to the 20 ml mark on the syringe. \n\n \n3. Empty water into open mixing bottle \n\n Slowly pushing the plunger all the way into the syringe. \n\n \n4. Take only the prescribed number of sachets for one dose out of the kit. \n\n 25 mg dose — 1 sachet \n\n 50 mg dose — 2 sachets \n\n 75 mg dose — 3 sachets \n\n \n\n5. Add the powder from the prescribed number of sachets to \nthe bottle. \n\n Tap the top of each sachet to make sure the contents fall to \nthe bottom \n\n Cut off the top of each sachet with scissors \n\n Empty all contents of each sachet into the mixing bottle \n\n Make sure not to spill the powder outside the mixing bottle. \n\n \n6. Screw the lid onto the mixing bottle. Make sure the cap is firmly pushed onto the lid, so it is \n\nclosed. \n \n\n7. Gently and slowly shake the mixing bottle backwards and \n\nforwards for at least 20 seconds to mix the water with the powder. \n\n Don’t shake the bottle hard — that could make the medicine \nfoam. \n\n \nTo give a dose to a child \n\n8. Make sure the plunger is pushed all the way into the syringe. \n\n Pull cap off the lid of the mixing bottle \n\n Insert the syringe tip into the hole in the bottle lid. \n\n9. Fill the syringe with the medicine. \n\n Turn the mixing bottle upside-down together with the \nsyringe. \n\n Pull back the plunger until all the medicine is in the syringe. \n\n The medicine is a dark brown liquid. \n\n Remove the syringe from the bottle. \n\n \n \n\n\n\n131 \n\n10. Give the medicine to the child. Do this straight away when \n\nyou have mixed the dose. \n\n Place the tip of the syringe into the inside of the child’s \ncheek. \n\n Slowly push the plunger all the way down so the medicine \ngoes into the child’s mouth. \n\nMake sure the child has time to swallow. \n\n \n\n \n\nIMPORTANT: \nYou have now given the child nearly all of their dose of medicine. But there will still be some left in \n\nthe bottle, even though you may not be able to see it. \n\nNow you need to complete steps 11 to 13 to make sure the child receives all of the medicine. \n\n11. Again fill the syringe, this time with 10 ml of drinking water. \n\n Start with the plunger pushed all the way down into the \nsyringe. \n\n Put the tip of the syringe all the way into the water \n\n Pull back on the plunger to the 10 ml mark on the syringe. \n\n \n12. Empty the water into the mixing bottle. \n\n Insert the tip of the syringe into the hole in the lid of the \nmixing bottle. \n\n Slowly push the plunger all the way into the syringe. \n\n Push the cap firmly back on to the lid of the mixing bottle. \n\n \n13. Repeat steps 7 to 10 – gently shake the bottle to mix the rest of the medicine, then give all the \n\nrest of the liquid to the child. \n\nTo clean up \n\n14. If you have spilt any powder or mixed medicine, clean it up with a damp disposable cloth. \n\nYou may choose to wear disposable gloves so your skin doesn’t get stained. \n\n Dispose of the cloth and gloves used to clean up the spillage in your household waste. \n\n15. Clean the mixing equipment. \n\n Throw away the used oral dosing syringe. A new oral dosing syringe should be used to \nprepare each dose of Revolade for oral suspension. \n\n Rinse the mixing bottle and lid under running water. (The mixing bottle may become stained \nfrom the medicine. This is normal.) \n\n Let all the equipment dry in the air. \n\n Wash your hands with soap and water. \n\nAfter you have used all 30 sachets in the kit, dispose of the bottle. Always start with a complete \n\nnew kit for each 30 sachets. \n\n \n\nKeep Revolade powder for oral suspension, including the dosing kit, and all medicines out of the \n\nreach of children. \n\n \n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. PACKAGE LEAFLET"},"Section_1":{"kind":"string","value":"{'Title': '1. what revolade is and what it is used for', 'Section_Content': 'revolade contains eltrombopag, which belongs to a group of medicines called thrombopoietin receptor agonists. it is used to help increase the number of platelets in your blood. platelets are blood cells that help to reduce or prevent bleeding. revolade is used to treat a bleeding disorder called immune (primary) thrombocytopenia (itp) in patients aged 1 year and above who have already taken other medicines (corticosteroids or immunoglobulins), which have not worked. itp is caused by a low blood platelet count (thrombocytopenia). people with itp have an increased risk of bleeding. symptoms patients with itp may notice include petechiae (pinpoint- sized flat round red spots under the skin), bruising, nosebleeds, bleeding gums and not being able to control bleeding if they are cut or injured. revolade can also be used to treat low platelet count (thrombocytopenia) in adults with hepatitis c virus (hcv) infections, if they have had problems with side effects while on interferon treatment. many people with hepatitis c have low platelet counts, not only as a result of the disease, but also due to some of the antiviral medicines that are used to treat it. taking revolade may make it easier for you to complete a full course of antiviral medicine (peginterferon and ribavirin). revolade may also be used to treat adult patients with low blood counts caused by severe aplastic anaemia (saa). saa is a disease in which the bone marrow is damaged, causing a deficiency of the red blood cells (anaemia), white blood cells (leukopenia) and platelets (thrombocytopenia).', 'Entity_Recognition': [{'Text': 'revolade', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 4, 'BeginOffset': 18, 'EndOffset': 29, 'Score': 0.641822338104248, 'Text': 'eltrombopag', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a 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0.7418974041938782}]}, {'Id': 24, 'BeginOffset': 764, 'EndOffset': 772, 'Score': 0.8226613402366638, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 25, 'BeginOffset': 792, 'EndOffset': 799, 'Score': 0.805935263633728, 'Text': 'injured', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'revolade', 'Type': 'TREATMENT', 'BeginOffset': 801, 'EndOffset': 809}, {'Id': 26, 'BeginOffset': 836, 'EndOffset': 854, 'Score': 0.6267729997634888, 'Text': 'low platelet count', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.4995175898075104}]}, {'Id': 27, 'BeginOffset': 856, 'EndOffset': 872, 'Score': 0.9905648231506348, 'Text': 'thrombocytopenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9248627424240112}]}, {'Text': 'hepatitis c virus (hcv) infections', 'Type': 'PROBLEM', 'BeginOffset': 889, 'EndOffset': 923}, {'Id': 31, 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medicine', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 1259, 'EndOffset': 1272, 'Score': 0.9911662936210632, 'Text': 'peginterferon', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 1277, 'EndOffset': 1286, 'Score': 0.999302864074707, 'Text': 'ribavirin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'low blood counts', 'Type': 'PROBLEM', 'BeginOffset': 1344, 'EndOffset': 1360}, {'Text': 'severe aplastic anaemia (saa)', 'Type': 'PROBLEM', 'BeginOffset': 1371, 'EndOffset': 1400}, {'Text': 'a disease', 'Type': 'PROBLEM', 'BeginOffset': 1409, 'EndOffset': 1418}, {'Id': 3, 'BeginOffset': 1432, 'EndOffset': 1443, 'Score': 0.8706006407737732, 'Text': 'bone marrow', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'a deficiency of the red blood cells', 'Type': 'PROBLEM', 'BeginOffset': 1464, 'EndOffset': 1499}, {'Text': 'anaemia)', 'Type': 'PROBLEM', 'BeginOffset': 1501, 'EndOffset': 1509}, {'Id': 51, 'BeginOffset': 1511, 'EndOffset': 1528, 'Score': 0.5559437274932861, 'Text': 'white blood cells', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 36, 'BeginOffset': 1530, 'EndOffset': 1540, 'Score': 0.9486033916473389, 'Text': 'leukopenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.911952018737793}]}, {'Id': 52, 'BeginOffset': 1546, 'EndOffset': 1555, 'Score': 0.4649380147457123, 'Text': 'platelets', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 37, 'BeginOffset': 1557, 'EndOffset': 1573, 'Score': 0.9588358998298645, 'Text': 'thrombocytopenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8895142674446106}]}]}"},"Section_2":{"kind":"string","value":"{'Title': '2. what you need to know before you take revolade', 'Section_Content': \"do not take revolade if you are allergic to eltrombopag or any of the other ingredients of this medicine (listed in section 6 under 'what revolade contains'). check with your doctor if you think this applies to you. warnings and precautions talk to your doctor before taking revolade: if you have liver problems. people who have low platelet counts as well as advanced chronic (long-term) liver disease are more at risk of side effects, including life-threatening liver damage and blood clots. if your doctor considers that the benefits of taking revolade outweigh the risks, you will be closely monitored during treatment. if you are at risk of blood clots in your veins or arteries, or you know that blood clots are common in your family. you may be at higher risk of blood clots: - as you get older - if you have had to stay in bed for a long time - if you have cancer - if you are taking the contraceptive birth control pill or hormone replacement therapy - if you have recently had surgery or received a physical injury - if you are very overweight (obese) - if you are a smoker - if you have advanced chronic liver disease if any of these apply to you, tell your doctor before starting treatment. you should not take revolade unless your doctor considers that the expected benefits outweigh the risk of blood clots. if you have cataracts (the lens of the eye getting cloudy) if you have another blood condition, such as myelodysplastic syndrome (mds). your doctor will carry out tests to check that you do not have this blood condition before you start revolade. if you have mds and take revolade, your mds may get worse. tell your doctor if any of these apply to you. eye examinations your doctor will recommend that you are checked for cataracts. if you do not have routine eye-tests your doctor should arrange regular testing. you may also be checked for the occurrence of any bleeding in or around your retina (the light-sensitive layer of cells at the back of the eye). you will need regular tests before you start taking revolade, your doctor will carry out blood tests to check your blood cells, including platelets. these tests will be repeated at intervals while you are taking it. blood tests for liver function revolade can cause blood test results that may be signs of liver damage - an increase of some liver enzymes, especially bilirubin and alanine / aspartate transaminases. if you are taking interferon-based treatments together with revolade to treat low platelet count due to hepatitis c, some liver problems can get worse. you will have blood tests to check your liver function before you start taking revolade and at intervals while you are taking it. you may need to stop taking revolade if the amount of these substances increases too much, or if you get other signs of liver damage. read the information 'liver problems' in section 4 of this leaflet. blood tests for platelet count if you stop taking revolade, your blood platelet count is likely to become low again within several days. the platelet count will be monitored, and your doctor will discuss appropriate precautions with you. a very high blood platelet count may increase the risk of blood clotting. however blood clots can also form with normal or even low platelet counts. your doctor will adjust your dose of revolade to ensure that your platelet count does not become too high. get medical help immediately if you have any of these signs of a blood clot: swelling, pain or tenderness in one leg sudden shortness of breath especially together with sharp pain in the chest or rapid breathing abdominal (stomach) pain, enlarged abdomen, blood in your stools tests to check your bone marrow in people who have problems with their bone marrow, medicines like revolade could make the problems worse. signs of bone marrow changes may show up as abnormal results in your blood tests. your doctor may also carry out tests to directly check your bone marrow during treatment with revolade. checks for digestive bleeding if you are taking interferon-based treatments together with revolade you will be monitored for any signs of bleeding in your stomach or intestine after you stop taking revolade. heart monitoring your doctor may consider it necessary to monitor your heart during treatment with revolade and carry out an electrocardiogram (ecg) test. older people (65 years and above) there are limited data on the use of revolade in patients aged 65 years and older. care should be taken when using revolade if you are aged 65 years or above. children and adolescents revolade is not recommended for children aged under 1 year who have itp. it is also not recommended for people under 18 years with low platelet counts due to hepatitis c or severe aplastic anaemia. other medicines and revolade tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. this includes medicines obtained without prescription and vitamins. some everyday medicines interact with revolade including prescription and non-prescription medicines and minerals. these include: antacid medicines to treat indigestion, heartburn or stomach ulcers (see also 'when to take it' in section 3) medicines called statins, to lower cholesterol some medicines to treat hiv infection, such as lopinavir and/or ritonavir ciclosporin used in the context of transplantations or immune diseases minerals such as iron, calcium, magnesium, aluminium, selenium and zinc which may be found in vitamin and mineral supplements (see also 'when to take it' in section 3) medicines such as methotrexate and topotecan, to treat cancer talk to your doctor if you take any of these. some of them are not to be taken with revolade, or the dose may need adjusting, or you may need to alter the timing of when you take them. your doctor will review the medicines you are taking, and suggest suitable replacements if necessary. if you are also taking medicines to prevent blood clots there is a greater risk of bleeding. your doctor will discuss this with you. if you are taking corticosteroids, danazol, and/or azathioprine you may need to take a lower dose or to stop taking them while you are taking revolade. revolade with food and drink do not take revolade with dairy foods or drinks as the calcium in dairy products affects the absorption of the medicine. for more information, see 'when to take it' in section 3. pregnancy and breast-feeding don't use revolade if you are pregnant unless your doctor specifically recommends it. the effect of revolade during pregnancy is not known. tell your doctor if you are pregnant, think you may be pregnant, or are planning to have a baby. use a reliable method of contraception while you're taking revolade, to prevent pregnancy if you do become pregnant during treatment with revolade, tell your doctor. don't breast-feed while you are taking revolade. it is not known whether revolade passes into breast-milk. if you are breast-feeding or planning to 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is one 50 mg tablet of revolade a day. if you are of asian origin (chinese, japanese, taiwanese, thai or korean) you may need to start at a lower dose of 25 mg. children (1 to 5 years) — the usual starting dose for itp is one 25 mg tablet of revolade a day. for hepatitis c adults - the usual starting dose for hepatitis c is one 25 mg tablet of revolade a day. if you are of asian origin (chinese, japanese, taiwanese, thai or korean) you will start on the same 25 mg dose. for saa adults - the usual starting dose for saa is one 50 mg tablet of revolade a day. if you are of asian origin (chinese, japanese, taiwanese, thai or korean) you may need to start at a lower dose of 25 mg. revolade may take 1 to 2 weeks to work. based on your response to revolade your doctor may recommend that your daily dose is changed. how to take the tablets swallow the tablet whole, with some water. when to take it make sure that in the 4 hours before you take revolade and the 2 hours after you take revolade you don't consume any of the following: dairy foods such as cheese, butter, yoghurt or ice cream milk or milk shakes, drinks containing milk, yoghurt or cream antacids, a type of medicine for indigestion and heartburn some mineral and vitamin supplements including iron, calcium, magnesium, aluminium, selenium and zinc if you do, the medicine will not be properly absorbed into your body. for more advice about suitable foods and drinks, talk to your doctor. if you take more revolade than you should contact a doctor or pharmacist immediately. if possible show them the pack, or this leaflet. youwill be monitored for any signs or symptoms of side effects and given appropriate treatment immediately. if you forget to take revolade take the next dose at the usual time. do not take more than one dose of revolade in one day. if you stop taking revolade don't stop taking revolade without talking to your doctor. if your doctor advises you to stop treatment, your platelet count will then be checked each week for four weeks. see also 'bleeding or bruising after you stop treatment' in section 4. if you have any further questions on the use of this medicine, ask your doctor or pharmacist. no dairy products, antacids or mineral supplements take revolade for 4 hours before you take revolade... ... and for 2 hours after 106\", 'Entity_Recognition': [{'Text': 'revolade', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Id': 0, 'BeginOffset': 167, 'EndOffset': 175, 'Score': 0.4695754051208496, 'Text': 'revolade', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 246, 'EndOffset': 254, 'Score': 0.46186569333076477, 'Text': 'revolade', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 29, 'BeginOffset': 371, 'EndOffset': 374, 'Score': 0.7969675660133362, 'Text': 'itp', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': 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12846}]}"},"Section_5":{"kind":"string","value":"{'Title': '5. how to store revolade', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and the blister. this medicine does not require any special storage conditions. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': \"what revolade contains the active substance in revolade is eltrombopag. 12.5 mg film-coated tablets each film-coated tablet contains eltrombopag olamine equivalent to 12.5 mg eltrombopag. 25 mg film-coated tablets each film-coated tablet contains eltrombopag olamine equivalent to 25 mg eltrombopag. 50 mg film-coated tablets each film-coated tablet contains eltrombopag olamine equivalent to 50 mg eltrombopag. 75 mg film-coated tablets each film-coated tablet contains eltrombopag olamine equivalent to 75 mg eltrombopag. the other ingredients are: hypromellose, macrogol 400, magnesium stearate, mannitol (e421), microcrystalline cellulose, povidone, sodium starch glycolate, titanium dioxide (e171). revolade 12.5 mg and 25 mg film-coated tablets also contain polysorbate 80 (e433). revolade 50 mg film-coated tablets also contain iron oxide red (e172) and iron oxide yellow (e172). revolade 75 mg film-coated tablets also contain iron oxide red (e172) and iron oxide black (e172). what revolade looks like and contents of the pack revolade 12.5 mg film-coated tablets are round, biconvex, white, debossed with 'gs mz1' and '12.5' on one side. revolade 25 mg film-coated tablets are round, biconvex, white, debossed with 'gs nx3' and '25' on one side. revolade 50 mg film-coated tablets are round, biconvex, brown, debossed with 'gs ufu' and '50' on one side. revolade 75 mg film-coated tablets are round, biconvex, pink, debossed with 'gs ffs' and '75' on one side. they are supplied in aluminum blisters in a carton containing 14 or 28 film-coated tablets and multipacks containg 84 (3 packs of 28) film-coated tablets). not all pack sizes may be available in your country.\", 'Entity_Recognition': [{'Text': 'revolade', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 59, 'EndOffset': 70, 'Score': 0.7694530487060547, 'Text': 'eltrombopag', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.6871616244316101, 'RelationshipScore': 0.9999998807907104, 'RelationshipType': 'STRENGTH', 'Id': 1, 'BeginOffset': 72, 'EndOffset': 79, 'Text': '12.5 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.7121841907501221, 'RelationshipScore': 0.9999977350234985, 'RelationshipType': 'FORM', 'Id': 2, 'BeginOffset': 80, 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1624}]}"}}},{"rowIdx":1059,"cells":{"ID":{"kind":"string","value":"D88405464CAD9C406AE56D99F2ACED75"},"URL":{"kind":"string","value":"https://www.ema.europa.eu/documents/product-information/kovaltry-epar-product-information_en.pdf"},"Product_Name":{"kind":"string","value":"Kovaltry"},"Full_Content":{"kind":"string","value":"1 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX I \n \n\nSUMMARY OF PRODUCT CHARACTERISTICS \n \n\n\n\n2 \n\n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 250 IU powder and solvent for solution for injection \nKovaltry 500 IU powder and solvent for solution for injection \nKovaltry 1000 IU powder and solvent for solution for injection \nKovaltry 2000 IU powder and solvent for solution for injection \nKovaltry 3000 IU powder and solvent for solution for injection \n \n \n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \nKovaltry 250 IU powder and solvent for solution for injection \nKovaltry contains approximately 250 IU (100 IU / 1 mL) of recombinant human coagulation \nfactor VIII (INN: octocog alfa) after reconstitution. \n \nKovaltry 500 IU powder and solvent for solution for injection \nKovaltry contains approximately 500 IU (200 IU / 1 mL) of recombinant human coagulation \nfactor VIII (INN: octocog alfa) after reconstitution. \n \nKovaltry 1000 IU powder and solvent for solution for injection \nKovaltry contains approximately 1000 IU (400 IU / 1 mL) of recombinant human coagulation \nfactor VIII (INN: octocog alfa) after reconstitution. \n \nKovaltry 2000 IU powder and solvent for solution for injection \nKovaltry contains approximately 2000 IU (400 IU / 1 mL) of recombinant human coagulation \nfactor VIII (INN: octocog alfa) after reconstitution. \n \nKovaltry 3000 IU powder and solvent for solution for injection \nKovaltry contains approximately 3000 IU (600 IU / 1 mL) of recombinant human coagulation \nfactor VIII (INN: octocog alfa) after reconstitution. \n \nThe potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The specific \nactivity of Kovaltry is approximately 4000 IU/mg protein. \n \nOctocog alfa (Full length recombinant human coagulation factor VIII (rDNA)) is a purified protein \nthat has 2,332 amino acids. It is produced by recombinant DNA technology in baby hamster kidney \ncells (BHK) into which the human factor VIII gene has been introduced. Kovaltry is prepared without \nthe addition of any human or animal derived protein in the cell culture process, purification or final \nformulation. \n \nFor the full list of excipients, see section 6.1. \n \n \n3. PHARMACEUTICAL FORM \n \nPowder and solvent for solution for injection \n \nPowder: solid, white to slightly yellow. \nSolvent: water for injections, a clear solution. \n \n \n\n\n\n3 \n\n4. CLINICAL PARTICULARS \n \n4.1 Therapeutic indications \n \nTreatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII \ndeficiency). Kovaltry can be used for all age groups. \n \n4.2 Posology and method of administration \n \nTreatment should be under the supervision of a physician experienced in the treatment of haemophilia. \n \nTreatment monitoring \n \nDuring the course of treatment, appropriate determination of factor VIII levels is advised to guide the \ndose to be administered and the frequency of repeated infusions. Individual patients may vary in their \nresponse to factor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweight \nmay require adjustment in underweight or overweight patients. \n \nIn the case of major surgical interventions in particular, precise monitoring of the substitution therapy \nby means of coagulation analysis (plasma factor VIII activity) is indispensable. \n \nPosology \n \nThe dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, \non the location and extent of the bleeding and on the patient's clinical condition. \n \nThe number of units of factor VIII administered is expressed in International Units (IU), which are \nrelated to the current WHO standard for factor VIII products. Factor VIII activity in plasma is \nexpressed either as a percentage (relative to normal human plasma) or in International Units (relative \nto an International Standard for factor VIII in plasma). \n \nOne International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in \none mL of normal human plasma. \n \nOn demand treatment \n \nThe calculation of the required dose of factor VIII is based on the empirical finding that \n1 International Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by 1.5% \nto 2.5% of normal activity. \nThe required dose is determined using the following formula: \n \nRequired units = body weight (kg) x desired factor VIII rise (% or IU/dL) x reciprocal of observed \nrecovery (i.e. 0.5 for recovery of 2.0%). \n \nThe amount to be administered and the frequency of administration should always be targeted to the \nclinical effectiveness required in the individual case. \n \nIn the case of the following haemorrhagic events, the factor VIII activity should not fall below the \ngiven level (in % of normal) in the corresponding period. The following table can be used to guide \ndosing in bleeding episodes and surgery: \n \n\n\n\n4 \n\nTable 1: Guide for dosing in bleeding episodes and surgery \nDegree of haemorrhage/ \nType of surgical procedure \n\nFactor VIII level \nrequired (%) (IU/dL) \n\nFrequency of doses (hours)/ \nDuration of therapy (days) \n\nHaemorrhage \n \nEarly haemarthrosis, muscle \nbleeding or oral bleeding \n\n \n \n\n20 - 40 \n\nRepeat every 12 to 24 hours. At \nleast 1 day, until the bleeding \nepisode as indicated by pain is \nresolved or healing is achieved. \n\nMore extensive \nhaemarthrosis, muscle \nbleeding or haematoma \n\n30 - 60 Repeat infusion every 12 - 24 hours \nfor 3 - 4 days or more until pain and \nacute disability are resolved. \n\nLife threatening \nhaemorrhages \n\n60 - 100 Repeat infusion every 8 to 24 hours \nuntil threat is resolved \n\nSurgery \nMinor surgery \nincluding tooth extraction \n\n \n \n\n30 - 60 \n\n \nEvery 24 hours, at least 1 day, until \nhealing is achieved. \n\nMajor surgery 80 - 100 \n(pre- and post-\n\noperative) \n\nRepeat infusion every 8 - 24 hours \nuntil adequate wound healing, then \ntherapy for at least another 7 days to \nmaintain a factor VIII activity of \n30% to 60% (IU/dL). \n\n \nProphylaxis \nFor long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses for \nadolescents (≥ 12 years age) and adult patients are 20 to 40 IU of Kovaltry per kg body weight two to \nthree times per week. \nIn some cases, especially in younger patients, shorter dose intervals or higher doses may be necessary. \n \nPaediatric population \nA safety and efficacy study has been performed in children of 012 years (see section 5.1); limited data \nare available for children below 1 year. \nThe recommended prophylaxis doses are 20-50 IU/kg twice weekly, three times weekly or every other \nday according to individual requirements. For paediatric patients above the age of 12, the dose \nrecommendations are the same as for adults. \n \nMethod of administration \n \nIntravenous use. \n \nKovaltry should be injected intravenously over 2 to 5 minutes depending on the total volume. The rate \nof administration should be determined by the patient’s comfort level (maximal rate of infusion: \n2 mL/min). \nFor instructions on reconstitution of the medicinal product before administration, see section 6.6 and \nthe package leaflet. \n \n4.3 Contraindications \n \n\n Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. \n Known allergic reactions to mouse or hamster proteins. \n\n \n4.4 Special warnings and precautions for use \n \nTraceability \n \nIn order to improve traceability of biological medicinal products, the name and the batch number of \nthe administered product should be clearly recorded. \n \n\n\n\n5 \n\nHypersensitivity \n \nAllergic type hypersensitivity reactions are possible with Kovaltry. \nIf symptoms of hypersensitivity occur, patients should be advised to discontinue the use of the \nmedicinal product immediately and contact their physician. \nPatients should be informed of the early signs of hypersensitivity reactions including hives, \ngeneralised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. \n \nIn case of shock, standard medical treatment for shock should be implemented. \n \nInhibitors \n \nThe formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the \nmanagement of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins \ndirected against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) \nper mL of plasma using the modified assay. The risk of developing inhibitors is correlated to the \nseverity of the disease as well as the exposure to factor VIII , this risk being highest within the first \n50 exposure days but continues throughout life although the risk is uncommon. \n \nThe clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre \nposing less of a risk of insufficient clinical response than high titre inhibitors. \n \nIn general, all patients treated with coagulation factor VIII products should be carefully monitored for \nthe development of inhibitors by appropriate clinical observations and laboratory tests (see \nsection 4.2). \nIf the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with \nan appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients with \nhigh levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should \nbe considered. Management of such patients should be directed by physicians with experience in the \ncare of haemophilia and factor VIII inhibitors. \n \nCardiovascular events \n \nIn patients with existing cardiovascular risk factors, substitution therapy with FVIII may increase the \ncardiovascular risk. \n \nCatheter-related complications \n \nIf a central venous access device (CVAD) is required, risk of CVAD-related complications including \nlocal infections, bacteraemia and catheter site thrombosis should be considered. \n \nIt is strongly recommended that every time that Kovaltry is administered to a patient, the name and \nbatch number of the product are recorded in order to maintain a link between the patient and the batch \nof the medicinal product. \n \nPaediatric population \n \nThe listed warnings and precautions apply both to adults and children. \n \nSodium content \n \nThis medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially \n‘sodium-free’. \n \n\n\n\n6 \n\n4.5 Interactions with other medicinal products and other forms of interaction \n \nNo interactions of human coagulation factor VIII (rDNA) products with other medicinal products have \nbeen reported. \n \n4.6 Fertility, pregnancy and lactation \n \nPregnancy \n \nAnimal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence \nof haemophilia A in women, experience regarding the use of factor VIII during pregnancy is not \navailable. \nTherefore, factor VIII should be used during pregnancy only if clearly indicated. \n \nBreast-feeding \n \nIt is unknown whether Kovaltry is excreted in human milk. The excretion in animals has not been \nstudied. Therefore, factor VIII should be used during breast-feeding only if clearly indicated. \n \nFertility \n \nNo animal fertility studies have been conducted with Kovaltry and its effect on human fertility has not \nbeen established in controlled clinical trials. Since Kovaltry is a replacement protein of endogenous \nfactor VIII, no adverse effects on fertility are expected. \n \n4.7 Effects on ability to drive or use machines \n \nIf patients experience dizziness or other symptoms affecting their ability to concentrate and react, it is \nrecommended that they do not drive or use machines until the reaction subsides. \n \n4.8 Undesirable effects \n \nSummary of the safety profile \n \nHypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the \ninfusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, \nrestlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed and \nmay in some cases progress to severe anaphylaxis (including shock). \nDevelopment of antibodies to mouse and hamster protein with related hypersensitivity reactions may \noccur. \n \nDevelopment of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated \nwith factor VIII (FVIII), including with Kovaltry. If such inhibitors occur, the condition may manifest \nitself as an insufficient clinical response. In such cases, it is recommended that a specialised \nhaemophilia centre be contacted. \n \nTabulated list of adverse reactions \n \nThe table presented below is according to the MedDRA system organ classification (SOC and \nPreferred Term Level). Frequencies have been evaluated according to the following convention: very \ncommon (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) , rare (≥1/10,000 to \n<1/1,000); very rare (<1/10,000). \nWithin each frequency grouping, adverse reactions are presented in order of decreasing seriousness. \n \n\n\n\n7 \n\nTable 2: Frequency of adverse drug reactions in clinical trials \nMedDRA \nSystem Organ Class \n\nAdverse reactions Frequency \n \n\nBlood and lymphatic system disorders Lymphadenopathy common \n\nFVIII inhibition very common (PUPs)* \nuncommon (PTPs)* \n\nImmune system disorders Hypersensitivity uncommon \nPsychiatric disorders Insomnia common \nNervous system disorders Headache, dizziness common \n\nDysgeusia uncommon \nCardiac disorders Palpitation, sinus \n\ntachycardia \ncommon \n\nVascular disorders Flushing uncommon \n\nGastrointestinal disorders Abdominal pain, \nabdominal discomfort, \ndyspepsia \n\ncommon \n\nSkin and subcutaneous tissue disorders Pruritus, rash***, \ndermatitis allergic \n\ncommon \n \n\nUrticaria uncommon \n\nGeneral disorders and administration \nsite conditions \n\nPyrexia, chest \ndiscomfort, injection \nsite reactions ** \n\ncommon \n\n* Frequency is based on studies with all FVIII products which included patients with severe \nhaemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients \n** includes injection site extravasation, hematoma, infusion site pain, pruritus, swelling \n*** rash, rash erythematous, rash pruritic \n \nDescription of selected adverse reactions \n \nThe most frequently reported adverse reactions in PTPs were related to potential hypersensitivity \nreactions, including headache, pyrexia, pruritus, rash, and abdominal discomfort. \n \nImmunogenicity \nThe immunogenicity of Kovaltry was evaluated in previously treated patients (PTPs). \nDuring clinical trials with Kovaltry in approximately 200 pediatric and adult patients diagnosed with \nsevere hemophilia A (FVIII:C < 1%) with previous exposure to factor VIII concentrates ≥ 50 ED, one \ncase of transient low titer inhibitor occurred in the ongoing LEOPOLD Kids Part A extension study. \n \nPaediatric population \nIn completed clinical studies with 71 paediatric previously treated patients, the frequency, type and \nseverity of adverse reactions in children were found to be similar to those in adults. \n \nReporting of suspected adverse reactions \n \nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V. \n \n4.9 Overdose \n \nNo symptoms of overdose with recombinant human coagulation factor VIII have been reported. \n \n\n\n\n8 \n\n \n5. PHARMACOLOGICAL PROPERTIES \n \n5.1 Pharmacodynamic properties \n \nPharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII, ATC code B02BD02. \n \nMechanism of action \n \nThe factor VIII/von Willebrand factor (vWF) complex consists of two molecules (factor VIII and \nvWF) with different physiological functions. When infused into a haemophiliac patient, factor VIII \nbinds to vWF in the patient’s circulation. Activated factor VIII acts as a cofactor for activated \nfactor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts \nprothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. \nHaemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of \nfactor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either \nspontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels \nof factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and \ncorrection of the bleeding tendencies. \n \nOf note, annualised bleeding rate (ABR) is not comparable between different factor concentrates and \nbetween different clinical studies. \n \nKovaltry does not contain von Willebrand factor. \n \nPharmacodynamic effects \n \nThe activated partial thromboplastin time (aPTT) is prolonged in people with haemophilia. \nDetermination of aPTT is a conventional in vitro assay for biological activity of factor VIII. Treatment \nwith rFVIII normalizes the aPTT similar to that achieved with plasma-derived factor VIII. \n \nClinical efficacy and safety \n \nControl and Prevention of Bleeding \nTwo multi-centre, open-label, cross-over, uncontrolled, randomised studies in previously treated \nadults/adolescents with severe haemophilia A (< 1%) and one multi-centre, open-label, uncontrolled \nstudy in previously treated children < 12 years with severe haemophilia A were conducted. \n \nA total of 204 subjects have been included in the clinical trial program, 153 subjects ≥ 12 years and \n51 subjects < 12 years. 140 subjects were treated for at least 12 months, and 55 of these subjects for a \nmedian of 24 months. \n \nPaediatric population <12 years \nThe paediatric trial enrolled 51 PTPs with severe haemophilia A, 26 subjects in the age group 6-\n12 years and 25 subjects in the age group <6 years having accumulated a median number of 73 EDs \n(range: 37 to 103 EDs). Subjects were treated with 2 or 3 injections per week or up to every other day at \na dose of 25 to 50 IU/kg. Consumption for prophylaxis and treatment of bleeds, annualised bleed rates \nand success rate for bleed treatment are presented in Table 3 \n \n\n\n\n9 \n\nTable 3: Consumption and overall success rates (patients treated with prophylaxis only) \n Younger \n\nchildren \n(0 <6 \nyears) \n\nOlder \nchildren \n(6 <12 \nyears) \n\nAdolescents and adults \n12-65 years \n\nTotal \n\n \n \n\n Study 1 Study 2 \n \n\n2 x/week \ndosing \n\nStudy 2 \n \n\n3 x/week \ndosing \n\n \n\nStudy \nparticipants \n\n25 26 62 28 31 172 \n\n \n\nDose/prophylaxis \ninjection, IU/kg \nBW \nmedian (min, \nmax) \n\n36 IU/kg \n(21; \n\n58 IU/kg) \n\n32 IU/kg \n(22; \n\n50 IU/kg) \n\n31 IU/kg \n(21; \n\n43 IU/kg) \n\n30 IU/kg \n(21; \n\n34 IU/kg) \n\n37 IU/kg \n(30; \n\n42 IU/kg) \n\n32 IU/kg \n(21; \n\n58 IU/kg) \n \n\n \n\nABR – all bleeds \n(median, Q1,Q3) \n\n2.0 \n(0.0; 6.0) \n\n0.9 \n(0.0; 5.8) \n\n1.0 \n(0.0; 5.1) \n\n4.0 \n(0.0; 8.0) \n\n2.0 \n(0.0; 4.9) \n\n2.0 \n(0.0; 6.1) \n\n \n\nDose/injection for \nbleed treatment \nMedian (min; \nmax) \n\n39 IU/kg \n(21;72 IU\n\n/kg) \n\n32 IU/kg \n(22; \n\n50 IU/kg) \n\n29 IU/kg \n(13; \n\n54 IU/kg) \n\n28 IU/kg \n(19; \n\n39 IU/kg) \n\n31 IU/kg \n(21; \n\n49 IU/kg) \n\n31 IU/kg \n(13; \n\n72 IU/kg) \n\nSuccess rate* 92.4% 86.7% 86.3% 95.0% 97.7% 91.4% \n\nABR annualised bleed rate \nQ1 first quartile; Q3 third quartile \nBW: Body weight \n*Success rate defined as % of bleeds treated successfully with ≤ 2 infusions \n \n5.2 Pharmacokinetic properties \n \nThe pharmacokinetic (PK) profile of Kovaltry was evaluated in PTPs with severe haemophilia A \nfollowing 50 IU/kg in 21 subjects ≥ 18 years, 5 subjects ≥ 12 years and < 18 years and 19 subjects \n< 12 years of age. \n \nA population PK model was developed based on all available factor VIII measurements (from dense \nPK sampling and all recovery samples) throughout the 3 clinical studies allowing calculation of PK \nparameters for subjects in the various studies. The table 4 below provides PK parameters based on the \npopulation PK model. \n \n\n\n\n10 \n\nTable 4: PK parameters (geometric mean (%CV)) based on chromogenic assay. * \nPK parameter ≥ 18 years \n\nN=109 \n12-<18 years \n\nN=23 \n6-<12 years \n\nN=27 \n0-<6 years \n\nN=24 \nT1/2 (h) 14.8 (34) 13.3 (24) 14.1 (31) 13.3 (24) \n\nAUC (IU.h/dL)** 1,858 (38) 1,523 (27) 1,242 (35) 970 (25) \nCL (dL/h/kg) 0.03 (38) 0.03 (27) 0.04 (35) 0.05 (25) \nVss (dL/kg) 0.56 (14) 0.61 (14) 0.77 (15) 0.92 (11) \n\n* Based on population PK estimates \n**AUC calculated for a dose of 50 IU/kg \n \nRepeated PK measurements after 6 to 12 months of prophylaxis treatment with Kovaltry did not \nindicate any relevant changes in PK characteristics after long-term treatment. \n \nIn an international study involving 41 clinical laboratories, the performance of Kovaltry in FVIII:C \nassays was evaluated and compared to a marketed full length rFVIII product. Consistent results were \ndetermined for both products. The FVIII:C of Kovaltry can be measured in plasma with a one-stage \ncoagulation assay as well as with a chromogenic assay using the routine methods of the laboratory. \n \nThe analysis of all recorded incremental recoveries in previously treated patients demonstrated a \nmedian rise of > 2% (> 2 IU/dL) per IU/kg body weight for Kovaltry. This result is similar to the \nreported values for factor VIII derived from human plasma. There was no relevant change over the \n6-12 months treatment period. \n \nTable 5: Phase III incremental recovery results \nStudy participants N=115 \nChromogenic assay results \nMedian; (Q1; Q3) (IU/dL / IU/kg) \n\n2.3 (1.8; 2.6) \n\nOne-stage assay results \nMedian; (Q1; Q3) (IU/dL / IU/kg) \n\n2.2 (1.8; 2.4) \n\n \n5.3 Preclinical safety data \n \nNon-clinical data reveal no special risk for humans based on safety pharmacology, in vitro \ngenotoxicity, and short term repeat-dose toxicity studies. Repeat-dose toxicity studies longer than \n5 days, reproductive toxicity studies, and carcinogenicity studies, have not been performed. Such \nstudies are not considered meaningful due to the production of antibodies against the heterologous \nhuman protein in animals. Also factor VIII is an intrinsic protein and not known to cause any \nreproductive or carcinogenic effects. \n \n \n6. PHARMACEUTICAL PARTICULARS \n \n6.1 List of excipients \n \nPowder \nSucrose \nHistidine \nGlycine (E 640) \nSodium chloride \nCalcium chloride dihydrate (E 509) \nPolysorbate 80 (E 433) \nAcetic acid, glacial (for pH adjustment) (E 260) \n \nSolvent \nWater for injections \n \n\n\n\n11 \n\n6.2 Incompatibilities \n \nIn the absence of compatibility studies, this medicinal product must not be mixed with other medicinal \nproducts. \n \nOnly the provided infusion sets should be used for reconstitution and injection because treatment \nfailure can occur as a consequence of human recombinant coagulation factor VIII adsorption to the \ninternal surfaces of some infusion equipment. \n \n6.3 Shelf life \n \n30 months \n \nThe chemical and physical in-use stability after reconstitution has been demonstrated for 3 hours at \nroom temperature. \nAfter reconstitution, from a microbiological point of view, the product should be used immediately. If \nnot used immediately, in use storage times and conditions prior to use are the responsibility of the \nuser. \n \nDo not refrigerate after reconstitution. \n \n6.4 Special precautions for storage \n \nStore in a refrigerator (2 °C - 8 °C). \nDo not freeze. \nKeep the vial and the pre filled syringe in the outer carton in order to protect from light. \n \nWithin its overall shelf life of 30 months the product when kept in its outer carton, may be stored up to \n25 °C for a limited period of 12 months. In this case, the product expires at the end of this 12 month \nperiod or the expiry date on the product vial, whichever is earlier. The new expiry date must be noted \non the outer carton. \n \nFor storage conditions after reconstitution of the medicinal product, see section 6.3. \n \n6.5 Nature and contents of container and special equipment for use, administration or \n\nimplantation \n \nEach single package of Kovaltry contains: \n• one vial with powder (10 mL clear glass type 1 vial with grey halogenobutyl rubber blend \n\nstopper and aluminium seal) \n• one pre-filled syringe with 2.5 mL (for 250 IU, 500 IU and 1000 IU) or 5 mL (for 2000 IU and \n\n3000 IU) solvent (clear glass cylinder type 1 with grey bromobutyl rubber blend stopper) \n• syringe plunger rod \n• vial adapter \n• one venipuncture set \n \nPack sizes \n 1 single pack. \n 1 multipack with 30 single packs. \nNot all pack sizes may be marketed. \n \n6.6 Special precautions for disposal and other handling \n \nDetailed instructions for preparation and administration are contained in the package leaflet provided \nwith Kovaltry. \n \nThe reconstituted medicinal product is a clear and colourless solution. \n\n\n\n12 \n\nKovaltry powder should only be reconstituted with the supplied solvent (2.5 mL or 5 mL water for \ninjections) in the prefilled syringe and the vial adapter. For infusion, the product must be prepared \nunder aseptic conditions. If any component of the package is opened or damaged, do not use this \ncomponent. \nAfter reconstitution the solution is clear. Parenteral medicinal products should be inspected visually \nfor particulate matter and discoloration prior to administration. Do not use Kovaltry if you notice \nvisible particulate matter or turbidity. \n \nAfter reconstitution, the solution is drawn back into the syringe. Kovaltry should be reconstituted and \nadministered with the components (vial adapter, prefilled syringe, venipuncture set) provided with \neach package. \n \nThe reconstituted product must be filtered prior to administration to remove potential particulate \nmatter in the solution. Filtering is achieved by using the vial adapter. \nThe venipuncture set provided with the product must not be used for drawing blood because it \ncontains an in line filter. \n \nFor single use only. \nAny unused medicinal product or waste material should be disposed of in accordance with local \nrequirements. \n \n \n7. MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n8. MARKETING AUTHORISATION NUMBERS \n \nEU/1/15/1076/002 1 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/012 - 1 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \nEU/1/15/1076/004 - 1 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/014 - 1 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \nEU/1/15/1076/006 - 1 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/016 - 1 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \nEU/1/15/1076/008 - 1 x (Kovaltry 2000 IU - solvent (5 mL); pre-filled syringe (5 mL)) \nEU/1/15/1076/010 - 1 x (Kovaltry 3000 IU - solvent (5 mL); pre-filled syringe (5 mL)) \nEU/1/15/1076/017 30 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/018 - 30 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \nEU/1/15/1076/019 - 30 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/020 - 30 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \nEU/1/15/1076/021 - 30 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/022 - 30 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \nEU/1/15/1076/023 - 30 x (Kovaltry 2000 IU - solvent (5 mL); pre-filled syringe (5 mL)) \nEU/1/15/1076/024 - 30 x (Kovaltry 3000 IU - solvent (5 mL); pre-filled syringe (5 mL)) \n \n \n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n \nDate of first authorisation: 18 February 2016 \nDate of latest renewal: \n \n \n\n\n\n13 \n\n10. DATE OF REVISION OF THE TEXT \n \nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency http://www.ema.europa.eu. \n \n\n\n\n14 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX II \n\n \n\nA. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND \nMANUFACTURER RESPONSIBLE FOR BATCH RELEASE \n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n\n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n \n\n \n\n\n\n15 \n\nA. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND \nMANUFACTURER RESPONSIBLE FOR BATCH RELEASE \n\n \nName and address of the manufacturer of the biological active substance \n\nBayer HealthCare LLC \n800 Dwight Way \nBerkeley \nCA 94710 \nUnited States \n\nName and address of the manufacturer responsible for batch release \n\nBayer AG \nKaiser-Wilhelm-Allee \n51368 Leverkusen \nGermany \n\n \n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n \nMedicinal product subject to restricted medical prescription (see Annex I: Summary of Product \nCharacteristics, section 4.2). \n \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n \n Periodic safety update reports (PSURs) \n\n \nThe requirements for submission of PSURs for this medicinal product are set out in the list of Union \nreference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any \nsubsequent updates published on the European medicines web-portal. \n\n \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n \n Risk management plan (RMP) \n\n \nThe marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities \nand interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing \nauthorisation and any agreed subsequent updates of the RMP. \n\nAn updated RMP should be submitted: \n\n At the request of the European Medicines Agency; \n\n Whenever the risk management system is modified, especially as the result of new \ninformation being received that may lead to a significant change to the benefit/risk profile or \nas the result of an important (pharmacovigilance or risk minimisation) milestone being \nreached. \n\n \n\n\n\n16 \n\n Obligation to conduct post-authorisation measures \n \nThe MAH shall complete, within the stated timeframe, the below measures: \n \n\nDescription Due date \nPost-authorisation Efficacy Study: In order to investigate the safety and efficacy of \nKovaltry in previously untreated patients, the MAH should submit the results of the \nongoing study “13400 - Leopold Kids Part B” \n\n12/2022 \n\n \nPost-authorisation Efficacy Study: In order to investigate the safety and efficacy of \nlong term treatment with Kovaltry, the MAH should submit the results of the ongoing \nstudy “13400 - Leopold Kids extension” \n\n12/2022 \n\n \n \n\n\n\n17 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX III \n \n\nLABELLING AND PACKAGE LEAFLET \n \n\n\n\n18 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nA. LABELLING \n\n\n\n19 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nOUTER CARTON OF A SINGLE PACK (INCLUDING BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 250 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 250 IU (100 IU / 1 mL) octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \nFor reconstitution read package leaflet before use. \n \n\n \n \n \n\n\n\n20 \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \nOF THE SIGHT AND REACH OF CHILDREN \n\n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. Do not freeze. \n \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/002 – 1 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/012 – 1 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n\n\n\n21 \n\n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 250 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC \nSN \nNN \n \n \n\n\n\n22 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nOUTER LABEL OF MULTIPACK WITH 30 SINGLE PACKS (INCLUDING BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 250 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 250 IU (100 IU / 1 mL) octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \nMultipack with 30 single packs, each containing: \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \n\n\n\n23 \n\nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. \nDo not freeze. \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/017 – 30 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/018 – 30 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 250 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n\n\n\n24 \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC \nSN \nNN \n \n \n\n\n\n25 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nINNER CARTON OF A MULTIPACK (WITHOUT BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 250 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 250 IU (100 IU / 1 mL) octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \nComponent of a multipack, can’t be sold separately. \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \nFor reconstitution read package leaflet before use. \n \n\n \n \n \n\n\n\n26 \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \nOF THE SIGHT AND REACH OF CHILDREN \n\n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. Do not freeze. \n \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/017 – 30 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/018 – 30 x (Kovaltry 250 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n\n\n\n27 \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n \nMedicinal product subject to medical prescription. \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 250 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \n \n\n\n\n28 \n\n \nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVIAL WITH POWDER FOR SOLUTION FOR INJECTION \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n \nKovaltry 250 IU powder for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \nIntravenous use. \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n250 IU (octocog alfa) (100 IU/mL after reconstitution). \n \n \n6. OTHER \n \nBayer-Logo \n \n \n\n\n\n29 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nOUTER CARTON OF A SINGLE PACK (INCLUDING BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 500 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 500 IU (200 IU / 1 mL) octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \nFor reconstitution read package leaflet before use. \n \n\n \n \n \n\n\n\n30 \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \nOF THE SIGHT AND REACH OF CHILDREN \n\n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. Do not freeze. \n \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/004 – 1 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/014 – 1 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n\n\n\n31 \n\n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 500 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC \nSN \nNN \n \n \n\n\n\n32 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nOUTER LABEL OF MULTIPACK WITH 30 SINGLE PACKS (INCLUDING BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 500 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 500 IU (200 IU / 1 mL)octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \nMultipack with 30 single packs, each containing: \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \n\n\n\n33 \n\nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. \nDo not freeze. \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/019 – 30 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/020 – 30 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 500 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n\n\n\n34 \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC \nSN \nNN \n \n \n\n\n\n35 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nINNER CARTON OF A MULTIPACK (WITHOUT BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 500 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 500 IU (200 IU / 1 mL) octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \nComponent of a multipack, can’t be sold separately. \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \nFor reconstitution read package leaflet before use. \n \n\n \n \n \n\n\n\n36 \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \nOF THE SIGHT AND REACH OF CHILDREN \n\n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. Do not freeze. \n \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/019 – 30 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/020 – 30 x (Kovaltry 500 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n\n\n\n37 \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n \nMedicinal product subject to medical prescription. \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 500 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \n \n\n\n\n38 \n\n \nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVIAL WITH POWDER FOR SOLUTION FOR INJECTION \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n \nKovaltry 500 IU powder for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \nIntravenous use. \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n500 IU (octocog alfa) (200 IU/mL after reconstitution). \n \n \n6. OTHER \n \nBayer-Logo \n \n \n\n\n\n39 \n\n \n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nOUTER CARTON OF A SINGLE PACK (INCLUDING BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 1000 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 1000 IU (400 IU / 1 mL) octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \nFor reconstitution read package leaflet before use. \n \n\n \n \n \n\n\n\n40 \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \nOF THE SIGHT AND REACH OF CHILDREN \n\n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. Do not freeze. \n \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/006 – 1 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/016 – 1 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n\n\n\n41 \n\n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 1000 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC \nSN \nNN \n \n \n\n\n\n42 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nOUTER LABEL OF MULTIPACK WITH 30 SINGLE PACKS (INCLUDING BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 1000 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 1000 IU (400 IU / 1 mL) octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \nMultipack with 30 single packs, each containing: \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \n\n\n\n43 \n\nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. \nDo not freeze. \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/021 – 30 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/022 – 30 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 1000 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n\n\n\n44 \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC \nSN \nNN \n \n \n\n\n\n45 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nINNER CARTON OF A MULTIPACK (WITHOUT BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 1000 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 1000 IU (400 IU / 1 mL) octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \nComponent of a multipack, can’t be sold separately. \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \nFor reconstitution read package leaflet before use. \n \n\n \n \n \n\n\n\n46 \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \nOF THE SIGHT AND REACH OF CHILDREN \n\n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. Do not freeze. \n \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/021 – 30 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (3 mL)) \nEU/1/15/1076/022 – 30 x (Kovaltry 1000 IU - solvent (2.5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n\n\n\n47 \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n \nMedicinal product subject to medical prescription. \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 1000 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \n \n\n\n\n48 \n\n \nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVIAL WITH POWDER FOR SOLUTION FOR INJECTION \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n \nKovaltry 1000 IU powder for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \nIntravenous use. \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n1000 IU (octocog alfa) (400 IU/mL after reconstitution). \n \n \n6. OTHER \n \nBayer-Logo \n \n\n\n\n49 \n\n \n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nOUTER CARTON OF A SINGLE PACK (INCLUDING BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 2000 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 2000 IU (400 IU / 1 mL) octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \nFor reconstitution read package leaflet before use. \n \n\n \n \n \n\n\n\n50 \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \nOF THE SIGHT AND REACH OF CHILDREN \n\n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. Do not freeze. \n \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/008 – 1 x (Kovaltry 2000 IU - solvent (5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n\n\n\n51 \n\n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 2000 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC \nSN \nNN \n \n \n\n\n\n52 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nOUTER LABEL OF MULTIPACK WITH 30 SINGLE PACKS (INCLUDING BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 2000 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n 2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 2000 IU (400 IU / 1 mL) octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \nMultipack with 30 single packs, each containing: \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \n\n\n\n53 \n\nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. \nDo not freeze. \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/023 – 30 x (Kovaltry 2000 IU - solvent (5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 2000 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n\n\n\n54 \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC \nSN \nNN \n \n\n\n\n55 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nINNER CARTON OF A MULTIPACK (WITHOUT BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 2000 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 2000 IU (400 IU / 1 mL) octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \nComponent of a multipack, can’t be sold separately. \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \nFor reconstitution read package leaflet before use. \n \n\n \n \n \n\n\n\n56 \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \nOF THE SIGHT AND REACH OF CHILDREN \n\n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. Do not freeze. \n \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/023 – 30 x (Kovaltry 2000 IU - solvent (5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \nMedicinal product subject to medical prescription. \n \n\n\n\n57 \n\n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 2000 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \n \n\n\n\n58 \n\n \nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVIAL WITH POWDER FOR SOLUTION FOR INJECTION \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n \nKovaltry 2000 IU powder for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \nIntravenous use. \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n2000 IU (octocog alfa) (400 IU/mL after reconstitution). \n \n \n6. OTHER \n \nBayer-Logo \n \n\n\n\n59 \n\n \n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nOUTER CARTON OF A SINGLE PACK (INCLUDING BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 3000 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 3000 IU (600 IU / 1 mL) octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \nFor reconstitution read package leaflet before use. \n \n\n \n \n \n\n\n\n60 \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \nOF THE SIGHT AND REACH OF CHILDREN \n\n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. Do not freeze. \n \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/010 – 1 x (Kovaltry 3000 IU - solvent (5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n\n\n\n61 \n\n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 3000 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC \nSN \nNN \n \n \n\n\n\n62 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nOUTER LABEL OF MULTIPACK WITH 30 SINGLE PACKS (INCLUDING BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 3000 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 3000 IU (600 IU / 1 mL)octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \nMultipack with 30 single packs, each containing: \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \n\n\n\n63 \n\nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. \nDo not freeze. \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/024 – 30 x (Kovaltry 3000 IU - solvent (5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 3000 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n\n\n\n64 \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC \nSN \nNN \n \n\n\n\n65 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nINNER CARTON OF A MULTIPACK (WITHOUT BLUE BOX) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nKovaltry 3000 IU powder and solvent for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nKovaltry contains 3000 IU (600 IU / 1 mL) octocog alfa after reconstitution. \n \n \n3. LIST OF EXCIPIENTS \n \nSucrose, histidine, glycine (E 640), sodium chloride, calcium chloride dihydrate (E 509), \npolysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \npowder and solvent for solution for injection \n \nComponent of a multipack, can’t be sold separately. \n \n1 vial with powder, 1 pre-filled syringe with water for injections, 1 vial adapter and 1 venipuncture \nset. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nFor intravenous use. Single dose administration only. \nRead the package leaflet before use. \n \nFor reconstitution read package leaflet before use. \n \n\n \n \n \n\n\n\n66 \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \nOF THE SIGHT AND REACH OF CHILDREN \n\n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \nEXP (End of the 12 month period, if stored up to 25 °C): ................ \nDo not use after this date. \n \nMay be stored at temperatures up to 25 °C for up to 12 months within the expiry date indicated on the \nlabel. Note the new expiry date on the carton. \nAfter reconstitution, the product must be used within 3 hours. Do not refrigerate after \nreconstitution. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. Do not freeze. \n \nKeep the vial and the pre-filled syringe in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused solution must be discarded. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nBayer AG \n51368 Leverkusen \nGermany \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/15/1076/024 – 30 x (Kovaltry 3000 IU - solvent (5 mL); pre-filled syringe (5 mL)) \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \nMedicinal product subject to medical prescription. \n \n\n\n\n67 \n\n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nKovaltry 3000 \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \n \n\n\n\n68 \n\n \nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVIAL WITH POWDER FOR SOLUTION FOR INJECTION \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n \nKovaltry 3000 IU powder for solution for injection \n \noctocog alfa (recombinant human coagulation factor VIII) \nIntravenous use. \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n3000 IU (octocog alfa) (600 IU/mL after reconstitution). \n \n \n6. OTHER \n \nBayer-Logo \n \n \n\n\n\n69 \n\n \nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nPRE-FILLED SYRINGE WITH WATER FOR INJECTIONS \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND IF NECESSARY ROUTE(S) OF \n\nADMINISTRATION \n \nwater for injections \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n2.5 mL [for reconstitution of strengths 250/500/1000 IU] \n \n \n6. OTHER \n \n \n \n\n\n\n70 \n\n \nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nPRE-FILLED SYRINGE WITH WATER FOR INJECTIONS \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND IF NECESSARY ROUTE(S) OF \n\nADMINISTRATION \n \nwater for injections \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n5 mL [for reconstitution of strengths 2000/3000 IU] \n \n \n6. OTHER \n \n \n \n\n\n\n71 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nB. PACKAGE LEAFLET \n \n\n\n\n72 \n\nPackage Leaflet: Information for the user \n \n\nKovaltry 250 IU powder and solvent for solution for injection \nKovaltry 500 IU powder and solvent for solution for injection \n\nKovaltry 1000 IU powder and solvent for solution for injection \nKovaltry 2000 IU powder and solvent for solution for injection \nKovaltry 3000 IU powder and solvent for solution for injection \n\noctocog alfa (recombinant human coagulation factor VIII) \n \n \nRead all of this leaflet carefully before you start using this medicine because it contains \nimportant information for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor or pharmacist. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side \n\neffects not listed in this leaflet. See section 4. \n \nWhat is in this leaflet \n1. What Kovaltry is and what it is used for \n2. What you need to know before you use Kovaltry \n3. How to use Kovaltry \n4. Possible side effects \n5. How to store Kovaltry \n6. Contents of the pack and other information \n \n \n1. What Kovaltry is and what it is used for \n \nKovaltry contains the active substance human recombinant coagulation factor VIII, also called octocog \nalfa. Kovaltry is prepared by recombinant technology without addition of any human- or \nanimal derived components in the manufacturing process. Factor VIII is a protein naturally found in \nthe blood that helps to clot it. \n \nKovaltry is used to treat and prevent bleeding in adults, adolescents and children of all ages with \nhaemophilia A (hereditary factor VIII deficiency). \n \n \n2. What you need to know before you use Kovaltry \n \nDo not use Kovaltry if you are \n allergic to octocog alfa or to any of the other ingredients of this medicine (listed in section 6). \n allergic to mouse or hamster proteins. \n \nWarnings and precautions \nTalk to your doctor or pharmacist if you have: \n tightness in the chest, dizziness (including when you get up from sitting or lying down), itchy \n\nnettle-rash, wheezing, feeling sick or faint. These may be signs of a rare severe sudden allergic \nreaction to Kovaltry. Stop administering the product immediately and seek medical advice \nif this occurs. \n\n bleeding that is not being controlled with your usual dose of Kovaltry. The formation of \ninhibitors (antibodies) is a known complication that can occur during treatment with all \nFactor VIII medicines. These inhibitors, especially at high levels, stop the treatment working \nproperly, patients receiving Kovaltry will be monitored carefully for the development of these \n\n\n\n73 \n\ninhibitors. If your or your child’s bleeding is not being controlled with Kovaltry, tell your \ndoctor immediately. \n\n previously developed factor VIII inhibitors to a different product. If you switch factor VIII \nproducts, you may be at risk of your inhibitor coming back. \n\n a confirmed heart disease or are at risk of heart disease. \n to use a central venous access device for the administration of Kovaltry. You may be at risk of \n\ndevice related complications where the catheter is inserted including: \n- local infections \n- bacteria in the blood \n- a blood clot in the blood vessel. \n\n \nChildren and adolescents \nThe listed warnings and precautions apply to patients of all ages, adults and children. \n \nOther medicines and Kovaltry \nTell your doctor or pharmacist if you are using, have recently used or might use any other medicines. \n \nPregnancy and breast-feeding \nIf you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask \nyour doctor for advice before using this medicine. \n \nKovaltry is not likely to affect the fertility in male or female patients, as the active substance is \nnaturally occurring in the body. \n \nDriving and using machines \nIf you experience dizziness or any other symptoms affecting your ability to concentrate and react, do \nnot drive or use machines until the reaction subsides. \n \nKovaltry contains sodium \nThis medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-\nfree’. \n \n \n3. How to use Kovaltry \n \nTreatment with Kovaltry will be started by a doctor who is experienced in the care of patients with \nhaemophilia A. Always use this medicine exactly as your doctor has told you. Check with your doctor \nif you are not sure. \nThe number of factor VIII units is expressed in International Units (IU). \n \nTreatment of bleeding \n To treat a bleed, your doctor will calculate and adjust your dose and how often it should be given, \ndepending on factors such as: \n your weight \n the severity of your haemophilia A \n where the bleed is and how serious it is \n whether you have inhibitors and how high their level is \n the factor VIII level that is needed. \n \nPrevention of bleeding \nIf you are using Kovaltry to prevent bleeding, your doctor will calculate the dose for you. This will \nusually be in the range of 20 to 40 IU of octocog alfa per kg of body weight, injected two or three \ntimes per week. However, in some cases, especially for younger patients, shorter dose intervals or \nhigher doses may be necessary. \n \n\n\n\n74 \n\nLaboratory tests \nLaboratory tests at suitable intervals help to ensure you always have adequate factor VIII levels. For \nmajor surgery in particular, your blood clotting must be closely monitored. \n \nUse in children and adolescents \nKovaltry can be used in children of all ages. In children below the age of 12 higher doses or more \nfrequent injections than prescribed for adults may be needed. \n \nPatients with inhibitors \nIf you have been told by your doctor that you have developed factor VIII inhibitors you may need to \nuse a larger dose of Kovaltry to control bleeding. If this dose does not control your bleeding your \ndoctor may consider giving you another product. \nSpeak to your doctor if you would like further information on this. \nDo not increase the dose of Kovaltry to control your bleeding without checking with your doctor. \n \nDuration of treatment \nUsually, Kovaltry treatment for haemophilia is needed life-long. \n \nHow Kovaltry is given \nKovaltry is injected into a vein over 2 to 5 minutes depending on the total volume and your comfort \nlevel and should be used within 3 hours after reconstitution. \n \nHow Kovaltry is prepared for administration \nUse only the components (vial adapter, pre filled syringe containing solvent and venipuncture set) \nprovided with each package of this medicine. Please contact your doctor if these components cannot \nbe used. Do not use if any component of the package is opened or damaged. \n \nThe reconstituted product must be filtered by using the vial adapter before administration to remove \nany possible particles in the solution. \n \nDo not use the venipuncture set provided for drawing blood because it contains an in-line filter. \n \nThis medicine must not be mixed with other infusion solutions. Do not use solutions containing \nvisible particles or that are cloudy. Follow the instructions for use given by your doctor and provided \nat the end of this leaflet. \n \nIf you use more Kovaltry than you should \nTell your doctor if this occurs. No cases of overdose have been reported. \n \nIf you forget to use Kovaltry \nAdminister your next dose immediately and continue at regular intervals as advised by your doctor. \nDo not use a double dose to make up for a forgotten dose. \n \nIf you stop using Kovaltry \nDo not stop using this medicine without checking with your doctor. \n \nIf you have any further questions on the use of this medicine, ask your doctor. \n \n \n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. \n \n\n\n\n75 \n\nThe most serious side effects are allergic reactions which may be severe allergic reaction. Stop \ninjecting Kovaltry immediately and speak to your doctor at once if such reactions occur. The \nfollowing symptoms could be an early warning of these reactions: \n chest tightness/general feeling of being unwell \n dizziness \n feeling faint upon standing indicating a reduction in blood pressure \n feeling sick (nausea) \n \nFor children not previously treated with factor VIII medicines, inhibitor antibodies (see section 2) may \nform very commonly (more than 1 in 10 patients). For patients who have received previous treatment \nwith factor VIII (more than 150 days of treatment) inhibitor antibodies (see section 2) may form \nuncommonly (less than 1 in 100 patients). If this happens your medicine may stop working properly \nand you may experience persistent bleeding. If this happens, please contact your doctor immediately. \n \nOther possible side effects: \n \nCommon (may affect up to 1 in 10 users): \n lymph nodes enlarged (swelling under the skin of the neck, armpit or groin) \n heart palpitations (feeling your heart beating hard, rapidly, or irregularly) \n rapid heartbeat \n stomach pain or discomfort \n indigestion \n fever \n local reactions where you injected the medicine (e.g. bleeding under the skin, intense itching, \n\nswelling, burning sensation, temporary redness) \n headache \n trouble sleeping \n rash/itchy rash \n \nUncommon (may affect up to 1 in 100 users): \n dysgeusia (strange taste) \n urticaria (itchy rash) \n flushing (redness of the face) \n \nReporting of side effects \nIf you get any side effects, talk to your doctor. This includes any possible side effects not listed in this \nleaflet. You can also report side effects directly via the national reporting system listed in Appendix V. \nBy reporting side effects, you can help provide more information on the safety of this medicine. \n \n \n5. How to store Kovaltry \n \nKeep this medicine out of the sight and reach of children. \n \nDo not use this medicine after the expiry date which is stated on labels and cartons. The expiry date \nrefers to the last day of that month. \n \nStore in a refrigerator (2 °C – 8 °C). Do not freeze. \nStore this medicine in the original package in order to protect from light. \n \nThis medicine may be stored at room temperature (up to 25 °C) for up to 12 months when you keep it \nin its outer carton. If you store it at room temperature it expires after 12 months or at the expiry date if \nthis is earlier. \nThe new expiry date must be noted on the outer carton when the medicine is removed from the \nrefrigerator. \n \n\n\n\n76 \n\nDo not refrigerate the solution after reconstitution. The reconstituted solution must be used within \n3 hours. This product is for single use only. Any unused solution must be discarded. \n \nDo not use this medicine if you notice any particles in the solution or if the solution is cloudy. \n \nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \nthrow away medicines you no longer use. These measures will help protect the environment. \n \n \n6. Contents of the pack and other information \n \nWhat Kovaltry contains \n \nThe active substance is octocog alfa (human coagulation factor VIII). Each vial of Kovaltry contains \nnominally 250, 500, 1000, 2000 or 3000 IU octocog alfa. \nThe other ingredients are sucrose, histidine, glycine (E 640), sodium chloride, calcium chloride \ndihydrate (E 509), polysorbate 80 (E 433), acetic acid glacial (E 260) and water for injections. \n \nWhat Kovaltry looks like and contents of the pack \n \nKovaltry is provided as a powder and solvent for solution for injection. The powder is dry and white \nto slightly yellow . The solvent is a clear liquid. \n \nEach single pack of Kovaltry contains \n a glass vial with powder \n a pre filled syringe with solvent \n a separate plunger rod \n a vial adapter \n a venipuncture set (for injection into a vein). \n \nKovaltry is available in pack sizes of: \n 1 single pack \n 1 multipack with 30 single packs \nNot all pack sizes may be marketed. \n \nMarketing Authorisation Holder \nBayer AG \n51368 Leverkusen \nGermany \n \nManufacturer \nBayer AG \nKaiser-Wilhelm-Allee \n51368 Leverkusen \nGermany \n \n \n\n\n\n77 \n\nFor any information about this medicine, please contact the local representative of the Marketing \nAuthorisation Holder. \n \nBelgië/Belgique/Belgien \nBayer SA-NV \nTél/Tel: +32-(0)2-535 63 11 \n\nLietuva \nUAB Bayer \nTel. +37 05 23 36 868 \n\nБългария \nБайер България ЕООД \nTел.: +359-(0)2-424 72 80 \n\nLuxembourg/Luxemburg \nBayer SA-NV \nTél/Tel: +32-(0)2-535 63 11 \n\nČeská republika \nBayer s.r.o. \nTel: +420 266 101 111 \n\nMagyarország \nBayer Hungária KFT \nTel:+36 14 87-41 00 \n\nDanmark \nBayer A/S \nTlf: +45 45 23 50 00 \n\nMalta \nAlfred Gera and Sons Ltd. \nTel: +35 621 44 62 05 \n\nDeutschland \nBayer Vital GmbH \nTel: +49 (0)214-30 513 48 \n\nNederland \nBayer B.V. \nTel: +31-(0)297-28 06 66 \n\nEesti \nBayer OÜ \nTel: +372 655 8565 \n\nNorge \nBayer AS \nTlf: +47 23 13 05 00 \n\nΕλλάδα \nBayer Ελλάς ΑΒΕΕ \nΤηλ: +30-210-61 87 500 \n\nÖsterreich \nBayer Austria Ges.m.b.H. \nTel: +43-(0)1-711 46-0 \n\nEspaña \nBayer Hispania S.L. \nTel: +34-93-495 65 00 \n\nPolska \nBayer Sp. z o.o. \nTel: +48 22 572 35 00 \n\nFrance \nBayer HealthCare \nTél (N° vert): +33-(0)800 87 54 54 \n\nPortugal \nBayer Portugal, Lda. \nTel: +351 21 416 42 00 \n\nHrvatska \nBayer d.o.o. \nTel: +385-(0)1-6599 900 \n\nRomânia \nSC Bayer SRL \nTel: +40 21 529 59 00 \n\nIreland \nBayer Limited \nTel: +353 1 216 3300 \n\nSlovenija \nBayer d. o. o. \nTel: +386 (0)1 58 14 400 \n\nÍsland \nIcepharma hf. \nSími: +354 540 8000 \n\nSlovenská republika \nBayer spol. s r.o. \nTel. +421 2 59 21 31 11 \n\nItalia \nBayer S.p.A. \nTel: +39 02 397 81 \n\nSuomi/Finland \nBayer Oy \nPuh/Tel: +358- 20 785 21 \n\nΚύπρος \nNOVAGEM Limited \nTηλ: +357 22 48 38 58 \n\nSverige \nBayer AB \nTel: +46 (0) 8 580 223 00 \n\nLatvija \nSIA Bayer \nTel: +371 67 84 55 63 \n\nUnited Kingdom \nBayer plc \nTel: +44-(0)118 206 3000 \n\n \nThis leaflet was last revised in \n \nDetailed information on this medicine is available on the website of the European Medicines Agency \nhttp://www.ema.europa.eu \n \n------------------------------------------------------------------------------------------------------------------------- \n \n\n\n\n78 \n\nDetailed instructions for reconstitution and administration of Kovaltry \n \nYou will need alcohol swabs, gauze pads, plasters and tourniquet. These items are not included in the \nKovaltry package. \n \n1. Wash your hands thoroughly using soap and warm water. \n \n2. Hold an unopened vial and also a syringe in your hands to warm it to a comfortable temperature \n\n(do not exceed 37 °C). \n \n3. Remove the protective cap from the vial (A).Wipe the rubber stopper on the \n\nvial with an alcohol swab and allow the stopper to air dry before use. \n \n\n \n4. Place the powder vial on a firm, non slip surface. Peel off the paper cover on \n\nthe plastic housing of the vial adapter. Do not remove the adapter from the \nplastic housing. Holding the adapter housing, place over the powder vial and \nfirmly press down (B). The adapter will snap over the vial cap. Do not \nremove the adapter housing at this point. \n\n \n\n5. Hold the pre filled syringe with solvent upright. Grasp the plunger rod as per \nthe picture and attach the rod by turning it firmly clockwise into the threaded \nstopper (C). \n\n \n\n6. Holding the syringe by the barrel, snap the syringe cap off the tip (D). Do not \ntouch the syringe tip with your hand or any surface. Set the syringe aside for \nfurther use. \n\n \n\n \n7. Now remove and discard the adapter housing (E). \n \n\n \n8. Attach the pre filled syringe to the threaded vial adapter by turning \n\nclockwise (F). \n \n\n \n9. Inject the solvent by slowly pushing down on the plunger rod (G). \n \n\n \n10. Swirl vial gently until all the powder is dissolved (H). Do not shake vial. Be \n\nsure that the powder is completely dissolved. Look to check there are no \nparticles or discoloration before you use the solution. Do not use solutions \ncontaining visible particles or that are cloudy. \n\n \n \n\n\n\n79 \n\n11. Hold the vial on the end above the vial adapter and syringe (I). Fill the \nsyringe by drawing the plunger out slowly and smoothly. Ensure that the full \ncontent of the vial is drawn into the syringe. Hold the syringe upright and \npush the plunger until no air is left in the syringe. \n\n \n \n\n12. Apply a tourniquet to your arm. \n \n13. Determine the point of injection and clean the skin with an alcohol swab. \n \n14. Puncture the vein and secure the venipuncture set with a plaster. \n \n15. Holding the vial adapter in place, remove the syringe from the vial adapter \n\n(the adapter should remain attached to the vial). Attach the syringe to the \nvenipuncture set (J). Ensure that no blood enters the syringe. \n\n \n\n \n16. Remove tourniquet. \n \n17. Inject the solution into a vein over 2 to 5 minutes, keeping an eye on the position of the needle. \n\nThe speed of injection should be based on your comfort, but should not be faster than 2 mL per \nminute. \n\n \n18. If a further dose is needed, use a new syringe with the powder reconstituted as described above. \n \n19. If no further dose is required, remove the venipuncture set and syringe. Hold a pad firmly over \n\nthe injection site on your outstretched arm for about 2 minutes. Finally, apply a small pressure \ndressing to the injection site and consider if a plaster is necessary. \n\n \n20. It is recommended that every time you use Kovaltry, you note down the name and the batch \n\nnumber of the product. \n \n21. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist or \n\nphysician how to throw away medicines you no longer use. These measures will help protect the \nenvironment \n\n \n \n \n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. PACKAGE LEAFLET"},"Section_1":{"kind":"string","value":"{'Title': '1. what kovaltry is and what it is used for', 'Section_Content': 'kovaltry contains the active substance human recombinant coagulation factor viii, also called octocog alfa. kovaltry is prepared by recombinant technology without addition of any human- or animal derived components in the manufacturing process. factor viii is a protein naturally found in the blood that helps to clot it. kovaltry is used to treat and prevent bleeding in adults, adolescents and children of all ages with haemophilia a (hereditary factor viii deficiency).', 'Entity_Recognition': [{'Text': 'kovaltry', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'kovaltry', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 8}, {'Text': 'factor viii', 'Type': 'PROBLEM', 'BeginOffset': 245, 'EndOffset': 256}, {'Text': 'a protein naturally', 'Type': 'PROBLEM', 'BeginOffset': 260, 'EndOffset': 279}, {'Text': 'the blood', 'Type': 'PROBLEM', 'BeginOffset': 289, 'EndOffset': 298}, {'Id': 0, 'BeginOffset': 313, 'EndOffset': 317, 'Score': 0.5138537287712097, 'Text': 'clot', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'kovaltry', 'Type': 'TREATMENT', 'BeginOffset': 322, 'EndOffset': 330}, {'Id': 1, 'BeginOffset': 360, 'EndOffset': 368, 'Score': 0.9824122786521912, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6611321568489075}]}, {'Text': 'haemophilia a (hereditary factor viii deficiency', 'Type': 'PROBLEM', 'BeginOffset': 422, 'EndOffset': 470}]}"},"Section_2":{"kind":"string","value":"{'Title': '2. what you need to know before you use kovaltry', 'Section_Content': \"do not use kovaltry if you are allergic to octocog alfa or to any of the other ingredients of this medicine (listed in section 6). allergic to mouse or hamster proteins. warnings and precautions talk to your doctor or pharmacist if you have: tightness in the chest, dizziness (including when you get up from sitting or lying down), itchy nettle-rash, wheezing, feeling sick or faint. these may be signs of a rare severe sudden allergic reaction to kovaltry. stop administering the product immediately and seek medical advice if this occurs. bleeding that is not being controlled with your usual dose of kovaltry. the formation of inhibitors (antibodies) is a known complication that can occur during treatment with all factor viii medicines. these inhibitors, especially at high levels, stop the treatment working properly, patients receiving kovaltry will be monitored carefully for the development of these 73 inhibitors. if your or your child's bleeding is not being controlled with kovaltry, tell your doctor immediately. previously developed factor viii inhibitors to a different product. if you switch factor viii products, you may be at risk of your inhibitor coming back. a confirmed heart disease or are at risk of heart disease. to use a central venous access device for the administration of kovaltry. you may be at risk of device related complications where the catheter is inserted including: - local infections - bacteria in the blood - a blood clot in the blood vessel. children and adolescents the listed warnings and precautions apply to patients of all ages, adults and children. other medicines and kovaltry tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. pregnancy and breast-feeding if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using this medicine. kovaltry is not likely to affect the fertility in male or female patients, as the active substance is naturally occurring in the body. driving and using machines if you experience dizziness or any other symptoms affecting your ability to concentrate and react, do not drive or use machines until the reaction subsides. kovaltry contains sodium this medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium- free'.\", 'Entity_Recognition': [{'Text': 'kovaltry', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 5, 'BeginOffset': 11, 'EndOffset': 19, 'Score': 0.9291138052940369, 'Text': 'kovaltry', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.651614248752594}]}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 31, 'EndOffset': 39}, {'Text': 'octocog alfa', 'Type': 'TREATMENT', 'BeginOffset': 43, 'EndOffset': 55}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 94, 'EndOffset': 107}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 131, 'EndOffset': 139}, {'Text': 'hamster proteins', 'Type': 'TREATMENT', 'BeginOffset': 152, 'EndOffset': 168}, {'Text': 'tightness in the chest', 'Type': 'PROBLEM', 'BeginOffset': 242, 'EndOffset': 264}, {'Id': 13, 'BeginOffset': 266, 'EndOffset': 275, 'Score': 0.9967398047447205, 'Text': 'dizziness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9553428888320923}]}, {'Text': 'itchy nettle', 'Type': 'PROBLEM', 'BeginOffset': 332, 'EndOffset': 344}, {'Id': 14, 'BeginOffset': 345, 'EndOffset': 349, 'Score': 0.9952226281166077, 'Text': 'rash', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9434462785720825}]}, {'Id': 15, 'BeginOffset': 351, 'EndOffset': 359, 'Score': 0.9987958669662476, 'Text': 'wheezing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9502016305923462}]}, {'Id': 16, 'BeginOffset': 361, 'EndOffset': 373, 'Score': 0.8277669548988342, 'Text': 'feeling sick', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8076450228691101}]}, {'Id': 17, 'BeginOffset': 377, 'EndOffset': 382, 'Score': 0.7045062780380249, 'Text': 'faint', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.625039279460907}]}, {'Text': 'a rare severe sudden allergic reaction', 'Type': 'PROBLEM', 'BeginOffset': 406, 'EndOffset': 444}, {'Id': 7, 'BeginOffset': 448, 'EndOffset': 456, 'Score': 0.8631829023361206, 'Text': 'kovaltry', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 19, 'BeginOffset': 541, 'EndOffset': 549, 'Score': 0.9736354947090149, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6952850222587585}]}, {'Id': 8, 'BeginOffset': 603, 'EndOffset': 611, 'Score': 0.9145236611366272, 'Text': 'kovaltry', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'inhibitors (antibodies', 'Type': 'PROBLEM', 'BeginOffset': 630, 'EndOffset': 652}, {'Text': 'a known complication', 'Type': 'PROBLEM', 'BeginOffset': 657, 'EndOffset': 677}, {'Text': 'all factor viii medicines', 'Type': 'TREATMENT', 'BeginOffset': 715, 'EndOffset': 740}, {'Text': 'these inhibitors', 'Type': 'TREATMENT', 'BeginOffset': 742, 'EndOffset': 758}, {'Text': 'the treatment', 'Type': 'TREATMENT', 'BeginOffset': 792, 'EndOffset': 805}, {'Id': 9, 'BeginOffset': 843, 'EndOffset': 851, 'Score': 0.4354632496833801, 'Text': 'kovaltry', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'these 73 inhibitors', 'Type': 'TREATMENT', 'BeginOffset': 903, 'EndOffset': 922}, {'Text': '73', 'Type': 'NUMBER', 'BeginOffset': 909, 'EndOffset': 911}, {'Text': \"your child's bleeding\", 'Type': 'PROBLEM', 'BeginOffset': 935, 'EndOffset': 956}, {'Id': 10, 'BeginOffset': 986, 'EndOffset': 994, 'Score': 0.6330475211143494, 'Text': 'kovaltry', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 35, 'BeginOffset': 1013, 'EndOffset': 1024, 'Score': 0.9999961853027344, 'Text': 'immediately', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_MEDICATION_NAME', 'Traits': [], 'Attributes': [{'Type': 'BRAND_NAME', 'Score': 0.6330475211143494, 'RelationshipScore': 0.7837417125701904, 'RelationshipType': 'OVERLAP', 'Id': 10, 'BeginOffset': 986, 'EndOffset': 994, 'Text': 'kovaltry', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 36, 'BeginOffset': 1026, 'EndOffset': 1036, 'Score': 0.9999951124191284, 'Text': 'previously', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_TREATMENT_NAME', 'Traits': [], 'Attributes': [{'Type': 'TREATMENT_NAME', 'Score': 0.43307793140411377, 'RelationshipScore': 0.7870045900344849, 'RelationshipType': 'OVERLAP', 'Id': 31, 'BeginOffset': 1047, 'EndOffset': 1069, 'Text': 'factor viii inhibitors', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Id': 31, 'BeginOffset': 1047, 'EndOffset': 1069, 'Score': 0.43307793140411377, 'Text': 'factor viii inhibitors', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 32, 'BeginOffset': 1108, 'EndOffset': 1128, 'Score': 0.5286291241645813, 'Text': 'factor viii products', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'your inhibitor', 'Type': 'TREATMENT', 'BeginOffset': 1152, 'EndOffset': 1166}, {'Id': 21, 'BeginOffset': 1192, 'EndOffset': 1205, 'Score': 0.8747243285179138, 'Text': 'heart disease', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9246860146522522}]}, {'Id': 22, 'BeginOffset': 1224, 'EndOffset': 1237, 'Score': 0.95883709192276, 'Text': 'heart disease', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.941597580909729}]}, {'Text': 'a central venous access device', 'Type': 'TREATMENT', 'BeginOffset': 1246, 'EndOffset': 1276}, {'Text': 'the administration of kovaltry', 'Type': 'TREATMENT', 'BeginOffset': 1281, 'EndOffset': 1311}, {'Text': 'device related complications', 'Type': 'PROBLEM', 'BeginOffset': 1335, 'EndOffset': 1363}, {'Id': 33, 'BeginOffset': 1374, 'EndOffset': 1394, 'Score': 0.629087507724762, 'Text': 'catheter is inserted', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'PROCEDURE_NAME', 'Traits': []}, {'Id': 23, 'BeginOffset': 1408, 'EndOffset': 1424, 'Score': 0.3505181074142456, 'Text': 'local infections', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8943473696708679}]}, {'Id': 24, 'BeginOffset': 1427, 'EndOffset': 1435, 'Score': 0.7116748094558716, 'Text': 'bacteria', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.5093894600868225}]}, {'Text': 'the blood', 'Type': 'PROBLEM', 'BeginOffset': 1439, 'EndOffset': 1448}, {'Text': 'a blood clot in the blood vessel', 'Type': 'PROBLEM', 'BeginOffset': 1451, 'EndOffset': 1483}, {'Text': 'other medicines', 'Type': 'TREATMENT', 'BeginOffset': 1598, 'EndOffset': 1613}, {'Text': 'any other medicines', 'Type': 'TREATMENT', 'BeginOffset': 1708, 'EndOffset': 1727}, {'Id': 26, 'BeginOffset': 1729, 'EndOffset': 1738, 'Score': 0.9160908460617065, 'Text': 'pregnancy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9056209921836853}]}, {'Id': 27, 'BeginOffset': 1769, 'EndOffset': 1777, 'Score': 0.9909971952438354, 'Text': 'pregnant', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9484641551971436}]}, {'Id': 28, 'BeginOffset': 1814, 'EndOffset': 1822, 'Score': 0.993920087814331, 'Text': 'pregnant', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9508618712425232}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1895, 'EndOffset': 1908}, {'Id': 29, 'BeginOffset': 1936, 'EndOffset': 1956, 'Score': 0.40753310918807983, 'Text': 'affect the fertility', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.49241867661476135}, {'Name': 'DIAGNOSIS', 'Score': 0.7360492944717407}]}, {'Id': 4, 'BeginOffset': 2039, 'EndOffset': 2043, 'Score': 0.6335557103157043, 'Text': 'body', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 43, 'BeginOffset': 2090, 'EndOffset': 2099, 'Score': 0.9967314004898071, 'Text': 'dizziness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.850432276725769}]}, {'Text': 'any other symptoms', 'Type': 'PROBLEM', 'BeginOffset': 2103, 'EndOffset': 2121}, {'Text': 'the reaction', 'Type': 'PROBLEM', 'BeginOffset': 2206, 'EndOffset': 2218}, {'Id': 38, 'BeginOffset': 2229, 'EndOffset': 2237, 'Score': 0.39185065031051636, 'Text': 'kovaltry', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'sodium this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2247, 'EndOffset': 2267}, {'Text': '1 mmol sodium', 'Type': 'TREATMENT', 'BeginOffset': 2287, 'EndOffset': 2300}]}"},"Section_3":{"kind":"string","value":"{'Title': '3. how to use kovaltry', 'Section_Content': 'treatment with kovaltry will be started by a doctor who is experienced in the care of patients with haemophilia a. always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure. the number of factor viii units is expressed in international units (iu). treatment of bleeding to treat a bleed, your doctor will calculate and adjust your dose and how often it should be given, depending on factors such as: your weight the severity of your haemophilia a where the bleed is and how serious it is whether you have inhibitors and how high their level is the factor viii level that is needed. prevention of bleeding if you are using kovaltry to prevent bleeding, your doctor will calculate the dose for you. this will usually be in the range of 20 to 40 iu of octocog alfa per kg of body weight, injected two or three times per week. however, in some cases, especially for younger patients, shorter dose intervals or higher doses may be necessary. laboratory tests laboratory tests at suitable intervals help to ensure you always have adequate factor viii levels. for major surgery in particular, your blood clotting must be closely monitored. use in children and adolescents kovaltry can be used in children of all ages. in children below the age of 12 higher doses or more frequent injections than prescribed for adults may be needed. patients with inhibitors if you have been told by your doctor that you have developed factor viii inhibitors you may need to use a larger dose of kovaltry to control bleeding. if this dose does not control your bleeding your doctor may consider giving you another product. speak to your doctor if you would like further information on this. do not increase the dose of kovaltry to control your bleeding without checking with your doctor. duration of treatment usually, kovaltry treatment for haemophilia is needed life-long. how kovaltry is given kovaltry is injected into a vein over 2 to 5 minutes depending on the total volume and your comfort level and should be used within 3 hours after reconstitution. how kovaltry is prepared for administration use only the components (vial adapter, pre filled syringe containing solvent and venipuncture set) provided with each package of this medicine. please contact your doctor if these components cannot be used. do not use if any component of the package is opened or damaged. the reconstituted product must be filtered by using the vial adapter before administration to remove any possible particles in the solution. do not use the venipuncture set provided for drawing blood because it contains an in-line filter. this medicine must not be mixed with other infusion solutions. do not use solutions containing visible particles or that are cloudy. follow the instructions for use given by your doctor and provided at the end of this leaflet. if you use more kovaltry than you should tell your doctor if this occurs. no cases of overdose have been reported. if you forget to use kovaltry administer your next dose immediately and continue at regular intervals as advised by your doctor. do not use a double dose to make up for a forgotten dose. if you stop using kovaltry do not stop using this medicine without checking with your doctor. if you have any further questions on the use of this medicine, ask your doctor.', 'Entity_Recognition': [{'Text': 'kovaltry', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 1, 'BeginOffset': 15, 'EndOffset': 23, 'Score': 0.6045933365821838, 'Text': 'kovaltry', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 100, 'EndOffset': 111, 'Score': 0.7080158591270447, 'Text': 'haemophilia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7179270386695862}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 126, 'EndOffset': 139}, {'Text': 'factor viii units', 'Type': 'TREATMENT', 'BeginOffset': 235, 'EndOffset': 252}, {'Id': 11, 'BeginOffset': 308, 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indicating a reduction in blood pressure feeling sick (nausea) for children not previously treated with factor viii medicines, inhibitor antibodies (see section 2) may form very commonly (more than 1 in 10 patients). for patients who have received previous treatment with factor viii (more than 150 days of treatment) inhibitor antibodies (see section 2) may form uncommonly (less than 1 in 100 patients). if this happens your medicine may stop working properly and you may experience persistent bleeding. if this happens, please contact your doctor immediately. other possible side effects: common (may affect up to 1 in 10 users): lymph nodes enlarged (swelling under the skin of the neck, armpit or groin) heart palpitations (feeling your heart beating hard, rapidly, or irregularly) rapid heartbeat stomach pain or discomfort indigestion fever local reactions where you injected the medicine (e.g. bleeding under the skin, intense itching, swelling, burning sensation, temporary redness) headache trouble sleeping rash/itchy rash uncommon (may affect up to 1 in 100 users): dysgeusia (strange taste) urticaria (itchy rash) flushing (redness of the face) reporting of side effects if you get any side effects, talk to your doctor. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects, you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'kovaltry', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 14, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9666398763656616, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6314204931259155}]}, {'Id': 15, 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children. do not use this medicine after the expiry date which is stated on labels and cartons. the expiry date refers to the last day of that month. store in a refrigerator (2 8 ). do not freeze. store this medicine in the original package in order to protect from light. this medicine may be stored at room temperature (up to 25 ) for up to 12 months when you keep it in its outer carton. if you store it at room temperature it expires after 12 months or at the expiry date if this is earlier. the new expiry date must be noted on the outer carton when the medicine is removed from the refrigerator. do not refrigerate the solution after reconstitution. the reconstituted solution must be used within 3 hours. this product is for single use only. any unused solution must be discarded. do not use this medicine if you notice any particles in the solution or if the solution is cloudy. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'kovaltry', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 226, 'EndOffset': 227}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 252, 'EndOffset': 265}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 377, 'EndOffset': 379}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 392, 'EndOffset': 394}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 493, 'EndOffset': 495}, {'Text': 'the reconstituted solution', 'Type': 'TREATMENT', 'BeginOffset': 705, 'EndOffset': 731}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 752, 'EndOffset': 753}, {'Text': 'any unused solution', 'Type': 'TREATMENT', 'BeginOffset': 798, 'EndOffset': 817}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 848, 'EndOffset': 861}, {'Text': 'cloudy', 'Type': 'PROBLEM', 'BeginOffset': 928, 'EndOffset': 934}]}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': 'what kovaltry contains the active substance is octocog alfa (human coagulation factor viii). each vial of kovaltry contains nominally 250, 500, 1000, 2000 or 3000 iu octocog alfa. the other ingredients are sucrose, histidine, glycine (e 640), sodium chloride, calcium chloride dihydrate (e 509), polysorbate 80 (e 433), acetic acid glacial (e 260) and water for injections. what kovaltry looks like and contents of the pack kovaltry is provided as a powder and solvent for solution for injection. the powder is dry and white to slightly yellow . the solvent is a clear liquid. each single pack of kovaltry contains a glass vial with powder a pre filled syringe with solvent a separate plunger rod a vial adapter a venipuncture set (for injection into a vein). kovaltry is available in pack sizes of: 1 single pack 1 multipack with 30 single packs not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'kovaltry', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'octocog alfa', 'Type': 'TREATMENT', 'BeginOffset': 47, 'EndOffset': 59}, {'Id': 2, 'BeginOffset': 61, 'EndOffset': 90, 'Score': 0.5069359540939331, 'Text': 'human coagulation factor viii', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 3, 'BeginOffset': 106, 'EndOffset': 114, 'Score': 0.8263447284698486, 'Text': 'kovaltry', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 134, 'EndOffset': 137}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 139, 'EndOffset': 142}, {'Text': '1000', 'Type': 'NUMBER', 'BeginOffset': 144, 'EndOffset': 148}, {'Text': '2000', 'Type': 'NUMBER', 'BeginOffset': 150, 'EndOffset': 154}, {'Text': '3000', 'Type': 'NUMBER', 'BeginOffset': 158, 'EndOffset': 162}, {'Id': 5, 'BeginOffset': 166, 'EndOffset': 178, 'Score': 0.893954336643219, 'Text': 'octocog alfa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.5058310031890869, 'RelationshipScore': 0.9982574582099915, 'RelationshipType': 'STRENGTH', 'Id': 4, 'BeginOffset': 134, 'EndOffset': 165, 'Text': '250, 500, 1000, 2000 or 3000 iu', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 6, 'BeginOffset': 206, 'EndOffset': 213, 'Score': 0.7239546179771423, 'Text': 'sucrose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'histidine, glycine (e', 'Type': 'TREATMENT', 'BeginOffset': 215, 'EndOffset': 236}, {'Id': 10, 'BeginOffset': 243, 'EndOffset': 258, 'Score': 0.9997001886367798, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 260, 'EndOffset': 286, 'Score': 0.9993336796760559, 'Text': 'calcium chloride dihydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 288, 'EndOffset': 293, 'Score': 0.5170265436172485, 'Text': 'e 509', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 296, 'EndOffset': 310, 'Score': 0.8174399733543396, 'Text': 'polysorbate 80', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 14, 'BeginOffset': 312, 'EndOffset': 317, 'Score': 0.6266178488731384, 'Text': 'e 433', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 15, 'BeginOffset': 320, 'EndOffset': 339, 'Score': 0.99806147813797, 'Text': 'acetic acid glacial', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.35631537437438965, 'RelationshipScore': 0.9999990463256836, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 17, 'BeginOffset': 362, 'EndOffset': 372, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 16, 'BeginOffset': 341, 'EndOffset': 346, 'Score': 0.425204336643219, 'Text': 'e 260', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.35631537437438965, 'RelationshipScore': 0.837584912776947, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 17, 'BeginOffset': 362, 'EndOffset': 372, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 362, 'EndOffset': 372}, {'Text': 'the pack kovaltry', 'Type': 'TREATMENT', 'BeginOffset': 415, 'EndOffset': 432}, {'Text': 'a powder and solvent for solution', 'Type': 'TREATMENT', 'BeginOffset': 448, 'EndOffset': 481}, {'Text': 'injection', 'Type': 'TREATMENT', 'BeginOffset': 486, 'EndOffset': 495}, {'Text': 'the powder', 'Type': 'TREATMENT', 'BeginOffset': 497, 'EndOffset': 507}, {'Text': 'white to slightly yellow', 'Type': 'PROBLEM', 'BeginOffset': 519, 'EndOffset': 543}, {'Text': 'kovaltry', 'Type': 'TREATMENT', 'BeginOffset': 597, 'EndOffset': 605}, {'Text': 'a glass vial', 'Type': 'TREATMENT', 'BeginOffset': 615, 'EndOffset': 627}, {'Text': 'powder a pre filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 633, 'EndOffset': 660}, {'Text': 'solvent a separate plunger rod a vial adapter a venipuncture set', 'Type': 'TREATMENT', 'BeginOffset': 666, 'EndOffset': 730}, {'Id': 0, 'BeginOffset': 753, 'EndOffset': 757, 'Score': 0.6870084404945374, 'Text': 'vein', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'kovaltry', 'Type': 'TREATMENT', 'BeginOffset': 760, 'EndOffset': 768}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 800, 'EndOffset': 801}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 814, 'EndOffset': 815}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 831, 'EndOffset': 833}]}"}}},{"rowIdx":1060,"cells":{"ID":{"kind":"string","value":"4845D3160FDE0A0270C5AFDDFC80E5BE"},"URL":{"kind":"string","value":"https://www.ema.europa.eu/documents/product-information/ammonaps-epar-product-information_en.pdf"},"Product_Name":{"kind":"string","value":"Ammonaps"},"Full_Content":{"kind":"string","value":"1 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX I \n \n\nSUMMARY OF PRODUCT CHARACTERISTICS \n\n\n\n2 \n\n1. NAME OF THE MEDICINAL PRODUCT \n \nAMMONAPS 500 mg tablets. \n \n \n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \nEach tablet contains 500 mg sodium phenylbutyrate. \n \nEach AMMONAPS tablet contains 62 mg of sodium. \n \nFor the full list of excipients, see section 6.1. \n \n \n3. PHARMACEUTICAL FORM \n \nTablet. \n \nThe tablets are off-white, oval and embossed with “UCY 500”. \n \n \n4. CLINICAL PARTICULARS \n \n4.1 Therapeutic indications \n \nAMMONAPS is indicated as adjunctive therapy in the chronic management of urea cycle disorders, \ninvolving deficiencies of carbamylphosphate synthetase, ornithine transcarbamylase or \nargininosuccinate synthetase. \n \nIt is indicated in all patients with neonatal-onset presentation (complete enzyme deficiencies, \npresenting within the first 28 days of life). It is also indicated in patients with late-onset disease \n(partial enzyme deficiencies, presenting after the first month of life) who have a history of \nhyperammonaemic encephalopathy. \n \n4.2 Posology and method of administration \n \nAMMONAPS treatment should be supervised by a physician experienced in the treatment of urea \ncycle disorders. \n \nThe use of AMMONAPS tablets is indicated for adults and children who are able to swallow tablets. \nAMMONAPS is also available as granules for infants, children who are unable to swallow tablets and \nfor patients with dysphagia. \n \nThe daily dose should be individually adjusted according to the patient’s protein tolerance and the \ndaily dietary protein intake needed to promote growth and development. \n \nThe usual total daily dose of sodium phenylbutyrate in clinical experience is: \n• 450 - 600 mg/kg/day in children weighing less than 20 kg \n• 9.9 - 13.0 g/m2/day in children weighing more than 20 kg, adolescents and adults. \nThe safety and efficacy of doses in excess of 20 g/day (40 tablets) have not been established. \n \nTherapeutic monitoring: Plasma levels of ammonia, arginine, essential amino acids (especially \nbranched chain amino acids), carnitine and serum proteins should be maintained within normal limits. \nPlasma glutamine should be maintained at levels less than 1,000 µmol/l. \n \nNutritional management: AMMONAPS must be combined with dietary protein restriction and, in \nsome cases, essential amino acid and carnitine supplementation. \n\n\n\n3 \n\n \nCitrulline or arginine supplementation is required for patients diagnosed with neonatal-onset form of \ncarbamyl phosphate synthetase or ornithine transcarbamylase deficiency at a dose of 0.17 g/kg/day or \n3.8 g/m2/day. \nArginine supplementation is required for patients diagnosed with deficiency of argininosuccinate \nsynthetase at a dose of 0.4 - 0.7 g/kg/day or 8.8 - 15.4 g/m2/day. \n \nIf caloric supplementation is indicated, a protein-free product is recommended. \n \nThe total daily dose of AMMONAPS should be divided into equal amounts and given with each meal \n(e.g. three times per day). The tablets should be taken with a large volume of water. \n \n4.3 Contraindications \n \n− Pregnancy. \n− Breast-feeding. \n− Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. \n \n4.4 Special warnings and precautions for use \n \nAMMONAPS tablets should not be used in patients with dysphagia due to the potential risk of \noesophageal ulceration if tablets are not promptly delivered to the stomach. \n \nEach AMMONAPS tablet contains 62 mg (2.7 mmol) of sodium, corresponding to 2.5 g (108 mmol) \nof sodium per 20 g of sodium phenylbutyrate, which is the maximum daily dose. AMMONAPS \nshould therefore be used with caution in patients with congestive heart failure or severe renal \ninsufficiency, and in clinical conditions where there is sodium retention with oedema. \n \nSince the metabolism and excretion of sodium phenylbutyrate involves the liver and kidneys, \nAMMONAPS should be used with caution in patients with hepatic or renal insufficiency. \n \nSerum potassium should be monitored during therapy since renal excretion of phenylacetylglutamine \nmay induce a urinary loss of potassium. \n \nEven on therapy, acute hyperammonaemic encephalopathy may occur in a number of patients. \n \nAMMONAPS is not recommended for the management of acute hyperammonaemia, which is a \nmedical emergency. \n \nIn children unable to swallow tablets, it is recommended to use AMMONAPS granules instead. \n \n4.5 Interaction with other medicinal products and other forms of interaction \n \nConcurrent administration of probenecid may affect renal excretion of the conjugation product of \nsodium phenylbutyrate. \n \nThere have been published reports of hyperammonaemia being induced by haloperidol and by \nvalproate. Corticosteroids may cause the breakdown of body protein and thus increase plasma \nammonia levels. More frequent monitoring of plasma ammonia levels is advised when these \nmedications have to be used. \n \n4.6 Fertility, pregnancy and lactation \n \nPregnancy \nThe safety of this medicinal product for use in human pregnancy has not been established. Evaluation \nof experimental animal studies has shown reproductive toxicity, i.e. effects on the development of the \nembryo or the foetus. Prenatal exposure of rat pups to phenylacetate (the active metabolite of \n\n\n\n4 \n\nphenylbutyrate) produced lesions in cortical pyramidal cells; dendritic spines were longer and thinner \nthan normal and reduced in number. The significance of these data in pregnant women is not known; \ntherefore the use of AMMONAPS is contra-indicated during pregnancy (see section 4.3). \nEffective contraceptive measures must be taken by women of child-bearing potential. \n \nLactation \nWhen high doses of phenylacetate (190 - 474 mg/kg) were given subcutaneously to rat pups, \ndecreased proliferation and increased loss of neurons were observed, as well as a reduction in CNS \nmyelin. Cerebral synapse maturation was retarded and the number of functioning nerve terminals in \nthe cerebrum was reduced, which resulted in impaired brain growth. It has not been determined if \nphenylacetate is secreted in human milk and therefore the use of AMMONAPS is contra-indicated \nduring lactation (see section 4.3). \n \n4.7 Effects on ability to drive and use machines \n \nNo studies on the effects on the ability to drive and use machines have been performed. \n \n4.8 Undesirable effects \n \nIn clinical trials with AMMONAPS, 56 % of the patients experienced at least one adverse event and \n78 % of these adverse events were considered as not related to AMMONAPS. \n \nAdverse reactions mainly involved the reproductive and gastrointestinal system. \nThe adverse reactions are listed below, by system organ class and by frequency. Frequency is defined \nas very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare \n(≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available \ndata). Within each frequency grouping, undesirable effects are presented in order of decreasing \nseriousness. \n \nBlood and lymphatic system disorders \nCommon: Anaemia, thrombocytopenia, leukopenia, leukocytosis, thrombocytosis \nUncommon: Aplastic anaemia, ecchymosis \n \nMetabolism and nutrition disorders \nCommon: Metabolic acidosis, alkalosis, decreased appetite \n \nPsychiatric disorders \nCommon: Depression, irritability \n \nNervous system disorders \nCommon: Syncope, headache \n \nCardiac disorders \nCommon: Oedema \nUncommon: Arrhythmia \n \nGastrointestinal disorders \nCommon: Abdominal pain, vomiting, nausea, constipation, dysgeusia \nUncommon: Pancreatitis, peptic ulcer, rectal haemorrhage, gastritis \n \nSkin and subcutaneous tissue disorders \nCommon: Rash, abnormal skin odour \n \nRenal and urinary disorders \nCommon: Renal tubular acidosis \n \n\n\n\n5 \n\nReproductive system and breast disorders \nVery common: Amenorrhoea, irregular menstruation \n \nInvestigations \nCommon: Decreased blood potassium, albumin, total protein and phosphate. Increased blood alkaline \nphosphatase, transaminases, bilirubin, uric acid, chloride, phosphate and sodium. Increased weight. \n \nA probable case of toxic reaction to AMMONAPS (450 mg/kg/d) was reported in an 18-year old \nanorectic female patient who developed a metabolic encephalopathy associated with lactic acidosis, \nsevere hypokalaemia, pancytopaenia, peripheral neuropathy, and pancreatitis. She recovered following \ndose reduction except for recurrent pancreatitis episodes that eventually prompted treatment \ndiscontinuation. \n \nReporting of suspected adverse reactions \nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V. \n \n4.9 Overdose \n \nOne case of overdose occurred in a 5-month old infant with an accidental single dose of 10 g \n(1370 mg/kg). The patient developed diarrhoea, irritability and metabolic acidosis with hypokalaemia. \nThe patient recovered within 48 hours after symptomatic treatment. \n \nThese symptoms are consistent with the accumulation of phenylacetate, which showed dose-limiting \nneurotoxicity when administered intravenously at doses up to 400 mg/kg/day. Manifestations of \nneurotoxicity were predominantly somnolence, fatigue and light-headedness. Less frequent \nmanifestations were confusion, headache, dysgeusia, hypacusis, disorientation, impaired memory and \nexacerbation of a pre-existing neuropathy. \nIn the event of an overdose, discontinue the treatment and institute supportive measures. \nHaemodialysis or peritoneal dialysis may be beneficial. \n \n \n5. PHARMACOLOGICAL PROPERTIES \n \n5.1 Pharmacodynamic properties \n \nPharmacotherapeutic group: various alimentary tract and metabolism products, ATC code: A16A X03. \n \nSodium phenylbutyrate is a pro-drug and is rapidly metabolised to phenylacetate. Phenylacetate is a \nmetabolically active compound that conjugates with glutamine via acetylation to form \nphenylacetylglutamine which is then excreted by the kidneys. On a molar basis, \nphenylacetylglutamine is comparable to urea (each containing 2 moles of nitrogen) and therefore \nprovides an alternate vehicle for waste nitrogen excretion. Based on studies of phenylacetylglutamine \nexcretion in patients with urea cycle disorders it is possible to estimate that, for each gram of sodium \nphenylbutyrate administered, between 0.12 and 0.15 g of phenylacetylglutamine nitrogen are \nproduced. As a consequence, sodium phenylbutyrate reduces elevated plasma ammonia and glutamine \nlevels in patients with urea cycle disorders. It is important that the diagnosis is made early and \ntreatment is initiated immediately to improve the survival and the clinical outcome. \n \nPreviously, neonatal-onset presentation of urea cycle disorders was almost universally fatal within the \nfirst year of life, even when treated with peritoneal dialysis and essential amino acids or their nitrogen-\nfree analogues. With haemodialysis, use of alternative waste nitrogen excretion pathways (sodium \nphenylbutyrate, sodium benzoate and sodium phenylacetate), dietary protein restriction, and, in some \ncases, essential amino acid supplementation, the survival rate in new-borns diagnosed after birth (but \nwithin the first month of life) increased to almost 80 % with most deaths occurring during an episode \n\n\n\n6 \n\nof acute hyperammonaemic encephalopathy. Patients with neonatal-onset disease had a high incidence \nof mental retardation. \n \nIn patients diagnosed during gestation and treated prior to any episode of hyperammonaemic \nencephalopathy, survival was 100 %, but even in these patients, many subsequently demonstrated \ncognitive impairment or other neurologic deficits. \n \nIn late-onset deficiency patients, including females heterozygous for ornithine transcarbamylase \ndeficiency, who recovered from hyperammonaemic encephalopathy and were then treated chronically \nwith dietary protein restriction and sodium phenylbutyrate, the survival rate was 98 %. The majority of \nthe patients who were tested had an IQ in the average to low average/borderline mentally retarded \nrange. Their cognitive performance remained relatively stable during phenylbutyrate therapy. \n \nReversal of pre-existing neurologic impairment is not likely to occur with treatment, and neurologic \ndeterioration may continue in some patients. \n \nAMMONAPS may be required life-long unless orthotopic liver transplantation is elected. \n \n5.2 Pharmacokinetic properties \n \nPhenylbutyrate is known to be oxidised to phenylacetate which is enzymatically conjugated with \nglutamine to form phenylacetylglutamine in the liver and kidney. Phenylacetate is also hydrolysed by \nesterases in liver and blood. \n \nPlasma and urine concentrations of phenylbutyrate and its metabolites have been obtained from fasting \nnormal adults who received a single dose of 5 g of sodium phenylbutyrate and from patients with urea \ncycle disorders, haemoglobinopathies and cirrhosis receiving single and repeated oral doses up to \n20 g/day (uncontrolled studies). The disposition of phenylbutyrate and its metabolites has also been \nstudied in cancer patients following intravenous infusion of sodium phenylbutyrate (up to 2 g/m²) or \nphenylacetate. \n \nAbsorption \nPhenylbutyrate is rapidly absorbed under fasting conditions. After a single oral dose of 5 g of sodium \nphenylbutyrate, in the form of tablets, measurable plasma levels of phenylbutyrate are detected \n15 minutes after dosing. The mean time to peak concentration is 1.35 hour and the mean peak \nconcentration 218 µg/ml. The elimination half-life was estimated to be 0.8 hours. \nThe effect of food on absorption is unknown. \n \nDistribution \nThe volume of distribution of phenylbutyrate is 0.2 l/kg. \n \nBiotransformation \nAfter a single dose of 5 g of sodium phenylbutyrate, in the form of tablets, measurable plasma levels \nof phenylacetate and phenylacetylglutamine are detected 30 and 60 minutes respectively after dosing. \nThe mean time to peak concentration is 3.74 and 3.43 hours, respectively, and the mean peak \nconcentration is 48.5 and 68.5 µg/ml, respectively. The elimination half-life was estimated to be 1.2 \nand 2.4 hours, respectively. \n \nStudies with high intravenous doses of phenylacetate showed non linear pharmacokinetics \ncharacterised by saturable metabolism to phenylacetylglutamine. Repeated dosing with phenylacetate \nshowed evidence of an induction of clearance. \nIn the majority of patients with urea cycle disorders or haemoglobinopathies receiving various doses \nof phenylbutyrate (300 - 650 mg/kg/day up to 20 g/day) no plasma level of phenylacetate could be \ndetected after overnight fasting. In patients with impaired hepatic function the conversion of \nphenylacetate to phenylacetylglutamine may be relatively slower. Three cirrhotic patients (out of 6) \nwho received repeated oral administration of sodium phenylbutyrate (20 g/day in three doses) showed \n\n\n\n7 \n\nsustained plasma levels of phenylacetate on the third day that were five times higher than those \nachieved after the first dose. \n \nIn normal volunteers gender differences were found in the pharmacokinetic parameters of \nphenylbutyrate and phenylacetate (AUC and Cmax about 30 - 50 % greater in females), but not \nphenylacetylglutamine. This may be due to the lipophilicity of sodium phenylbutyrate and consequent \ndifferences in volume of distribution. \n \nElimination \nApproximately 80 - 100 % of the medicinal product is excreted by the kidneys within 24 hours as the \nconjugated product, phenylacetylglutamine. \n \n5.3 Preclinical safety data \n \nSodium phenylbutyrate was negative in 2 mutagenicity tests, i.e. the Ames test and the micronucleus \ntest. Results indicate that sodium phenylbutyrate did not induce any mutagenic effects in the Ames test \nwith or without metabolic activation. \nMicronucleus test results indicate that sodium phenylbutyrate was considered not to have produced \nany clastogenic effect in rats treated at toxic or non-toxic dose levels (examined 24 and 48 hours after \na single oral administration of 878 to 2800 mg/kg). Carcinogenicity and fertility studies have not been \nconducted with sodium phenylbutyrate. \n \n \n6. PHARMACEUTICAL PARTICULARS \n \n6.1 List of excipients \n \nMicrocrystalline cellulose \nMagnesium stearate \nColloidal anhydrous silica \n \n6.2 Incompatibilities \n \nNot applicable. \n \n6.3 Shelf life \n \n2 years. \n \n6.4 Special precautions for storage \n \nDo not store above 30°C. \n \n6.5 Nature and contents of container \n \nHDPE bottles, with child resistant caps, containing 250 or 500 tablets. \n \nNot all pack sizes may be marketed. \n \n6.6 Special precautions for disposal \n \nAny unused medicinal product or waste material should be disposed of in accordance with local \nrequirements. \n \n \n\n\n\n8 \n\n7. MARKETING AUTHORISATION HOLDER \n \nImmedica Pharma AB \nSE-113 29 Stockholm \nSweden \n \n \n8. MARKETING AUTHORISATION NUMBERS \n \nEU/1/99/120/001 (250 tablets) \nEU/1/99/120/002 (500 tablets) \n \n \n9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION \n \nDate of first authorisation: 08/12/1999 \nDate of latest renewal: 08/12/2009 \n \n \n10. DATE OF REVISION OF THE TEXT \n \n \n \n \nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency http://www.ema.europa.eu/. \n\n\n\n9 \n\n1. NAME OF THE MEDICINAL PRODUCT \n \nAMMONAPS 940 mg/g granules \n \n \n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \nEach gram of granules contains 940 mg of sodium phenylbutyrate. \n \nOne small spoon of AMMONAPS granules contains 149 mg of sodium. \nOne medium sized spoon of AMMONAPS granules contains 408 mg of sodium. \nOne large spoon of AMMONAPS granules contains 1200 mg of sodium. \n \nFor the full list of excipients, see section 6.1. \n \n \n3. PHARMACEUTICAL FORM \n \nGranules. \n \nThe granules are off-white. \n \n \n4. CLINICAL PARTICULARS \n \n4.1 Therapeutic indications \n \nAMMONAPS is indicated as adjunctive therapy in the chronic management of urea cycle disorders, \ninvolving deficiencies of carbamylphosphate synthetase, ornithine transcarbamylase or \nargininosuccinate synthetase. \nIt is indicated in all patients with neonatal-onset presentation (complete enzyme deficiencies, \npresenting within the first 28 days of life). It is also indicated in patients with late-onset disease \n(partial enzyme deficiencies, presenting after the first month of life) who have a history of \nhyperammonaemic encephalopathy. \n \n4.2 Posology and method of administration \n \nAMMONAPS treatment should be supervised by a physician experienced in the treatment of urea \ncycle disorders. \n \nAMMONAPS granules should be administered orally (to infants and children unable to swallow \ntablets and to patients with dysphagia) or via gastrostomy or nasogastric tube. \n \nThe daily dose should be individually adjusted according to the patient’s protein tolerance and the \ndaily dietary protein intake needed to promote growth and development. \n \nThe usual total daily dose of sodium phenylbutyrate in clinical experience is: \n• 450 - 600 mg/kg/day in neonates, infants and children weighing less than 20 kg \n• 9.9 - 13.0 g/m2/day in children weighing more than 20 kg, adolescents and adults. \nThe safety and efficacy of doses in excess of 20 g/day have not been established. \n \nTherapeutic monitoring: Plasma levels of ammonia, arginine, essential amino acids (especially \nbranched chain amino acids), carnitine and serum proteins should be maintained within normal limits. \nPlasma glutamine should be maintained at levels less than 1,000 µmol/l. \n \nNutritional management: AMMONAPS must be combined with dietary protein restriction and, in \nsome cases, essential amino acid and carnitine supplementation. \n\n\n\n10 \n\n \nCitrulline or arginine supplementation is required for patients diagnosed with neonatal-onset form of \ncarbamyl phosphate synthetase or ornithine transcarbamylase deficiency at a dose of 0.17 g/kg/day or \n3.8 g/m2/day. \nArginine supplementation is required for patients diagnosed with deficiency of argininosuccinate \nsynthetase at a dose of 0.4 - 0.7 g/kg/day or 8.8 - 15.4 g/m2/day. \n \nIf caloric supplementation is indicated, a protein-free product is recommended. \n \nThe total daily dose should be divided into equal amounts and given with each meal or feeding (e.g. 4-\n6 times per day in small children). When taken orally, the granules are to be mixed with solid foods \n(such as mashed potatoes or apple sauce) or liquid foods (such as water, apple juice, orange juice or \nprotein-free infant formulas). \n \nThree dosing spoons are provided which dispense 1.2 g, 3.3 g or 9.7 g of sodium phenylbutyrate. \nLightly shake the bottle before dispensing. \n \n4.3 Contraindications \n \n− Pregnancy. \n− Breast-feeding. \n− Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. \n \n4.4 Special warnings and precautions for use \n \nAMMONAPS granules contain 124 mg (5.4 mmol) of sodium per gram of sodium phenylbutyrate, \ncorresponding to 2.5 g (108 mmol) of sodium per 20 g of sodium phenylbutyrate, which is the \nmaximum daily dose. AMMONAPS should therefore be used with caution in patients with congestive \nheart failure or severe renal insufficiency, and in clinical conditions where there is sodium retention \nwith oedema. \n \nSince the metabolism and excretion of sodium phenylbutyrate involves the liver and kidneys, \nAMMONAPS should be used with caution in patients with hepatic or renal insufficiency. \n \nSerum potassium should be monitored during therapy since renal excretion of phenylacetylglutamine \nmay induce a urinary loss of potassium. \n \nEven on therapy, acute hyperammonaemic encephalopathy may occur in a number of patients. \n \nAMMONAPS is not recommended for the management of acute hyperammonaemia, which is a \nmedical emergency. \n \n4.5 Interaction with other medicinal products and other forms of interaction \n \nConcurrent administration of probenecid may affect renal excretion of the conjugation product of \nsodium phenylbutyrate. \n \nThere have been published reports of hyperammonaemia being induced by haloperidol and by \nvalproate. Corticosteroids may cause the breakdown of body protein and thus increase plasma \nammonia levels. More frequent monitoring of plasma ammonia levels is advised when these \nmedications have to be used. \n \n4.6 Fertility, pregnancy and lactation \n \nPregnancy \nThe safety of this medicinal product for use in human pregnancy has not been established. Evaluation \nof experimental animal studies has shown reproductive toxicity, i.e. effects on the development of the \n\n\n\n11 \n\nembryo or the foetus. Prenatal exposure of rat pups to phenylacetate (the active metabolite of \nphenylbutyrate) produced lesions in cortical pyramidal cells; dendritic spines were longer and thinner \nthan normal and reduced in number. The significance of these data in pregnant women is not known; \ntherefore the use of AMMONAPS is contra-indicated during pregnancy (see section 4.3). \nEffective contraceptive measures must be taken by women of child-bearing potential. \n \nLactation \nWhen high doses of phenylacetate (190 - 474 mg/kg) were given subcutaneously to rat pups, \ndecreased proliferation and increased loss of neurons were observed, as well as a reduction in CNS \nmyelin. Cerebral synapse maturation was retarded and the number of functioning nerve terminals in \nthe cerebrum was reduced, which resulted in impaired brain growth. It has not been determined if \nphenylacetate is secreted in human milk and therefore the use of AMMONAPS is contra-indicated \nduring lactation (see section 4.3). \n \n4.7 Effects on ability to drive and use machines \n \nNo studies on the effects on the ability to drive and use machines have been performed. \n \n4.8 Undesirable effects \n \nIn clinical trials with AMMONAPS, 56 % of the patients experienced at least one adverse event and \n78 % of these adverse events were considered as not related to AMMONAPS. \n \nAdverse reactions mainly involved the reproductive and gastrointestinal system. \nThe adverse reactions are listed below, by system organ class and by frequency. Frequency is defined \nas very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare \n(≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available \ndata). Within each frequency grouping, undesirable effects are presented in order of decreasing \nseriousness. \n \nBlood and lymphatic system disorders \nCommon: Anaemia, thrombocytopenia, leukopenia, leukocytosis, thrombocytosis \nUncommon: Aplastic anaemia, ecchymosis \n \nMetabolism and nutrition disorders \nCommon: Metabolic acidosis, alkalosis, decreased appetite \n \nPsychiatric disorders \nCommon: Depression, irritability \n \nNervous system disorders \nCommon: Syncope, headache \n \nCardiac disorders \nCommon: Oedema \nUncommon: Arrhythmia \n \nGastrointestinal disorders \nCommon: Abdominal pain, vomiting, nausea, constipation, dysgeusia \nUncommon: Pancreatitis, peptic ulcer, rectal haemorrhage, gastritis \n \nSkin and subcutaneous tissue disorders \nCommon: Rash, abnormal skin odour \n \nRenal and urinary disorders \nCommon: Renal tubular acidosis \n \n\n\n\n12 \n\nReproductive system and breast disorders \nVery common: Amenorrhoea, irregular menstruation \n \nInvestigations \nCommon: Decreased blood potassium, albumin, total protein and phosphate. Increased blood alkaline \nphosphatase, transaminases, bilirubin, uric acid, chloride, phosphate and sodium. Increased weight. \n \nA probable case of toxic reaction to AMMONAPS (450 mg/kg/d) was reported in an 18-year old \nanorectic female patient who developed a metabolic encephalopathy associated with lactic acidosis, \nsevere hypokalaemia, pancytopaenia, peripheral neuropathy, and pancreatitis. She recovered following \ndose reduction except for recurrent pancreatitis episodes that eventually prompted treatment \ndiscontinuation. \n \nReporting of suspected adverse reactions \n \nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V. \n \n4.9 Overdose \n \nOne case of overdose occurred in a 5-month old infant with an accidental single dose of 10 g \n(1370 mg/kg). The patient developed diarrhoea, irritability and metabolic acidosis with hypokalaemia. \nThe patient recovered within 48 hours after symptomatic treatment. \n \nThese symptoms are consistent with the accumulation of phenylacetate, which showed dose-limiting \nneurotoxicity when administered intravenously at doses up to 400 mg/kg/day. Manifestations of \nneurotoxicity were predominantly somnolence, fatigue and light-headedness. Less frequent \nmanifestations were confusion, headache, dysgeusia, hypacusis, disorientation, impaired memory and \nexacerbation of a pre-existing neuropathy. \nIn the event of an overdose, discontinue the treatment and institute supportive measures. \nHaemodialysis or peritoneal dialysis may be beneficial. \n \n \n5. PHARMACOLOGICAL PROPERTIES \n \n5.1 Pharmacodynamic properties \n \nPharmacotherapeutic group: various alimentary tract and metabolism products, ATC code: A16A X03. \n \nSodium phenylbutyrate is a pro-drug and is rapidly metabolised to phenylacetate. Phenylacetate is a \nmetabolically active compound that conjugates with glutamine via acetylation to form \nphenylacetylglutamine which is then excreted by the kidneys. On a molar basis, \nphenylacetylglutamine is comparable to urea (each containing 2 moles of nitrogen) and therefore \nprovides an alternate vehicle for waste nitrogen excretion. Based on studies of phenylacetylglutamine \nexcretion in patients with urea cycle disorders it is possible to estimate that, for each gram of sodium \nphenylbutyrate administered, between 0.12 and 0.15 g of phenylacetylglutamine nitrogen are \nproduced. As a consequence, sodium phenylbutyrate reduces elevated plasma ammonia and glutamine \nlevels in patients with urea cycle disorders. It is important that the diagnosis is made early and \ntreatment is initiated immediately to improve the survival and the clinical outcome. \n \nPreviously, neonatal-onset presentation of urea cycle disorders was almost universally fatal within the \nfirst year of life, even when treated with peritoneal dialysis and essential amino acids or their nitrogen-\nfree analogues. With haemodialysis, use of alternative waste nitrogen excretion pathways (sodium \nphenylbutyrate, sodium benzoate and sodium phenylacetate), dietary protein restriction, and, in some \ncases, essential amino acid supplementation, the survival rate in new-borns diagnosed after birth (but \n\n\n\n13 \n\nwithin the first month of life) increased to almost 80 % with most deaths occurring during an episode \nof acute hyperammonaemic encephalopathy. Patients with neonatal-onset disease had a high incidence \nof mental retardation. \n \nIn patients diagnosed during gestation and treated prior to any episode of hyperammonaemic \nencephalopathy, survival was 100 %, but even in these patients, many subsequently demonstrated \ncognitive impairment or other neurologic deficits. \n \nIn late-onset deficiency patients, including females heterozygous for ornithine transcarbamylase \ndeficiency, who recovered from hyperammonaemic encephalopathy and were then treated chronically \nwith dietary protein restriction and sodium phenylbutyrate, the survival rate was 98 %. The majority of \nthe patients who were tested had an IQ in the average to low average/borderline mentally retarded \nrange. Their cognitive performance remained relatively stable during phenylbutyrate therapy. \n \nReversal of pre-existing neurologic impairment is not likely to occur with treatment, and neurologic \ndeterioration may continue in some patients. \n \nAMMONAPS may be required life-long unless orthotopic liver transplantation is elected. \n \n5.2 Pharmacokinetic properties \n \nPhenylbutyrate is known to be oxidised to phenylacetate which is enzymatically conjugated with \nglutamine to form phenylacetylglutamine in the liver and kidney. Phenylacetate is also hydrolysed by \nesterases in liver and blood. \n \nPlasma and urine concentrations of phenylbutyrate and its metabolites have been obtained from fasting \nnormal adults who received a single dose of 5 g of sodium phenylbutyrate and from patients with urea \ncycle disorders, haemoglobinopathies and cirrhosis receiving single and repeated oral doses up to \n20 g/day (uncontrolled studies). The disposition of phenylbutyrate and its metabolites has also been \nstudied in cancer patients following intravenous infusion of sodium phenylbutyrate (up to 2 g/m²) or \nphenylacetate. \n \nAbsorption \nPhenylbutyrate is rapidly absorbed under fasting conditions. After a single oral dose of 5 g of sodium \nphenylbutyrate, in the form of granules, measurable plasma levels of phenylbutyrate are detected \n15 minutes after dosing. The mean time to peak concentration is 1 hour and the mean peak \nconcentration 195 µg/ml. The elimination half-life was estimated to be 0.8 hours. \nThe effect of food on absorption is unknown. \n \nDistribution \nThe volume of distribution of phenylbutyrate is 0.2 l/kg. \n \nBiotransformation \nAfter a single dose of 5 g of sodium phenylbutyrate, in the form of granules, measurable plasma levels \nof phenylacetate and phenylacetylglutamine are detected 30 and 60 minutes respectively after dosing. \nThe mean time to peak concentration is 3.55 and 3.23 hours, respectively, and the mean peak \nconcentration is 45.3 and 62.8 µg/ml, respectively. The elimination half-life was estimated to be 1.3 \nand 2.4 hours, respectively. \n \nStudies with high intravenous doses of phenylacetate showed non linear pharmacokinetics \ncharacterised by saturable metabolism to phenylacetylglutamine. Repeated dosing with phenylacetate \nshowed evidence of an induction of clearance. \nIn the majority of patients with urea cycle disorders or haemoglobinopathies receiving various doses \nof phenylbutyrate (300 - 650 mg/kg/day up to 20 g/day) no plasma level of phenylacetate could be \ndetected after overnight fasting. In patients with impaired hepatic function the conversion of \nphenylacetate to phenylacetylglutamine may be relatively slower. Three cirrhotic patients (out of 6) \nwho received repeated oral administration of sodium phenylbutyrate (20 g/day in three doses) showed \n\n\n\n14 \n\nsustained plasma levels of phenylacetate on the third day that were five times higher than those \nachieved after the first dose. \n \nIn normal volunteers gender differences were found in the pharmacokinetic parameters of \nphenylbutyrate and phenylacetate (AUC and Cmax about 30 - 50 % greater in females), but not \nphenylacetylglutamine. This may be due to the lipophilicity of sodium phenylbutyrate and consequent \ndifferences in volume of distribution. \n \nElimination \nApproximately 80 - 100 % of the medicinal product is excreted by the kidneys within 24 hours as the \nconjugated product, phenylacetylglutamine. \n \n5.3 Preclinical safety data \n \nSodium phenylbutyrate was negative in 2 mutagenicity tests, i.e. the Ames test and the micronucleus \ntest. Results indicate that sodium phenylbutyrate did not induce any mutagenic effects in the Ames test \nwith or without metabolic activation. \nMicronucleus test results indicate that sodium phenylbutyrate was considered not to have produced \nany clastogenic effect in rats treated at toxic or non-toxic dose levels (examined 24 and 48 hours after \na single oral administration of 878 to 2800 mg/kg). Carcinogenicity and fertility studies have not been \nconducted with sodium phenylbutyrate. \n \n \n6. PHARMACEUTICAL PARTICULARS \n \n6.1 List of excipients \n \nCalcium stearate \nColloidal anhydrous silica \n \n6.2 Incompatibilities \n \nNot applicable. \n \n6.3 Shelf life \n \n2 years. \n \n6.4 Special precautions for storage \n \nDo not store above 25oC \n \n6.5 Nature and contents of container \n \nHDPE bottles, with child resistant caps, containing 266 g or 532 g of granules. \n \nThree measuring spoons of different measures are provided. \n \nNot all pack sizes may be marketed. \n \n6.6 Special precautions for disposal and other handling \n \nIt is recommended that a heaped measuring spoon is removed from the container and a flat surface, \ne.g. the blade of a knife, is drawn across the top of the measure. This will give the following doses: \nsmall measure 1.2 g, medium measure 3.3 g and large measure 9.7 g of sodium phenylbutyrate. \n \n\n\n\n15 \n\nWhere a patient requires administration by tube, it is possible to re-constitute AMMONAPS in water \nprior to use (solubility for sodium phenylbutyrate is up to 5 g in 10 ml water). Please note that the re-\nconstituted granules will normally produce a milky white suspension. \n \nWhere AMMONAPS granules need to be added to food, liquid or water, it is important that it is taken \nimmediately after mixing. \n \nAny unused medicinal product or waste material should be disposed of in accordance with local \nrequirements. \n \n \n7. MARKETING AUTHORISATION HOLDER \n \nImmedica Pharma AB \nSE-113 29 Stockholm \nSweden \n \n \n8. MARKETING AUTHORISATION NUMBERS \n \nEU/1/99/120/003 (266 g granules) \nEU/1/99/120/004 (532 g granules) \n \n \n9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION \n \nDate of first authorisation: 08/12/1999 \nDate of latest renewal: 08/12/2009 \n \n \n10. DATE OF REVISION OF THE TEXT \n \n \n \n \nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency http://www.ema.europa.eu/. \n\n\n\n16 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX II \n \n\nA. MANUFACTURER RESPONSIBLE FOR BATCH \nRELEASE \n\n \nB. CONDITIONS OR RESTRICTIONS REGARDING \n\nSUPPLY AND USE \n \n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE \nMARKETING AUTHORISATION \n\n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE \n\nAND EFFECTIVE USE OF THE MEDICINAL PRODUCT \n \n\n \n \n\n \n \n\n\n\n17 \n\nA. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE \n \nName and address of the manufacturer responsible for batch release \n \nPATHEON France – BOURGOIN JALLIEU \n40 boulevard de Champaret \nBOURGOIN JALLIEU \n38300 \nFrance \n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n \nMedicinal product subject to restricted medical prescription (see Annex I: Summary of Product \nCharacteristics, section 4.2). \n \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n \nNot applicable. \n \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n \nNot applicable. \n \n \n \n \n \n \n\n\n\n18 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX III \n \n\nLABELLING AND PACKAGE LEAFLET \n \n\n\n\n19 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nA. LABELLING \n \n\n\n\n20 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE \nPACKAGING \n \nOUTER CARTON AND BOTTLE LABEL FOR TABLETS \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nAMMONAPS 500 mg tablets \nsodium phenylbutyrate \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nEach tablet contains 500 mg of sodium phenylbutyrate. \n \n \n3. LIST OF EXCIPIENTS \n \nContains sodium, see package leaflet for further information. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \n250 tablets \n500 tablets \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nOral use. \nRead the package leaflet before use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nDo not store above 30°C. \n \n \n\n\n\n21 \n\n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nImmedica Pharma AB \nSE-113 29 Stockholm \nSweden \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/99/120/001 250 tablets \nEU/1/99/120/002 500 tablets \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nAmmonaps 500 mg \n[outer packaging only] \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n<2D barcode carrying the unique identifier included.> \n \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC: {number} \nSN: {number} \nNN: {number} \n\n\n\n22 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE \nPACKAGING \n \nOUTER CARTON AND BOTTLE LABEL FOR GRANULES \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nAMMONAPS 940 mg/g granules. \nsodium phenylbutyrate \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \n1 g of granules contains 940 mg of sodium phenylbutyrate \n \n \n3. LIST OF EXCIPIENTS \n \nContains sodium, see package leaflet for further information. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \n266 g granules \n532 g granules \nThree measuring spoons of different measures are provided. \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nOral use. \nRead the package leaflet before use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \n \n\n\n\n23 \n\n \n9. SPECIAL STORAGE CONDITIONS \n \nDo not store above 25°C. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nImmedica Pharma AB \nSE-113 29 Stockholm \nSweden \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/99/120/003 266 g granules \nEU/1/99/120/004 532 g granules \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \n[Justification for not including Braille accepted] \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n<2D barcode carrying the unique identifier included.> \n \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC: {number} \nSN: {number} \nNN: {number} \n \n\n\n\n24 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nB. PACKAGE LEAFLET \n \n \n\n\n\n25 \n\nPackage leaflet: Information for the user \n \n\nAMMONAPS 500 mg tablets \nSodium phenylbutyrate \n\n \nRead all of this leaflet carefully before you start taking this medicine because it contains \nimportant information for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor or pharmacist. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side \n\neffects not listed in this leaflet. See section 4. \n \nWhat is in this leaflet \n1. What AMMONAPS is and what it is used for \n2. What you need to know before you take AMMONAPS \n3. How to take AMMONAPS \n4. Possible side effects \n5. How to store AMMONAPS \n6. Contents of the pack and other information \n \n \n1. What AMMONAPS is and what it is used for \n \nAMMONAPS is prescribed to patients with urea cycle disorders. Patients with these rare disorders \nhave a deficiency of certain liver enzymes and are therefore unable to eliminate nitrogen waste. \nNitrogen is a building block of proteins, because of this, there is a build up of nitrogen in the body \nafter eating protein. Nitrogen waste, in the form of ammonia, is especially toxic for the brain and \nleads, in severe cases, to reduced levels of consciousness and to coma. \n \nAMMONAPS helps the body to eliminate nitrogen waste, reducing the amount of ammonia in your \nbody. \n \n \n2. What you need to know before you take AMMONAPS \n \nDo not take AMMONAPS \n- if you are pregnant. \n- if you are breast-feeding. \n- if you are allergic to sodium phenylbutyrate or any of the other ingredients of this medicine \n\n(listed in section 6). \n \nWarnings and precautions \nTalk to your doctor before taking AMMONAPS \n- if you have difficulty swallowing. AMMONAPS tablets can get stuck in the oesophagus and \n\ncause ulcers. If you have difficulty swallowing it is recommended to use AMMONAPS \ngranules instead. \n\n- if you suffer from heart failure, a decrease in your kidney function or other diseases, where the \nretention of the sodium salt contained in this medicine, may make your condition worse. \n\n- if you have decreased kidney or liver function, since AMMONAPS is eliminated from the body \nthrough the kidney and liver. \n\n- when given to small children, since they may not be able to swallow the tablets and may choke. \nIt is recommended to use AMMONAPS granules instead. \n\n \nAMMONAPS must be combined with a diet reduced in proteins designed especially for you by the \ndoctor and the dietician. You must follow this diet carefully. \n\n\n\n26 \n\n \nAMMONAPS does not completely prevent the occurrence of an acute excess of ammonia in the blood \nand is not appropriate for treating such a condition, which is a medical emergency. \n \nIf you require laboratory tests, it is important to remind your doctor that you are taking AMMONAPS, \nsince sodium phenylbutyrate may influence certain laboratory test results. \n \nOther medicines and AMMONAPS \nTell your doctor or pharmacist if you are taking, have recently taken or might take any other \nmedicines. \n \nIt is especially important to tell your doctor if you are taking medicines containing: \n- valproic acid (an antiepileptic drug), \n- haloperidol (used in certain psychotic disorders), \n- corticosteroids (cortisone-like medicines that are used to provide relief for inflamed areas of the \n\nbody), \n- probenecid (for treatment of hyperuricemia associated with gout). \n \nThese medicines may change the effect of AMMONAPS and you will need more frequent blood \ncontrols. If you are uncertain if your medicines contain these substances, you should check with your \ndoctor or pharmacist. \n\n \nPregnancy and breast-feeding \nDo not use AMMONAPS if you are pregnant, because this medicine can harm your unborn baby. If \nyou are a woman who could get pregnant, you must use reliable contraception, during treatment with \nAMMONAPS. \nDo not use AMMONAPS if you are breast-feeding, because this medicine can pass into the breast-\nmilk and harm your baby. \n \nDriving and using machines \nNo studies on the effects on the ability to drive and use machines have been performed. \n \nAMMONAPS contains sodium \nEach AMMONAPS tablet contains 62 mg of sodium. To be taken into consideration by patients on a \nsodium controlled diet. \n \n \n3. How to take AMMONAPS \n \nAlways take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist \nif you are not sure. \n \nDosage \nThe daily dose of AMMONAPS will be calculated from your protein tolerance, diet and body weight \nor body surface. You will need regular blood tests to determine the correct daily dose. Your doctor \nwill tell you how many tablets you should take. \n \nMethod of administration \nYou should take AMMONAPS by mouth in equally divided doses with each meal (for example three \ntimes per day).You should take AMMONAPS with a large volume of water. \n \nAMMONAPS must be taken with a special diet reduced in protein. \n \nAMMONAPS tablets should not be given to children who are not able to swallow tablets. It is \nrecommended that AMMONAPS granules are used instead. \n \n\n\n\n27 \n\nYou will need to have treatment and to follow a diet throughout your life, unless you have a successful \nliver transplantation. \n \nIf you take more AMMONAPS than you should \nPatients who have taken very high doses of AMMONAPS experienced: \n\n- sleepiness, tiredness, light-headedness and less frequently confusion, \n- headache, \n- changes in taste (taste disturbances), \n- decrease in hearing, \n- disorientation, \n- impaired memory, \n- worsening of existing neurological conditions. \n\n \nIf you experience any of these symptoms, you should immediately contact your doctor or the nearest \nhospital emergency department for supportive treatment. \n \nIf you forget to take AMMONAPS \nYou should take a dose as soon as possible with your next meal. Make sure that there are at least \n3 hours between two doses. Do not take a double dose to make up for a forgotten dose. \n \nIf you have any further questions on the use of this medicine, ask your doctor or pharmacist. \n \n \n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. \n \nThe frequency of possible side effects is listed below. \n \nVery common: Affects more than 1 user in 10 \nCommon: Affects 1 to 10 users in 100 \nUncommon: Affects 1 to 10 users in 1,000 \nRare: Affects 1 to 10 users in 10,000 \nVery rare: Affects less than 1 user in 10,000 \nNot known: Frequency cannot be estimated from the available data \n \nVery common side effects: irregular menstrual periods and cessation of menstrual periods. \nIf you are sexually active and your period stops altogether, do not assume that this is caused by \nAMMONAPS. If this occurs, please discuss it with your doctor, because the absence of your period \nmay be caused by pregnancy (see Pregnancy and breast-feeding section above). \n \nCommon side effects: changes in number of blood cells (red cells, white cells and platelets), reduced \nappetite, depression, irritability, headache, fainting, fluid retention (swelling), changes in taste (taste \ndisturbances),pain in the abdomen, vomiting, nausea, constipation, skin odour, rash, abnormal kidney \nfunction, weight gain, altered laboratory test values. \n \nUncommon side effects: deficiency in red blood cells due to bone marrow depression, bruising, altered \nheart rhythm, rectal bleeding, stomach irritation, stomach ulcer, inflammation of the pancreas. \n \nIf persistent vomiting occurs, you should contact your doctor immediately. \n \nReporting of side effects \nIf you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects \nnot listed in this leaflet. You can also report side effects directly via the national reporting system \nlisted in Appendix V. By reporting side effects you can help provide more information on the safety of \nthis medicine. \n\n\n\n28 \n\n \n \n5. How to store AMMONAPS \n \nKeep this medicine out of the sight and reach of children. \n \nDo not use this medicine after the expiry date which is stated on the carton and the bottle label after \n“EXP”. The expiry date refers to the last day of that month. \n \nDo not store above 30°C. \n \nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \nthrow away medicines you no longer use. These measures will help protect the environment. \n \n \n6. Contents of the pack and other information \n \nWhat AMMONAPS contains \n \n\n- The active substance is sodium phenylbutyrate. \nEach tablet of AMMONAPS contains 500 mg of sodium phenylbutyrate. \n\n- The other ingredients are microcrystalline cellulose, magnesium stearate and colloidal \nanhydrous silica. \n\n \nWhat AMMONAPS looks like and contents of the pack \nAMMONAPS tablets are off-white, oval and embossed with “UCY 500”. \n \nThe tablets are packaged in plastic bottles with child-resistant caps. Each bottle contains 250 or \n500 tablets. \n \nMarketing Authorisation Holder \nImmedica Pharma AB \nSE-113 29 Stockholm \nSweden \n \nManufacturer \nPATHEON France – BOURGOIN JALLIEU \n40 boulevard de Champaret \nBOURGOIN JALLIEU \n38300 \nFrance \n \nThis leaflet was last revised in \n \n \nDetailed information on this medicine is available on the European Medicines Agency web site: \nhttp://www.ema.europa.eu/. \n \n\n \n\n\n\n29 \n\nPackage leaflet: Information for the user \n \n\nAMMONAPS 940 mg/g granules \nSodium phenylbutyrate \n\n \nRead all of this leaflet carefully before you start taking this medicine because it contains \nimportant information for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor or pharmacist. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side \n\neffects not listed in this leaflet. See section 4. \n \nWhat is in this leaflet \n1. What AMMONAPS is and what it is used for \n2. What you need to know before you take AMMONAPS \n3. How to take AMMONAPS \n4. Possible side effects \n5. How to store AMMONAPS \n6. Contents of the pack and other information \n \n \n1. What AMMONAPS is and what it is used for \n \nAMMONAPS is prescribed to patients with urea cycle disorders. Patients with these rare disorders \nhave a deficiency of certain liver enzymes and are therefore unable to eliminate nitrogen waste. \nNitrogen is a building block of proteins, because of this there is a build up of nitrogen in the body after \neating protein. Nitrogen waste, in the form of ammonia, is especially toxic for the brain and leads, in \nsevere cases, to reduced levels of consciousness and to coma. \n \nAMMONAPS helps the body to eliminate nitrogen waste, reducing the amount of ammonia in your \nbody. \n \n \n2. What you need to know before you take AMMONAPS \n \nDo not take AMMONAPS \n- if you are pregnant. \n- if you are breast-feeding. \n- if you are allergic to sodium phenylbutyrate or any of the other ingredients of this medicine \n\n(listed in section 6). \n \nWarnings and precautions \nTalk to your doctor before taking AMMONAPS \n- if you suffer from heart failure, a decrease in your kidney function or other diseases where the \n\nretention of the sodium salt contained in this medicine may make your condition worse. \n- if you have decreased kidney or liver function, since AMMONAPS is eliminated from the body \n\nthrough the kidney and liver. \n \nAMMONAPS must be combined with a diet reduced in proteins, designed especially for you by the \ndoctor and the dietician. You must follow this diet carefully. \n \nAMMONAPS does not completely prevent the occurrence of an acute excess of ammonia in the blood \nand is not appropriate for treating such a condition, which is a medical emergency. \n \n\n\n\n30 \n\nIf you require laboratory tests, it is important to remind your doctor that you are taking AMMONAPS, \nsince sodium phenylbutyrate may influence certain laboratory test results. \n \nOther medicines and AMMONAPS \nTell your doctor or pharmacist if you are taking, have recently taken or might take any other \nmedicines. \n \nIt is especially important to tell your doctor if you are taking medicines containing: \n- valproic acid (an antiepileptic drug), \n- haloperidol (used in certain psychotic disorders), \n- corticosteroids (cortisone-like medicines that are used to provide relief for inflamed areas of the \n\nbody), \n- probenecid (for treatment of hyperuricemia associated with gout) \n \nThese medicines may change the effect of AMMONAPS and you will need more frequent blood \ncontrols. If you are uncertain if your medicines contain these substances, you should check with your \ndoctor or pharmacist. \n \nPregnancy and breast-feeding \nDo not use AMMONAPS if you are pregnant, because this medicine can harm your unborn baby. If \nyou are a woman who could get pregnant, you must use reliable contraception, during treatment with \nAMMONAPS. \n \nDo not use AMMONAPS if you are breast-feeding, because this medicine can pass into the breast-\nmilk and harm your baby. \n \nDriving and using machines \nNo studies on the effects on the ability to drive and use machines have been performed. \n \nAMMONAPS contains sodium \nOne small white spoon of AMMONAPS granules contains 149 mg of sodium. \nOne medium sized yellow spoon of AMMONAPS granules contains 408 mg of sodium. \nOne large blue spoon of AMMONAPS granules contains 1200 mg of sodium. \nTo be taken into consideration by patients on a sodium controlled diet. \n \n \n3. How to take AMMONAPS \n \nAlways take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist \nif you are not sure. \n \nDosage \nThe daily dose of AMMONAPS will be calculated from your protein tolerance, diet and body weight \nor body surface. You will need regular blood tests to determine the correct daily dose. Your doctor \nwill tell you the amount of granules you should take. \n \nMethod of administration \nYou should take AMMONAPS in equally divided doses by mouth, through a gastrostomy (tube that \ngoes through the abdomen to the stomach) or through a nasogastric tube (tube that goes through the \nnose to the stomach). \n \nAMMONAPS must be taken with a special diet reduced in protein. \n \nYou should take AMMONAPS with each meal or feeding. In small children this can be 4 to 6 times \nper day. \n \n\n\n\n31 \n\nTo measure the dose: \n• Shake the bottle lightly before opening \n• Use the correct spoon to dispense the following amount of Ammonaps: 1.2 g = small white \n\nspoon, 3.3 g = medium sized yellow spoon and 9.7 g = large blue spoon \n• Take a heaped spoonful of granules out of the bottle \n• Pass a flat surface, e.g. the back of a knife blade, over the top of the spoon to remove the excess \n\nof granules \n• The granules left in the spoon are one spoonful \n• Take the correct number of spoonfuls granules from the bottle \n \nWhen taken by mouth \nMix the measured dose with solid foods (such as mashed potatoes or apple sauce) or liquid foods \n(such as water, apple juice, orange juice or protein-free infant formulas) and take it immediately after \nmixing. \n \nPatients with a gastrostomy or nasogastric tube \nMix the granules with water until there are no dry granules left (stirring the solution helps to dissolve \nthe granules). When the granules are dissolved in water you get a milky white liquid. Take the solution \nimmediately after mixing. \n \nYou will need to have treatment and to follow a diet throughout your life, unless you have a successful \nliver transplantation. \n \nIf you take more AMMONAPS than you should \nPatients who have taken very high doses of AMMONAPS experienced: \n- sleepiness, tiredness, light-headedness and less frequently confusion, \n- headache, \n- changes in taste (taste disturbances), \n- decrease in hearing, \n- disorientation, \n- impaired memory, \n- worsening of existing neurological conditions. \n \n\nIf you experience any of these symptoms, you should immediately contact your doctor or the nearest \nhospital emergency department for supportive treatment. \n \nIf you forget to take AMMONAPS \nYou should take a dose as soon as possible with your next meal. Make sure that there are at least \n3 hours between two doses. Do not take a double dose to make up for a forgotten dose. \n \nIf you have any further questions on the use of this medicine, ask your doctor or pharmacist. \n \n \n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. \n \nThe frequency of possible side effects is listed below. \n \nVery common: Affects more than 1 user in 10 \nCommon: Affects 1 to 10 users in 100 \nUncommon: Affects 1 to 10 users in 1,000 \nRare: Affects 1 to 10 users in 10,000 \nVery rare: Affects less than 1 user in 10,000 \nNot known: Frequency cannot be estimated from the available data \n \n\n\n\n32 \n\nVery common side effects: irregular menstrual periods and cessation of menstrual periods. \nIf you are sexually active and your period stops altogether, do not assume that this is caused by \nAMMONAPS. If this occurs, please discuss it with your doctor, because the absence of your period \nmay be caused by pregnancy (see Pregnancy and breast-feeding section above). \n \nCommon side effects: changes in number of blood cells (red cells, white cells and platelets), reduced \nappetite, depression, irritability, headache, fainting, fluid retention (swelling), changes in taste (taste \ndisturbances),pain in the abdomen, vomiting, nausea, constipation, skin odour, rash, abnormal kidney \nfunction, weight gain, altered laboratory test values. \n \nUncommon side effects: deficiency in red blood cells due to bone marrow depression, bruising, altered \nheart rhythm, rectal bleeding, stomach irritation, stomach ulcer, inflammation of the pancreas. \n \nIf persistent vomiting occurs, you should contact your doctor immediately. \n \nReporting of side effects \nIf you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects \nnot listed in this leaflet. You can also report side effects directly via the national reporting system \nlisted in Appendix V. By reporting side effects you can help provide more information on the safety of \nthis medicine. \n \n \n5. How to store AMMONAPS \n \nKeep this medicine out of the sight and reach of children. \n \nDo not use this medicine after the expiry date which is stated on the carton and the bottle label after \n“EXP”. The expiry date refers to the last day of that month. \n \nDo not store above 25°C \n \nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \nthrow away medicines you no longer use. These measures will help protect the environment. \n \n \n6. Contents of the pack and other information \n \nWhat AMMONAPS contains \n \n- The active substance is sodium phenylbutyrate. \n\nOne gram of AMMONAPS granules contains 940 mg of sodium phenylbutyrate. \n- The other ingredients are calcium stearate and colloidal anhydrous silica. \n\n \nWhat AMMONAPS looks like and contents of the pack \nAMMONAPS granules are off-white. \n \nThe granules are packaged in plastic bottles with child-resistant caps. Each bottle contains 266 g or \n532 g of granules. Three spoons (one small white spoon, one medium sized yellow spoon and one \nlarge blue spoon) are included to measure your daily dose. \n \nMarketing Authorisation Holder \nImmedica Pharma AB \nSE-113 29 Stockholm \nSweden \n \nManufacturer \nPATHEON France – BOURGOIN JALLIEU \n\n\n\n33 \n\n40 boulevard de Champaret \nBOURGOIN JALLIEU \n38300 \nFrance \n \nThis leaflet was last revised in \n \n \nDetailed information on this medicine is available on the European Medicines Agency web site: \nhttp://www.ema.europa.eu/. \n\n \n \n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. 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difficulty swallowing it is recommended to use ammonaps granules instead. - if you suffer from heart failure, a decrease in your kidney function or other diseases, where the retention of the sodium salt contained in this medicine, may make your condition worse. - if you have decreased kidney or liver function, since ammonaps is eliminated from the body through the kidney and liver. - when given to small children, since they may not be able to swallow the tablets and may choke. it is recommended to use ammonaps granules instead. ammonaps must be combined with a diet reduced in proteins designed especially for you by the doctor and the dietician. you must follow this diet carefully. ammonaps does not completely prevent the occurrence of an acute excess of ammonia in the blood and is not appropriate for treating such a condition, which is a medical emergency. if you require laboratory tests, it is important to remind your doctor that you are taking ammonaps, since sodium phenylbutyrate 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ammonaps if you are breast-feeding, because this medicine can pass into the breast- milk and harm your baby. driving and using machines no studies on the effects on the ability to drive and use machines have been performed. ammonaps contains sodium each ammonaps tablet contains 62 mg of sodium. to be taken into consideration by patients on a sodium controlled diet.', 'Entity_Recognition': [{'Text': 'ammonaps', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 9, 'BeginOffset': 12, 'EndOffset': 20, 'Score': 0.38927316665649414, 'Text': 'ammonaps', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.4534144997596741}]}, {'Id': 22, 'BeginOffset': 34, 'EndOffset': 42, 'Score': 0.9948344230651855, 'Text': 'pregnant', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9369949102401733}]}, {'Id': 23, 'BeginOffset': 86, 'EndOffset': 119, 'Score': 0.3591480255126953, 'Text': 'allergic to sodium 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with each meal (for example three times per day).you should take ammonaps with a large volume of water. ammonaps must be taken with a special diet reduced in protein. ammonaps tablets should not be given to children who are not able to swallow tablets. it is recommended that ammonaps granules are used instead. you will need to have treatment and to follow a diet throughout your life, unless you have a successful liver transplantation. if you take more ammonaps than you should patients who have taken very high doses of ammonaps experienced: - sleepiness, tiredness, light-headedness and less frequently confusion, - headache, - changes in taste (taste disturbances), - decrease in hearing, - disorientation, - impaired memory, - worsening of existing neurological conditions. if you experience any of these symptoms, you should immediately contact your doctor or the nearest hospital emergency department for supportive treatment. if you forget to take ammonaps you should take a dose as soon as possible with your next meal. make sure that there are at least 3 hours between two doses. do not take a double dose to make up for a forgotten dose. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'ammonaps', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': 'ammonaps', 'Type': 'TREATMENT', 'BeginOffset': 146, 'EndOffset': 154}, {'Text': 'your protein tolerance', 'Type': 'TREATMENT', 'BeginOffset': 179, 'EndOffset': 201}, {'Text': 'regular blood tests', 'Type': 'TEST', 'BeginOffset': 255, 'EndOffset': 274}, {'Text': 'method of administration', 'Type': 'TREATMENT', 'BeginOffset': 372, 'EndOffset': 396}, {'Text': 'ammonaps', 'Type': 'TREATMENT', 'BeginOffset': 413, 'EndOffset': 421}, {'Text': 'a large volume of water', 'Type': 'TREATMENT', 'BeginOffset': 535, 'EndOffset': 558}, {'Text': 'ammonaps', 'Type': 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pregnancy and breast-feeding section above). common side effects: changes in number of blood cells (red cells, white cells and platelets), reduced appetite, depression, irritability, headache, fainting, fluid retention (swelling), changes in taste (taste disturbances),pain in the abdomen, vomiting, nausea, constipation, skin odour, rash, abnormal kidney function, weight gain, altered laboratory test values. uncommon side effects: deficiency in red blood cells due to bone marrow depression, bruising, altered heart rhythm, rectal bleeding, stomach irritation, stomach ulcer, inflammation of the pancreas. if persistent vomiting occurs, you should contact your doctor immediately. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more 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1770}]}"},"Section_5":{"kind":"string","value":"{'Title': '5. how to store ammonaps', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and the bottle label after \"exp\". the expiry date refers to the last day of that month. do not store above 30. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': 'what ammonaps contains - the active substance is sodium phenylbutyrate. each tablet of ammonaps contains 500 mg of sodium phenylbutyrate. - the other ingredients are microcrystalline cellulose, magnesium stearate and colloidal anhydrous silica. what ammonaps looks like and contents of the pack ammonaps tablets are off-white, oval and embossed with \"ucy 500\". the tablets are packaged in plastic bottles with child-resistant caps. each bottle contains 250 or 500 tablets.', 'Entity_Recognition': [{'Text': 'ammonaps', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 49, 'EndOffset': 70, 'Score': 0.9909177422523499, 'Text': 'sodium phenylbutyrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.2662223279476166, 'RelationshipScore': 0.9634901881217957, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 1, 'BeginOffset': 72, 'EndOffset': 83, 'Text': 'each tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 2, 'BeginOffset': 87, 'EndOffset': 104, 'Score': 0.4561344087123871, 'Text': 'ammonaps contains', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.2662223279476166, 'RelationshipScore': 0.9998350143432617, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 1, 'BeginOffset': 72, 'EndOffset': 83, 'Text': 'each tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 105, 'EndOffset': 108}, {'Id': 4, 'BeginOffset': 115, 'EndOffset': 136, 'Score': 0.9994053840637207, 'Text': 'sodium phenylbutyrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.2662223279476166, 'RelationshipScore': 0.9737232327461243, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 1, 'BeginOffset': 72, 'EndOffset': 83, 'Text': 'each tablet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.879055917263031, 'RelationshipScore': 0.9881565570831299, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 105, 'EndOffset': 111, 'Text': '500 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 5, 'BeginOffset': 166, 'EndOffset': 192, 'Score': 0.9953896999359131, 'Text': 'microcrystalline cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 194, 'EndOffset': 212, 'Score': 0.9952231049537659, 'Text': 'magnesium stearate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 217, 'EndOffset': 243, 'Score': 0.9738145470619202, 'Text': 'colloidal anhydrous silica', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the pack ammonaps tablets', 'Type': 'TREATMENT', 'BeginOffset': 286, 'EndOffset': 311}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 355, 'EndOffset': 358}, {'Text': 'the tablets', 'Type': 'TREATMENT', 'BeginOffset': 361, 'EndOffset': 372}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 453, 'EndOffset': 456}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 460, 'EndOffset': 463}]}"}}},{"rowIdx":1061,"cells":{"ID":{"kind":"string","value":"04034542AB28557EFC1CC133B66770F7"},"URL":{"kind":"string","value":"https://www.ema.europa.eu/documents/product-information/apealea-epar-product-information_en.pdf"},"Product_Name":{"kind":"string","value":"Apealea"},"Full_Content":{"kind":"string","value":"1 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX I \n \n\nSUMMARY OF PRODUCT CHARACTERISTICS \n\n\n\n2 \n\n1. NAME OF THE MEDICINAL PRODUCT \n \nApealea 60 mg powder for solution for infusion. \n \n \n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \nOne vial of powder contains 60 mg of paclitaxel. \n \nAfter reconstitution, each mL of solution contains 1 mg of paclitaxel (micellar). \n \nExcipients with known effect \n \nEach vial contains 3.77 mg (0.164 mmol) sodium. After reconstitution, each mL of solution contains \nup to approximately 3.60 mg (0.157 mmol) sodium. \n \nFor the full list of excipients, see section 6.1. \n \n \n3. PHARMACEUTICAL FORM \n \nPowder for solution for infusion. \n \nGreenish-yellow to yellow powder. \n \n \n4. CLINICAL PARTICULARS \n \n4.1 Therapeutic indications \n \nApealea in combination with carboplatin is indicated for the treatment of adult patients with first \nrelapse of platinum-sensitive epithelial ovarian cancer, primary peritoneal cancer and fallopian tube \ncancer (see section 5.1). \n \n4.2 Posology and method of administration \n \nApealea should only be administered under the supervision of a qualified oncologist in units \nspecialised in the administration of cytotoxic agents. It should not be interchanged with other \npaclitaxel formulations. \n \nPosology \n \nThe recommended dose of Apealea is 250 mg/m2 body surface area (BSA) given as an intravenous \ninfusion over 1 hour followed by carboplatin every three weeks for six cycles. The recommended dose \nof carboplatin is AUC = 5–6 mg/mL×min. \n \nDose adjustments and delays during treatment \nPatients who experience neutropenia (neutrophil count < 1.5 × 109/L), febrile neutropenia or \nthrombocytopenia (platelet count < 100 × 109/L) during treatment should have the next treatment cycle \ndelayed until neutrophil counts recover to ≥ 1.5 × 109/L and platelets recover to ≥ 100 × 109/L. For \nApealea, dose reductions of initially 50 mg/m2 and additionally 25 mg/m2 should be considered for \nsubsequent courses (see Table 1). \n \nIn the case of febrile neutropenia or low platelet count (< 75 × 109/L), the dose of carboplatin should \nbe reduced by 1 AUC unit in the treatment cycles following recovery. For appropriate use of \ncarboplatin, the prescriber is advised to consult the prescribing information for carboplatin as well. \n \n\n\n\n3 \n\nDose reductions or/and delays should be considered as a result of any clinically significant adverse \nreaction as presented in Table 1. \n \nTable 1. Treatment delay and dose level reductions for adverse drug reactions \n\nObservationa Delay of next cycle \nApealea/carboplatin \n\nApealea dose for subsequent courses \n(mg/m2)b \n\nHaematological toxicityb \n\nneutrophil count < 1.5 × 109/L \nor \nplatelet count < 100 × 109/L \nor \nfebrile neutropenia \n\nWithhold treatment until \nrecovery \n\nStandard dose: 250 \n\nPossible dose reductions: \n\nFirst dose level reduction: 200 \n\nSecond dose level reduction: 175 \n\nNervous system disorders \n\ngrade ≥ 2 peripheral sensory \nneuropathy \nor \ngrade ≥ 2 motor neuropathy \n\nWithhold treatment until \nrecovery to < grade 2 \n\nDose reduction: \n\nFirst dose level reduction: 200 \n\nPossible dose reduction: \n\nSecond dose level reduction: 175 \n\nAll other adverse reactions \n\nAny grade 4 toxicity Discontinue treatment \n\nAny grade 3 toxicity except \nnausea, vomiting and \ndiarrhoea \n\nWithhold treatment until \nsymptoms resolve to \ngrade ≤ 1 \n\nPossible dose reductions: \n\nFirst dose level reduction: 200 \n\nSecond dose level reduction: 175 \na Grade of the adverse reaction is defined according to Common Terminology Criteria for Adverse \nEvents (CTCAE). \nb The dose of carboplatin should be reduced by 1 AUC unit for treatment cycles following the \noccurrence of febrile neutropenia or low platelet count (< 75 × 109/L). \n \nSpecial populations \n \nHepatic impairment \nPatients with mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 × upper limit of normal (ULN) and \naspartate aminotransferase (AST) ≤ 10 × ULN) may be treated with the same doses as patients with \nnormal hepatic function. \n \nFor patients with moderate to severe impairment (total bilirubin > 1.5 to ≤ 5 × ULN and \nAST ≤ 10 × ULN), a 20% reduction in dose is recommended. The reduced dose may be escalated to \nthe dose for patients with normal hepatic function if the patient is tolerating the treatment for at least \ntwo cycles (see sections 4.4 and 5.2). \n \nFor patients with total bilirubin > 5 × ULN or AST > 10 × ULN, there are insufficient data to permit \ndosage recommendations (see sections 4.4 and 5.2). \n \nRenal impairment \nPatients with mildly or moderately impaired renal function (glomerular filtration rate (GFR) \n89−60 mL/min or GFR 59−30 mL/min, respectively) may be treated with Apealea without a dose \nmodification. Patients with severe renal impairment (GFR < 30 mL/min) should not be treated with \npaclitaxel (see section 5.2). \n \n\n\n\n4 \n\nElderly \nNo additional dosage reductions, other than those for all patients, are recommended for patients \n65 years and older. \n \nOf the 391 patients with ovarian cancer in the randomised study who received Apealea in combination \nwith carboplatin, 13% were between 65 and 74 years old. In this limited number of patients, anorexia, \nfatigue, myalgia, arthralgia, peripheral sensory neuropathy, and diarrhoea were observed more \nfrequently compared to patients younger than 65 years. Limited data are available on use in patients \n≥ 75 years (2% of the patients in the study). \n \nNon-Caucasian patients \nThere are limited data of Apealea in non-Caucasian patients and current data is insufficient to \nrecommend additional dose adjustments (see section 4.4). If neuropathy is observed, follow dose \nreduction recommendations in Table 1. \n \nPaediatric population \nThere is no relevant use of paclitaxel in the paediatric population for the indications of epithelial \novarian cancer, primary peritoneal cancer and fallopian tube cancer. The safety and efficacy of \nApealea in children and adolescents aged 0−17 years has not been established. \n \nMethod of administration \n \nApealea is for intravenous use. \n \nAfter reconstitution of the powder, the solution for infusion is a clear, greenish-yellow solution. The \nsolution should be administered by an intravenous infusion over approximately one hour \n(120−140 drops/min). Administration sets containing a 15 µm polyamide fluid filter should be used. It \nis important to flush the infusion set and catheter/cannula before and after the administration using the \nsolution for reconstitution in order to avoid accidental administration into the surrounding tissue and to \nensure administration of the complete dose. \n \nFor instructions on reconstitution of the medicinal product before administration, see section 6.6. \n \n4.3 Contraindications \n \nSevere hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see \nsection 4.4). \n \nBreast-feeding (see section 4.6). \n \nBaseline neutrophil count < 1.5 × 109/L. \n \n4.4 Special warnings and precautions for use \n \nHaematology \n \nPaclitaxel causes myelosuppression (primarily neutropenia). Neutropenia is a dose-dependent and \ndose-limiting adverse reaction. Therefore, frequent complete blood cell counts should be performed \nduring treatment with Apealea. In the pivotal study, about a third of the patients received granulocyte \ncolony stimulating factor (GCSF) to treat neutropenia and clinicians should consider whether \nindividual cases could benefit from GCSF. Patients should not be treated with subsequent cycles until \nneutrophils recover to ≥ 1.5 × 109/L and platelets recover to ≥ 100 × 109/L. Patients with low \nneutrophil count should be made aware of the increased risk of infections. The risk of \nmyelosuppression is increased due to the combination use with carboplatin. Dose recommendations \nfor Apealea as well as for carboplatin in the case of myelosuppression should be followed (see section \n4.2). \n \n\n\n\n5 \n\nNeuropathy \n \nPeripheral sensory neuropathy and peripheral neuropathy are very common adverse reactions. For \nCTCAE grade ≥ 2 sensory or motor neuropathy withhold treatment until resolution to < grade 2, \nfollowed by a dose reduction for all subsequent courses (see section 4.2). \n \nHepatic impairment \n \nPatients with hepatic impairment have not been studied with Apealea but may be at increased risk of \ntoxicity, particularly from myelosuppression. Administration in patients with hepatic impairment \ndefined as total bilirubin > 1 to ≤ 5 × ULN and AST ≤ 10 × ULN (see section 4.2) should therefore be \nperformed with caution and they should be closely monitored with regard to increased liver \nimpairment and myelosuppression. Patients that have total bilirubin > 5 × ULN or AST > 10 × ULN \nshould not be treated with paclitaxel. \n \nGastrointestinal symptoms \n \nGastrointestinal adverse reactions are very common. If patients experience nausea, vomiting and \ndiarrhoea following the administration of Apealea, they may be treated with antiemetics and/or \nantidiarrhoeal agents. Premedication may be considered in patients who have previously experienced \ngastrointestinal symptoms when being treated with cytotoxic medicinal products. \n \nInfusion-associated reactions \n \nLocal reactions at the infusion site are very common during Apealea infusions. The infusion site \nreactions observed include pain, phlebitis, discolouration, redness, oedema and rash. These reactions \nare more common on the first infusion and may be improved by slowing the rate of infusion. Patients \nwho experience severe pain or other reactions to the infusion of Apealea are recommended to be \nconsidered for a central venous catheter. Care should be taken to avoid accidental administration into \nthe surrounding tissue during intravenous administration. If any sign of extravasal injection occurs, \ntake immediate action: terminate the infusion, aspirate fluid from the catheter/cannula before the \nneedle is withdrawn, infuse the affected area with sterile saline or lactated or acetated Ringer’s \nsolution and closely monitor the area. To avoid accidental administration into the surrounding tissue \nand to ensure intravenous delivery of the complete dose, flush the infusion set and catheter/cannula \nbefore as well as after the administration. \n \nHypersensitivity \n \nMost hypersensitivity reactions related to Apealea are mild to moderate and mainly occur as skin and \nsubcutaneous tissue disorders, general disorders and administration site conditions, but serious \nhypersensitivity reactions including anaphylactic shock have been reported. Minor symptoms such as \nflushing or skin reactions do not require interruption of therapy. Moderate cases may require \npremedication with corticosteroids, antihistamines and/or H2 antagonists for the following treatment \ncycles. Severe reactions, such as hypotension requiring treatment, dyspnoea requiring bronchodilators, \nangioedema or generalised urticaria require immediate discontinuation of paclitaxel and initiation of \nsymptomatic treatment. Patients experiencing severe reactions should not be re-challenged with \npaclitaxel. Patients should be observed closely during treatment, particularly those patients who \npreviously suffered hypersensitivity reactions with any taxane formulation. \n \nThe true incidence, severity and time to onset of hypersensitivity reactions due to Apealea could not \nbe established during clinical development due to the combination treatment with carboplatin. Delayed \nreactions related to paclitaxel occurring during or after infusion of carboplatin cannot be excluded. \n \nAlopecia \n \nAlopecia is a very common adverse reaction and occurs early in treatment. It can have a marked \nimpact on the patients’ self-image and quality of life and patients should be counselled about the \n\n\n\n6 \n\nlikelihood of this adverse effect and on what measures might be available to mitigate it, for example \nthe use of cold caps. In studies with Apealea, 45% of patients reported alopecia during therapy. \n \nCardiotoxicity \n \nHeart failure has been observed in some patients receiving Apealea. In some of the cases, the patients \nhad previously been exposed to cardiotoxic medicinal products such as doxorubicin or had underlying \ncardiac history. These patients should be vigilantly monitored by physicians for the occurrence of \ncardiac events. \n \nPatients 65 years and older \n \nThere was no marked difference in overall tolerability between the 65–74 age group and younger \npatients. Limited data are available on use in patients ≥ 75 years. In view of this, and of the potential \nfor frailty and co-morbidities, elderly patients should be carefully monitored. \n \nRace \n \nThere are limited data on the use of Apealea in non-Caucasian patients. However, studies in breast \ncancer patients treated with paclitaxel-containing regimens indicate a possible increased risk of \nneuropathy in non-Caucasian patients (see section 4.2). \n \nExcipients \n \nWhen reconstituted, this medicinal product contains up to approximately 1.6 g sodium per dose \n(0.9 g/m2 BSA; 3.6 mg per mL), equivalent to 80% of the WHO recommended maximum daily intake \nof 2 g sodium for an adult. \n \n4.5 Interaction with other medicinal products and other forms of interaction \n \nNo studies have been performed to evaluate drug-drug interactions between Apealea and other \nmedicinal products. \n \nThe metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and \nCYP3A4 (see section 5.2). Therefore, caution should be exercised when administering paclitaxel \nconcomitantly with medicines known to inhibit either CYP2C8 or CYP3A4 (e.g. ketoconazole and \nother imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, \nsaquinavir, indinavir, and nelfinavir) because toxicity of paclitaxel may be increased due to higher \npaclitaxel exposure. Administering paclitaxel concomitantly with medicines known to induce either \nCYP2C8 or CYP3A4 (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not \nrecommended because efficacy may be compromised because of lower paclitaxel exposures. \n \nApealea contains a mixture of two retinoic acid derivatives as excipients. In vitro studies using human \nmicrosomes have shown these derivatives to have inhibitory activity on CYP2B6, CYP2C8, CYP2C9, \nand to a lesser extent on CYP2D6. In the absence of in vivo studies addressing inhibition of CYP2B6 \nand CYP2C9, the concomitant use of Apealea and substances metabolised primarily by these CYP \nenzymes should be exercised with caution. \n \nApealea is indicated to be used in combination with carboplatin (see section 4.1). Apealea should be \nadministered first, then carboplatin. Based on literature data, no clinically relevant pharmacokinetic \ninteraction between paclitaxel and carboplatin is expected. \n \nClinically relevant pharmacokinetic interaction has been observed between paclitaxel and cisplatin. \nWhen paclitaxel is given before cisplatin, the safety profile of solvent-based paclitaxel is consistent \nwith that reported for single-agent use. When solvent-based paclitaxel was given after cisplatin, \npatients showed a more profound myelosuppression and an approximately 20% decrease in paclitaxel \nclearance. A similar effect can be anticipated for Apealea (paclitaxel micellar). Patients treated with \n\n\n\n7 \n\npaclitaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in \ngynaecological cancers. \n \n4.6 Fertility, pregnancy and lactation \n \nWomen of childbearing potential/Contraception \n \nWomen of childbearing potential must use effective contraception during treatment and for six months \nafterwards. \n \nPregnancy \n \nThere are very limited data on the use of paclitaxel in pregnant women. Paclitaxel is suspected to \ncause serious birth defects when administered during pregnancy. Studies in animals have shown \nreproductive toxicity (see section 5.3). Paclitaxel should not be used during pregnancy unless the \nclinical condition requires this treatment. \n \nBreast-feeding \n \nPaclitaxel is excreted in human milk. Because of potential serious adverse reactions in children being \nbreastfed, Apealea is contraindicated during lactation. Breast-feeding must be discontinued for the \nduration of therapy. \n \nFertility \n \nStudies in animals being treated with paclitaxel have shown decreased fertility (see section 5.3). \n \n4.7 Effects on ability to drive and use machines \n \nApealea has moderate influence on the ability to drive or use machines. Apealea may cause adverse \nreactions such as fatigue (very common) and dizziness (common) that may affect the ability to drive or \nuse machinery. Patients should be advised not to drive or use machines if they feel tired or dizzy. \n \n4.8 Undesirable effects \n \nSummary of the safety profile \n \nThe most common clinically significant adverse reactions associated with the use of Apealea are \nneutropenia, gastrointestinal disorders, peripheral neuropathy, arthralgia/myalgia, and infusion site \nreactions. Approximately 86% of patients experienced adverse reactions. \n \nTabulated list of adverse reactions \n \nThe frequency of undesirable effects listed in Table 2 is defined using the following convention: \nvery common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare \n(≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the \navailable data). \n \nWithin each frequency grouping, adverse reactions are presented in order of decreasing seriousness. \n \nTable 2 lists adverse reactions associated with the administration of Apealea in combination with \ncarboplatin observed in a clinical study (N = 391) and adverse reactions from post-marketing \nexperience. The latter ones may be attributed to paclitaxel regardless of the treatment regimen. \n \n\n\n\n8 \n\nTable 2. Listing of adverse reactions \n\nSystem Organ Class Frequency Preferred term \n\nInfections and infestations Uncommon: Sepsis, abscess, pneumonia, influenza, \nrespiratory tract infection viral, herpes simplex, \ninfusion site cellulitis, tonsillitis, \nurinary tract infection, skin infection, cystitis \n\nNeoplasms benign, \nmalignant and unspecified \n(incl. cysts and polyps) \n\nUncommon: Metastatic pain \n\nBlood and lymphatic \nsystem disorders \n\nVery common: Neutropeniaa \n\nCommon: Febrile neutropeniaa, leukopeniaa, \nthrombocytopeniaa, granulocytopenia, anaemiaa \n\nUncommon: Disseminated intravascular coagulationa, \npancytopenia, haematotoxicity, coagulopathy \n\nImmune system disorders Common: Hypersensitivity \n\nUncommon: Anaphylactic shock, drug hypersensitivity \n\nMetabolism and nutrition \ndisorders \n\nVery common: Anorexia \n\nUncommon: Hyponatraemia, hypokalaemia, hypomagnesaemia, \ndehydration, decreased appetite \n\nPsychiatric disorders Uncommon: Depression, insomnia, anxiety \n\nNervous system disorders Very common: Peripheral sensory neuropathya,b, \nneuropathy peripherala,b \n\nCommon: Hypoaesthesia, dizziness, paraesthesia, \nperipheral motor neuropathy, dysgeusia, headache \n\nUncommon: Status epilepticus, coma, cerebrovascular accident, \nperipheral sensorimotor neuropathy, lethargy, \nhypotonia, neurotoxicity, polyneuropathy, \npolyneuropathy in malignant disease, \nburning sensation, somnolence, cognitive disorder, \nfacial palsy, encephalopathy, hydrocephalus \n\nEye disorders Uncommon: Vision blurred, eye irritation, ocular discomfort, \nlacrimation increased \n\nEar and labyrinth \ndisorders \n\nUncommon: Vertigo, deafness, inner ear disorder, tinnitus \n\nCardiac disorders Common: Angina pectoris, tachycardia \n\nUncommon: Cardiac arrest, cardiac failure chronic, cyanosis, \natrial fibrillation, sinus tachycardia, palpitations, \nsinus bradycardia \n\nVascular disorders Common: Hypotension, flushing, phlebitis, vein pain, \nhyperaemia \n\nUncommon: Circulatory collapse, venous thrombosis, vasculitis, \nthrombosis, hypertension, deep vein thrombosis, \nlymphoedema, phlebitis superficial, \nthrombophlebitis, blood pressure fluctuation, \nhaemorrhage, angiopathy, hot flush, pallor \n\n\n\n9 \n\nSystem Organ Class Frequency Preferred term \n\nRespiratory, thoracic and \nmediastinal disorders \n\nCommon: Dyspnoea, nasal congestion \n\nUncommon: Respiratory failure, epistaxis, cough, rhinorrhoea, \noropharyngeal pain, pharyngeal disorder, asphyxia, \nbronchospasm, dysphonia, rhinitis allergic, \nallergic cough, oropharyngeal discomfort \n\nGastrointestinal disorders Very common: Diarrhoeaa, nauseaa, vomitinga \n\nCommon: Abdominal pain, constipation, abdominal pain upper, \nflatulence, dry mouth, stomatitis \n\nUncommon: Abdominal distension, gastritis, \nabdominal discomfort, abdominal pain lower, \ndyspepsia, faecaloma, intestinal functional disorder, \ngingival bleeding, haematochezia, paraesthesia oral \n\nHepatobiliary disorders Uncommon: Hepatitis, liver disorder \n\nSkin and subcutaneous \ntissue disorders \n\nVery common: Alopeciaa \n\nCommon: Erythema, rash, pruritus, urticaria \n\nUncommon: Angioedema, rash generalised, skin discolouration, \nhyperhidrosis, rash papular, dermatitis bullous, \nswelling face, pigmentation disorder, dry skin, cold \nsweat, livedo reticularis, nail disorder, pruritus \nallergic, skin disorder \n\nNot known: Palmar-plantar erythrodysesthesia syndromec \n\nMusculoskeletal and \nconnective tissue disorders \n\nVery common: Arthralgiaa, myalgiaa \n\nCommon: Back pain, bone pain, musculoskeletal pain, \nmuscular weakness, pain in extremity \n\nUncommon: Haemarthrosis, musculoskeletal discomfort, \nsensation of heaviness \n\nRenal and urinary \ndisorders \n\nUncommon: Azotaemia \n\nReproductive system and \nbreast disorders \n\nUncommon: Vaginal haemorrhage, pelvic pain, breast pain \n\nGeneral disorders and \nadministration site \nconditions \n\nVery common: Astheniaa, fatiguea, infusion site reactiona,d \n\nCommon: Oedema peripheral, pain, pyrexia, chest discomfort, \nhyperthermia, face oedema \n\nUncommon: Death, multi-organ failure, oedema, administration \nsite pain, catheter site haemorrhage, catheter site \noedema, local swelling, generalised oedema, hernia, \nchest pain, influenza like illness, localised oedema, \nhypothermia, chills, feeling hot \n\nInvestigations Uncommon: Alanine aminotransferase increased \na See Description of selected adverse reactions. \nb Can persist beyond 6 months of paclitaxel discontinuation.c \nc As reported in the post-marketing surveillance of paclitaxel. \nd Includes the following preferred terms: infusion site pain, infusion site phlebitis, \ninfusion site reaction, infusion site discolouration, infusion site erythema, infusion site extravasation, \ninfusion site inflammation, infusion site oedema, infusion site paraesthesia, infusion site irritation, and \ninfusion site rash. \n\n\n\n10 \n\n \nDescription of selected adverse reactions \n \nIn the pivotal clinical study, patients were either treated with Apealea (paclitaxel micellar) at a dose of \n250 mg/m2 in combination with carboplatin or with solvent-based paclitaxel at a dose of 175 mg/m2 in \ncombination with carboplatin (N = 391 in each arm). Overall, there were higher rates of serious \nadverse events with paclitaxel micellar (41%) than with solvent-based paclitaxel (27%). In both \ngroups, the majority of the serious adverse events were haematological toxicities. There were no \ndifferences in Eastern Cooperative Oncology Group (ECOG) performance score between the two \nstudy groups at any time during or after treatment (mainly score 0 or 1). \n \nBlood and lymphatic system disorders \nAlmost all patients treated with Apealea had neutropenia of some grade, 79% of the patients had grade \n3 or 4. Neutropenia as a serious adverse reaction occurred in 29% of the patients and febrile \nneutropenia occurred in 3% of the patients. Neutropenia resolved to ≥ 1.5 × 109/L before the next \ncourse of treatment. Almost all patients experienced anaemia, decreased platelet count and decreased \nwhite blood cell count of any grade during the treatment period (98%, 93% and 98%, respectively). \nAnaemia as serious adverse event occurred in 5% of the patients, thrombocytopenia and leukopenia in \n3% and 6% of the patients, respectively. \n \nIn comparison to the patients receiving solvent-based paclitaxel, there were more patients in the group \nreceiving paclitaxel micellar who experienced haematological toxicities with grade 3 and 4. \nNeutropenia occurred in 79% and 66%, leukopenia in 53% and 34%, thrombocytopenia in 18% and \n10%, and anaemia in 24% and 14% of the patients in the treatment arms receiving either paclitaxel \nmicellar or solvent-based paclitaxel, respectively. \n \nDisseminated intravascular coagulation (DIC), often in association with sepsis or multi-organ failure, \nhas been reported. \n \nGastrointestinal disorders \nNausea (38%), vomiting (22%) and diarrhoea (15%) were among the most commonly reported \nadverse reactions in the study. \n \nNervous system disorders \nPeripheral neuropathies (including the preferred terms neuropathy peripheral, peripheral motor \nneuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, polyneuropathy, and \npolyneuropathy in malignant disease) were reported in 29% of the patients and were mostly (98%) \nmild to moderate (CTCAE grade ≤ 2). The average time to onset was 53 days from the first dose. \nPeripheral sensory neuropathy represented the most common reaction and was reported in 16% of \npatients. Other associated reactions were reported in 10% of the patients and were mostly (98%) mild \nto moderate (CTCAE grade ≤ 2). Paraesthesia and hypoaesthesia were the most common ones. During \nthe course of the pivotal study, 46% of the peripheral neuropathies as well as the majority (78%) of the \nassociated reactions resolved. The dose-dependency of frequency and severity of neurotoxicity was \nnot studied for Apealea, but has been observed for other paclitaxel formulations in other indications. \nFurther, it has been demonstrated that peripheral neuropathies can persist beyond 6 months of \npaclitaxel discontinuation. \n \nHypersensitivity reactions \nMost hypersensitivity reactions related to Apealea were mild to moderate (see section 4.4). The \nfrequency of paclitaxel-related hypersensitivity reactions was similar in both groups (5% of the \npatients receiving paclitaxel micellar and 7% of the patients receiving solvent-based paclitaxel), \nwhereas a higher frequency of carboplatin-related hypersensitivity reactions was observed in the group \nreceiving paclitaxel micellar (12% vs 7%). As a result of the combined treatment, it is not possible to \ndetermine whether this observation is due to Apealea or to other factors, and delayed reactions related \nto paclitaxel cannot be excluded. \n \n\n\n\n11 \n\nSkin and subcutaneous tissue disorders \nAlopecia was observed in 45% of patients and was abrupt in onset. Pronounced hair loss of ≥ 50% is \nexpected for the majority of patients who experience alopecia. \n \nMusculoskeletal and connective tissue disorders \nArthralgia occurred in 19% of patients and myalgia in 10%. \n \nGeneral disorders and administration site conditions \nAsthenia and fatigue were very common and occurred in 23% and 11% of patients, respectively. \nInfusion site reactions, such as pain, phlebitis, and erythema, were seen in 12% of patients (see \nsection 4.4). \n \nThere were more reports of infusion site pain in the group receiving paclitaxel micellar as compared to \nthe group treated with solvent-based paclitaxel (8% and 1%, respectively). \n \nAdditional experience from clinical studies \n \nApealea has been given as monotherapy in a total of 132 patients at doses ranging between 90 mg/m2 \nin a 3-week regimen to weekly doses of 250 mg/m2 for various indications. Based on the combined \ndata from monotherapy studies, very common adverse reactions and those of special interest were the \nfollowing: neutropenia (45%), fatigue (37%), leukopenia (33%), alopecia (30%), nausea (27%), \ninfusion site reactiona (23%), peripheral sensory neuropathy (20%), diarrhoea (17%), asthenia (15%), \npyrexia (12%), constipation (12%), arthralgia (12%), paraesthesia (11%), pain (11%), vomiting (9%), \nmyalgia (9%), peripheral motor neuropathy (5%), neuropathy (5%), neuropathy peripheral (5%), \nthrombocytopenia (4%), febrile neutropenia (2%), sepsis (2%), tachycardia (2%), phlebitis (2%), \nthrombosis (2%). \n \na Includes the following preferred terms: infusion site phlebitis, infusion site pain, injection site \nreaction, injection site inflammation, infusion site erythema, injection site extravasation, infusion site \nreaction, injection site oedema. \n \nReporting of suspected adverse reactions \n \nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V. \n \n4.9 Overdose \n \nThere is no known antidote for paclitaxel overdose. In the event of an overdose, the patient should be \nclosely monitored. Treatment should be directed at the major anticipated toxicities, which are nausea, \nvomiting, diarrhoea, myelosuppression, peripheral sensory neuropathy and peripheral neuropathy. \n \n \n5. PHARMACOLOGICAL PROPERTIES \n \n5.1 Pharmacodynamic properties \n \nPharmacotherapeutic group: Antineoplastic agents, taxanes, ATC code: L01CD01 \n \nMechanism of action \n \nPaclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers \nand stabilises microtubules by preventing depolymerisation. Stabilisation results in the inhibition of \nthe normal dynamic reorganisation of the microtubule network that is essential for vital interphase and \n\n\n\n12 \n\nmitotic cellular functions. In addition, paclitaxel induces microtubule bundle formation throughout the \ncell cycle and induces microtubule aster formation during mitosis. \n \nClinical efficacy and safety \n \nAn open, randomised, multicentre study was conducted in 789 women with recurrent epithelial \novarian cancer, primary peritoneal cancer and fallopian tube cancer to compare Apealea (paclitaxel \nmicellar) in combination with carboplatin with solvent-based paclitaxel in combination with \ncarboplatin. Patients were treated every three weeks for six cycles, either with Apealea 250 mg/m2 \ngiven as a 1-hour intravenous infusion (N = 391) or with solvent-based paclitaxel 175 mg/m2 given as \na 3-hour infusion (N = 391). The paclitaxel infusion was followed by carboplatin after an interval of \n30 minutes in both treatment arms. \n \nPatients were stratified based on relapse (first or second) and CA125 values. The proportions of \npatients treated at first or second relapse were then equal in both treatment groups (76% were treated \nat first relapse and 24% at second relapse). Patients who had pre-existing neuropathy of grade ≥ 2 or \nserious medical risk factors involving any of the major organ systems were not allowed to enter the \nstudy. The mean age was 56 years of age in both treatment groups (range 26–81). Most of the patients \nenrolled in the study had ECOG performance status of 0 or 1 (≥ 96%), in similar proportions between \nthe treatment arms. Only a few patients had ECOG performance status of 2. \n \nIn the clinical study, the proportion of patients receiving six treatment cycles was 81% in the group \ntreated with paclitaxel micellar and 87% in the group receiving solvent-based paclitaxel. The \ncorresponding median number of cycles (min;max) for the two groups were 6 (1;12) and 6 (1;9), \nrespectively. \n \nPatients received premedication prior to infusion of solvent-based paclitaxel, paclitaxel micellar and \ncarboplatin as summarised in Table 3 below. Premedication was not mandated prior to infusion of \npaclitaxel micellar. \n \nTable 3. Proportions of patients who received premedication prior to infusion of paclitaxel or \ncarboplatin or overall (safety population) \n\n Apealea (N = 391) \nPaclitaxel (solvent-based) \n\n(N = 391) \n\nType of \npremedication Overall Paclitaxel Carboplatin Overall Paclitaxel Carboplatin \n\nCorticosteroids 43% 6% 39% 99% 97% 15% \n\nAntihistamines 19% 4% 16% 85% 85% 9% \n\nH2 antagonists 5% 2% 2% 90% 90% 1% \n\nAntiemetics and \nantinauseants 87% 8% 81% 92% 38% 63% \n\n \nIn the study, 35% of the patients in the paclitaxel micellar group and 30% of the patients in the \nsolvent-based paclitaxel group, respectively, received GCSF to treat neutropenia. The median number \nof cycles with paclitaxel/carboplatin treatment for patients receiving GCSF was 6 in both groups. The \nmedian number of cycles with administration of GCSF was 3 (1;6) and the mean value 3.1, each in \nboth groups. \n \nThe principle measures of efficacy were progression-free survival (PFS) and overall survival (OS). \nPFS as the primary endpoint was evaluated by blinded assessment of computerised tomography \nimages using Response Evaluation Criteria in Solid Tumours (RECIST) 1.0. \n \n\n\n\n13 \n\nThere was no statistically significant difference in PFS or OS between the two treatment arms. A \nnon-inferiority analysis was conducted for PFS in the per-protocol (PP) population with pre-specified \nnon-inferiority margin. The non-inferiority criterion was met for PFS with the upper bound limit of the \none-sided 97.5% confidence interval (CI) for the associated hazard ratio being less than 1.2. The \nnon-inferiority criterion was met for OS in the PP population with the upper bound limit of the \none-sided 97.5% CI for the associated hazard ratio being less than 1.185 (Table 4; Figures 1 and 2). In \nthe intention-to-treat (ITT) population (n = 789), the hazard ratios for PFS and OS were 0.85 (95% CI: \n0.72;1.00) and 1.02 (95% CI: 0.85;1.22), respectively. Thereby, non-inferiority was shown in the ITT \npopulation for PFS, but not for OS. At the time of analysis of the OS data, death had occurred in 56% \nof the patients in the group treated with paclitaxel micellar compared to 60% in the group treated with \nsolvent-based paclitaxel (ITT population). \n \nTable 4. Non-inferiority analyses on PFS and OS in a randomised trial in patients with recurrent \nepithelial ovarian cancer, primary peritoneal cancer and fallopian tube cancer (PP population)a \n\n \nApealea \n\nQ3W 250 mg/m2 + carboplatin \n(N = 311) \n\nSolvent-based paclitaxel \nQ3W 175 mg/m2 + carboplatin \n\n(N = 333) \n\nProgression free survival (independent review) \n\nDeath or progression, n (%) 239 (77%) 270 (81%) \n\nMedian time to death or disease \nprogression [months] (95% CI) 10.3 (10.1;10.7) 10.1 (9.9;10.2) \n\nHazard ratio (95% CI) 0.86 (0.72;1.03) \n\nOverall survival \n\nNumber of deaths, n (%) 179 (58%) 206 (62%) \n\nMedian time to death [months] \n(95% CI) 25.7 (22.9;28.1) 24.8 (21.7;27.1) \n\nHazard ratio (95% CI) 0.95 (0.78;1.16) \na Primary population in non-inferiority analysis was predefined as the PP population \n \nFigure 1. Kaplan-Meier curve of PFS (PP population) \n\n \n\n \n\n \n\n \n\nPr\nob\n\nab\nilit\n\ny \nof\n\n p\nro\n\ngr\nes\n\nsi\non\n\n-fr\nee\n\n s\nur\n\nvi\nva\n\nl \n\n \n\n \n\nMonths \n\nApealea: \nsolvent-based paclitaxel: \n\n Number at risk \n\n Patients Events \n Apealea: 311 239 \n solvent-based paclitaxel: 333 270 \n\n \n\n\n\n14 \n\nFigure 2. Kaplan-Meier curve of OS (PP population) \n\n \n \nPost-hoc subgroup analysis by relapse \nAdditional subgroup analyses were conducted to investigate efficacy by relapse (first and second) in \nthe PP and the ITT population. PFS and OS results in the PP population are summarised in Figures 3 \nand 4. \n \nFigure 3. Forest plot for PFS by relapse (PP population) \n\n Apealea Solvent-based paclitaxel \n\nRelapse \n \n\nn Events \n(%) \n\nMedian \nmonths \n(95% CI) \n\n \n\nn Events \n(%) \n\nMedian \nmonths \n(95% CI) \n\n \nnon-inferiority \nmargin (1.2) \n\n \n\nHazard Ratio \n(95% CI) \n\n \n\n \n\n \n\n \n\nAll \n \n\n \n \n \n \n \n 311 239 \n\n(77%) \n10.3 \n\n(10.1;10.7) \n \n\n333 270 \n(81%) \n\n10.1 \n(9.9;10.2) 0.86 (0.72;1.03) \n\n \n \n\n \n \n\n \nFirst \n\n \n \n \n \n \n \n \n \n \n\n240 180 \n(75%) \n\n10.3 \n(10.2;11.3) \n\n \n\n257 209 \n(81%) \n\n10.1 \n(9.8;10.3) 0.82 (0.67;1.00) \n\n \n \n\n \n \n\n \nSecond \n\n \n \n \n \n \n \n 71 59 \n\n(83%) \n9.9 \n\n(8.6;10.6) \n \n\n76 61 \n(80%) \n\n10.1 \n(9.7;10.4) 1.01 (0.69;1.46) \n\n \n\n \n\n \n\nfavours \nApealea \n\nfavours \nsolvent-based paclitaxel \n\n \n\n \n\n \n\n \n\nPr\nob\n\nab\nilit\n\ny \nof\n\n s\nur\n\nvi\nva\n\nl \n\n \n\n \n\nMonths \n\nApealea: \nsolvent-based paclitaxel: \n Number at risk \n\n Patients Events \n Apealea: 311 179 \n solvent-based paclitaxel: 333 206 \n\n \n\n\n\n15 \n\nFigure 4. Forest plot for OS by relapse (PP population) \n\n Apealea Solvent-based paclitaxel \n\nRelapse \n \n\nn Events \n(%) \n\nMedian \nmonths \n(95% CI) \n\n \n\nn Events \n(%) \n\nMedian \nmonths \n(95% CI) \n\n \nnon-inferiority \nmargin (1.185) \n\n \n\nHazard Ratio \n(95% CI) \n\n \n\n \n\n \n\n \n\nAll \n \n\n \n \n \n \n \n 311 179 \n\n(58%) \n25.7 \n\n(22.9;28.1) \n \n\n333 206 \n(62%) \n\n24.8 \n(21.7;27.1) 0.95 (0.78;1.16) \n\n \n \n\n \n \n\n \nFirst \n\n \n \n \n \n \n \n \n \n \n\n240 139 \n(58%) \n\n26.1 \n(23.0;28.4) \n\n \n\n257 162 \n(63%) \n\n23.6 \n(21.3;27.1) 0.92 (0.73;1.16) \n\n \n \n\n \n \n\n \nSecond \n\n \n \n \n \n \n \n 71 40 \n\n(56%) \n23.2 \n\n(18.3;28.9) \n \n\n76 44 \n(58%) \n\n24.8 \n(19.2;30.0) 1.07 (0.68;1.68) \n\n \n\n \n\n \n\nfavours \nApealea \n\nfavours \nsolvent-based paclitaxel \n\n \n\nIn the ITT population, the hazard ratios for PFS in the subgroups of patients with first relapse and \nsecond relapse were 0.80 (95% CI: 0.66;0.97) and 1.04 (95% CI: 0.74;1.47), respectively. The hazard \nratios for OS in patients with first and second relapse were 0.98 (95% CI: 0.79;1.21) and 1.18 \n(95% CI: 0.79;1.75), respectively. Thus, the results in the subgroup of patients with first relapse are \nconsistent with the results in the overall population and in addition, there was an indication of PFS \nbenefit for Apealea. \n \nFor safety data comparing the results of combination treatment with Apealea (paclitaxel \nmicellar)/carboplatin and solvent-based paclitaxel/carboplatin, see section 4.8. \n \nPaediatric population \n \nThe European Medicines Agency has waived the obligation to submit the results of studies with \nApealea in all subsets of the paediatric population in the treatment of ovarian carcinoma (excluding \nrhabdomyosarcoma and germ cell tumours), peritoneal carcinoma (excluding blastomas and sarcomas) \nand fallopian tube carcinoma (excluding rhabdomyosarcoma and germ cell tumours) (see section 4.2 \nfor information on paediatric use). \n \n5.2 Pharmacokinetic properties \n \nWhen Apealea (paclitaxel micellar) is administered intravenously, its pharmacokinetic profile suggests \nthat the formulation immediately releases paclitaxel into the blood. The pharmacokinetics of paclitaxel \nwere studied in 22 patients with solid tumours after 1-hour infusions of Apealea (dose levels of 90 to \n275 mg/m2). In addition, a study with a crossover design compared total and unbound paclitaxel \nconcentrations in plasma after a 1-hour infusion of Apealea 260 mg/m2 with those after a 1-hour \ninfusion of albumin-bound paclitaxel at the same dose. Total plasma levels of paclitaxel were similar \nafter infusion of the two formulations. The plasma levels of unbound paclitaxel, i.e. the concentration \nthat represents pharmacologically active paclitaxel in the body, were demonstrated to be bioequivalent \n(Cmax and AUC) after administration of albumin-bound paclitaxel and Apealea. Based on limited data, \nCmax and AUC increased with dose after 1-hour infusions of Apealea in doses ranging from 150 to \n275 mg/m2. Dose-linearity could not be ascertained since a large inter-individual variability was \nobserved. \n \nDistribution \n \nPaclitaxel is distributed equally between plasma and blood as described in published in vitro data. The \nmean unbound fraction of paclitaxel (fu) varied between 5.2% and 4.3% over time after Apealea \n\n\n\n16 \n\ninfusion. This was in agreement with the mean fu after albumin-bound paclitaxel infusion which \nvaried between 5.5% and 4.5% over time. \n \nBinding of paclitaxel to both albumin and α1-acid glycoprotein has been reported, but other binding \nproteins such as lipoproteins might be important. There are no reports of active substances able to \ndisplace protein-bound paclitaxel, nor is paclitaxel a likely candidate as a displacer of other active \nsubstances given its low molar concentrations in plasma. Based on the published literature, in vitro \nstudies indicate that the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine does \nnot affect protein binding of paclitaxel. Paclitaxel has been shown in vitro to be a substrate for the \ninflux transporter proteins OATP1B3 and OATP1A2. \n \nDuring and after infusion of Apealea, paclitaxel rapidly leaves the plasma compartment with a \ndistribution half-life of about 0.6 hours. Thus, the distribution phase is essentially complete at 2 hours \nafter the end of infusion. The tissue distribution is extensive, with a volume of distribution on the \nterminal elimination phase of about 155 L/m2 corresponding to about 280 L for an average patient \nwith a body surface area of 1.8 m2. Thus, only about 1% of the paclitaxel in the body is located in \nplasma during the elimination phase. \n \nBiotransformation and elimination \n \nThe terminal half-life of paclitaxel after Apealea infusion varied about 5-fold between the subjects, \n5–23 hours. Likewise, total plasma clearance varied about 5-fold from 8 to 41 L/hour. The high \ninterindividual variability in clearance is believed to be a consequence of variability in hepatic enzyme \nactivity. \n \nThe biotransformation and elimination of paclitaxel have been reported in published studies; paclitaxel \nis mainly eliminated by hepatic metabolism and biliary excretion. The main metabolite of paclitaxel is \n6α-hydroxypaclitaxel. Other metabolites are 3’-p-hydroxypaclitaxel and 6α,3’-p-dihydroxypaclitaxel. \nThe formation of these metabolites is catalysed by CYP2C8 and CYP3A4. No pharmacologically \nactive metabolite has been found. In vitro and in vivo studies have demonstrated that paclitaxel is a \nsubstrate for the efflux protein P-glycoprotein. The major route of excretion of paclitaxel-derived \nmaterial in humans is the faeces, where 6α-hydroxypaclitaxel constitutes the main material. Renal \nexcretion accounts for a minor part, less than 15% of the dose. \n \nSpecial populations \n \nHepatic impairment \nNo clinical studies in patients with hepatic impairment have been undertaken with Apealea (see \nsections 4.2 and 4.4). A population pharmacokinetics study with albumin-bound paclitaxel \ndemonstrated that patients with mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 × ULN) have an \nelimination rate in the normal range. In contrast, patients with moderate hepatic impairment (total \nbilirubin > 1.5 to ≤ 3 × ULN) and severe hepatic impairment (total bilirubin > 3 to ≤ 5 × ULN) had a \n22% or a 26% reduction in paclitaxel elimination rate, respectively. Compared to patients with normal \nhepatic function, hepatically impaired patients with total bilirubin > 1.5 × ULN have an increase in \nmean paclitaxel AUC of approximately 20%. Hepatic impairment has no effect on mean paclitaxel \nCmax. Pharmacokinetic data for patients with total bilirubin > 5 × ULN are not available. \n \nRenal impairment \nNo clinical studies in patients with renal impairment have been undertaken with Apealea (see \nsection 4.2 for dose recommendations). Since renal elimination is a minor pathway for paclitaxel, \nincreased plasma levels are not expected in this patient group. A population pharmacokinetics study \nwith albumin-bound paclitaxel demonstrated that patients with mild and moderate renal impairment \n(creatinine clearance ≥ 30 to < 90 mL/min) have an elimination rate similar to that of patients with \nnormal renal function. Information is lacking for patients with severe renal impairment \n(GFR < 30 mL/min). \n \n\n\n\n17 \n\nEffects of age, gender, race and body size \nNo analysis of the effect of age, gender or body size on the elimination of Apealea has been \nundertaken. However, a population pharmacokinetics study of 168 patients (86 males and 82 females) \ntreated with solvent-based paclitaxel has been reported. On average, the paclitaxel elimination rate \nwas 20% higher in males compared to in females. With regard to age, the population model indicated \nan approximate 5% decline in paclitaxel elimination rate for each 10-year increase in age compared to \nthe median age of 56 years of the study. This amounted to a 14% decline in an 86-year-old patient \ncompared to one aged 56. Further it has been shown that the rate of paclitaxel elimination increased \nwith increasing body size. The model indicated that a 0.2 m2 increase in BSA would lead to a 9% \nincrease in the elimination rate. There is very little information available on whether the elimination of \npaclitaxel differs between races. \n \n5.3 Preclinical safety data \n \nMutagenesis, carcinogenesis, impairment of fertility \n \nIn vitro studies using different cell systems have shown paclitaxel to be clastogenic inducing \nchromosomal aberrations, micronuclei and DNA damage. Chromosomal aberrations have also been \ndetected in in vivo studies in mice and monkeys. Paclitaxel was devoid of mutagenic activity in the \nAmes test or the Chinese hamster ovary/hypoxanthine-guanine phosphoribosyl transferase \n(CHO/HGPRT) gene mutation assay. The carcinogenic activity of paclitaxel has not been studied. \nHowever, paclitaxel is potentially carcinogenic based on its mechanism of action and demonstrated \ngenotoxic activity. Paclitaxel at doses below the human therapeutic dose was associated with low \nfertility and foetal toxicity in rats. Repeat dose toxicity studies have shown non-reversible, toxic \neffects on male reproductive organs. \n \n \n6. PHARMACEUTICAL PARTICULARS \n \n6.1 List of excipients \n \nN-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt \nN-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt \nSodium hydroxide (for pH adjustment) \n \n6.2 Incompatibilities \n \nThis medicinal product must not be mixed with other medicinal products except those mentioned in \nsection 6.6. \n \n6.3 Shelf life \n \nUnopened vial \n \n3 years. \n \nAfter reconstitution \n \nChemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 8 °C in lactated \nand acetated Ringer’s solution and for 4 hours at 2 °C to 8 °C in sodium chloride 9 mg/mL (0.9%) \nsolution when protected from light. From a microbiological point of view, unless the method of \nopening and reconstituting precludes the risks of microbial contamination, the product should be used \nimmediately. If not used immediately, in-use storage times and conditions are the responsibility of the \nuser. \n \n\n\n\n18 \n\n6.4 Special precautions for storage \n \nStore in a refrigerator (2 °C – 8 °C). \nKeep the vial in the outer carton in order to protect from light. \n \nFor storage conditions after reconstitution of the medicinal product, see section 6.3. \n \n6.5 Nature and contents of container \n \nClear type I glass vial with a silicon coated butyl rubber stopper, an aluminium overseal and a plastic \nflip-off cap containing powder equivalent to 60 mg of paclitaxel. \n \nPack size: 1 vial. \n \n6.6 Special precautions for disposal and other handling \n \nAdministration precautions \n \nPaclitaxel is an antineoplastic medicinal product and as with other potentially toxic compounds, \ncaution should be exercised in handling Apealea. The use of gloves, goggles and protective clothing is \nrecommended. If the solution contacts the skin, the skin should be washed immediately and \nthoroughly with soap and water. If it contacts mucous membranes, the membranes should be flushed \nthoroughly with water. Apealea should only be prepared and administered by personnel appropriately \ntrained in the handling of cytotoxic agents. Pregnant and breast-feeding staff should not handle \nApealea. The reconstituted product should not be diluted. \n \nReconstitution of the medicinal product \n \nApealea is supplied as a sterile powder for reconstitution before use. After reconstitution, the solution \ncontains 1 mg/mL of paclitaxel formulated as micellar nanoparticles. The reconstituted solution for \ninfusion is a clear, greenish-yellow solution. \n \nProtect from direct and/or bright light throughout the preparation process. The (reconstituted) product \ncan only withstand short-term handling in absence of light protection. \n \nOnly reconstitute Apealea using one of the following commercially available solutions for \nreconstitution: \n\n- sodium chloride 9 mg/mL (0.9%) solution suitable for infusion; \n- lactated Ringer’s solution suitable for infusion; \n- acetated Ringer’s solution suitable for infusion. \n\n \nThe pH of lactated or acetated Ringer’s solution must be in the range of 5.0 to 7.5, and acceptable ion \nconcentrations of calcium and magnesium are listed below (Table 5). \n \nTable 5. Acceptable ion concentrations for calcium and magnesium in lactated and acetated \nRinger’s solutions suitable for reconstitution \n\nIon Range (mmol/L) \nCa2+ 1.0–3.5* \nMg2+ 0.0–2.5* \n\n* Solutions containing both Ca2+ and Mg2+ should have a total (combined) concentration of Ca2+ and \nMg2+ within the range of 1.0 to 3.5 mmol/L. \n \nApealea should be reconstituted using either one of the three suitable solutions for reconstitution and \naccording to the following steps: \n \n\n\n\n19 \n\na. Take the desired number of vials from the refrigerator. The powder should be greenish-yellow \nto yellow. In case of discolouration (orange), discard the vial. To reach room temperature, let \nthe vials stand protected from light for approximately 15 to 20 minutes not above 25 °C. \n\nb. Due to negative pressure in the vial, pressure must be equilibrated by a needle or a spike before \nand during injection of the solution for reconstitution. Using a sterile syringe, inject 60 mL of \nsolution for reconstitution per vial. The solution should be injected during approximately one \nminute towards the inner wall of the vial and not directly onto the powder as this will result in \nfoaming. \n\nc. Swirl the vial in an upright position for approximately 20 seconds. To keep the generation of \nfoam to a minimum, do not shake the vial. \n\nd. Protect from light and allow the vial to stand for three to five minutes. \ne. Swirl the vial again in upright position for approximately 20 seconds, then gently invert it five \n\ntimes. Do not shake. \nf. Continue to swirl the vial until the powder is completely dissolved., Alternatively, the vial may \n\nbe placed on a shaker and rotated for up to 20 minutes, while being protected from light (orbital \nshake pattern; 200–250 rpm). Steps c and to f should not be more than 30 minutes. \n\ng. The solution should be clear and greenish-yellow without visible particles or precipitates. If \nparticles, precipitates, discolouration (orange) or opalescence are observed, the solution should \nbe discarded. \n\nh. Inject the required amount of reconstituted Apealea into an empty, sterile ethylene-vinyl acetate \n(EVA) bag. Ensure that the solution is clear and place a light-protective bag over the EVA \ninfusion bag. \n\n \nCompatibility with administration sets made of DEHP-free PVC (i.e. polyvinyl chloride without the \nplasticizer di-(2-ethylhexyl) phthalate) has been demonstrated. However, compatibility with \nDEHP-containing administration sets has not been demonstrated. Administration sets containing a \n15 µm polyamide fluid filter should be used. \n \nAny unused medicinal product or waste material should be disposed of in accordance with local \nrequirements. \n \n \n7. MARKETING AUTHORISATION HOLDER \n \nOasmia Pharmaceutical AB \nVallongatan 1 \nSE-752 28 Uppsala \nSweden \nTel +46 18 50 54 40 \n \n \n8. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/18/1292/001 \n \n \n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n \nDate of first authorisation: 20 November 2018 \n \n \n10. DATE OF REVISION OF THE TEXT \n \nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency http://www.ema.europa.eu. \n\n\n\n20 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX II \n \n\nA. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE \n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY \n\nAND USE \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE \n\nMARKETING AUTHORISATION \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE \n\nSAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT \n\n\n\n21 \n\nA. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE \n \nName and address of the manufacturer(s) responsible for batch release \n \nOasmia Pharmaceutical AB \nVallongatan 1 \nSE-752 28 Uppsala \nSweden \n \n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n \nMedicinal product subject to restricted medical prescription (see Annex I: Summary of Product \nCharacteristics, section 4.2). \n \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n \n• Periodic safety update reports (PSURs) \n \nThe requirements for submission of PSURs for this medicinal product are set out in the list of Union \nreference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any \nsubsequent updates published on the European medicines web-portal. \n \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n \n• Risk management plan (RMP) \n \nThe marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities \nand interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation \nand any agreed subsequent updates of the RMP. \n \nAn updated RMP should be submitted: \n \n\n• At the request of the European Medicines Agency; \n \n• Whenever the risk management system is modified, especially as the result of new \n\ninformation being received that may lead to a significant change to the benefit/risk profile \nor as the result of an important (pharmacovigilance or risk minimisation) milestone being \nreached. \n\n\n\n22 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX III \n \n\nLABELLING AND PACKAGE LEAFLET \n\n\n\n23 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nA. LABELLING \n\n\n\n24 \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCARTON \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nApealea 60 mg powder for solution for infusion \npaclitaxel \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nOne vial of powder contains 60 mg paclitaxel. \n \nAfter reconstitution, each mL of solution contains 1 mg of paclitaxel (micellar). \n \n \n3. LIST OF EXCIPIENTS \n \nExcipients: N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt, \nN-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt, sodium hydroxide. See leaflet for further \ninformation. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nPowder for solution for infusion \n \n1 vial \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nRead the package leaflet before use. \n \nIntravenous use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \nCytotoxic: handle with caution. \n \nApealea should not be interchanged with other paclitaxel formulations. \n \n \n\n\n\n25 \n\n8. EXPIRY DATE \n \nEXP \n \nAfter reconstitution: use immediately. \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. \nKeep the vial in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nSingle-use vial \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nOasmia Pharmaceutical AB \nVallongatan 1 \n752 28 Uppsala \nSweden \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/18/1292/001 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nJustification for not including Braille accepted \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n\n\n\n26 \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC \nSN \nNN \n\n\n\n27 \n\nPARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING \n \nVIAL LABEL \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nApealea 60 mg powder for solution for infusion \npaclitaxel \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nOne vial of powder contains 60 mg paclitaxel. \n \nAfter reconstitution, each mL of solution contains 1 mg of paclitaxel (micellar). \n \n \n3. LIST OF EXCIPIENTS \n \nExcipients: N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt, \nN-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt, sodium hydroxide. See leaflet for further \ninformation. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nPowder for solution for infusion \n \n1 vial \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nRead the package leaflet before use. \n \nIntravenous use. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \nCytotoxic \n \nApealea should not be interchanged with other paclitaxel formulations. \n \n \n\n\n\n28 \n\n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. \nKeep the vial in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nOasmia Pharmaceutical AB \nUppsala, Sweden \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/18/1292/001 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nJustification for not including Braille accepted \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \n \n\n\n\n29 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nB. PACKAGE LEAFLET \n\n\n\n30 \n\nPackage leaflet: Information for the user \n \n\nApealea 60 mg powder for solution for infusion \npaclitaxel \n\n \n \nRead all of this leaflet carefully before you start using this medicine because it contains \nimportant information for you. \n \n• Keep this leaflet. You may need to read it again. \n• If you have any further questions, ask your doctor or nurse. \n• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects \n\nnot listed in this leaflet. See section 4. \n \nWhat is in this leaflet \n \n1. What Apealea is and what it is used for \n2. What you need to know before you are given Apealea \n3. How Apealea is given \n4. Possible side effects \n5. How to store Apealea \n6. Contents of the pack and other information \n \n \n1. What Apealea is and what it is used for \n \nApealea is a cancer medicine containing the active substance paclitaxel, which belongs to a group of \nmedicines called taxanes. Paclitaxel affects or stops growth of rapidly dividing cells, such as tumour \ncells. \n \nApealea is used to treat the following cancers in adults, in combination with another medicine called \ncarboplatin: \n• epithelial ovarian cancer – a cancer of the ovary, the organ that produces a woman’s egg cells \n• primary peritoneal cancer – a cancer of the cells lining the space between the wall of the belly \n\nand the internal organs \n• cancer of the fallopian tubes (the connection between the ovaries and the womb) \nIt is used when other therapies have not worked. \n \n \n2. What you need to know before you are given Apealea \n \nDo not use Apealea if you: \n \n• are allergic to paclitaxel or any of the other ingredients of this medicine (listed in section 6) \n• are breast-feeding \n• have a count of white blood cells called neutrophils below 1.5 × 109/L before start of the therapy \n \nTalk to your doctor or nurse, if you are not sure if any of the above applies to you. \n \nWarnings and precautions \n \nTalk to your doctor or nurse before you are given Apealea if you have: \n• reduced liver, kidney or heart function \n\nApealea is not recommended for patients with severely reduced liver or kidney function. \n• previously had nausea, vomiting and diarrhoea during cancer treatment \n\n\n\n31 \n\nContact your doctor immediately, if during treatment you develop: \n• fever, pain, chills, weakness or other signs of infection \n• severe nausea, vomiting or diarrhoea \n• severe reactions at the site of infusion \n• an allergic reaction \n• numbness, tingling, pricking sensation, sensitivity to touch or muscle weakness \nYou may need additional medicines if you develop any of these symptoms. Your doctor may wish to \ndelay further treatment with Apealea or reduce the dose. \n \nAsk your doctor or nurse about hair loss and what can be done to avoid it. \n \nYou will be observed closely during treatment: \n• regular blood tests to ensure it is safe for you to continue treatment \n• symptoms of allergic reaction during the infusion, such as: \n\n− reddening and swelling at the site of infusion \n− low blood pressure \n− breathing difficulties \n− puffing of the face \n\n \nChildren and adolescents \n \nApealea is not recommended for children and adolescents under 18 years, because it has not been \nstudied in this age group. \n \nOther medicines and Apealea \n \nTell your doctor if you are using, have recently used or might use any other medicines. \n \nIn particular, tell your doctor or nurse before you are given Apealea if you are using: \n• ketoconazole, or other medicines to treat fungal infections \n• erythromycin, rifampicin: medicines to treat bacterial infections \n• fluoxetine: a medicine to treat depression \n• gemfibrozil: a medicine to lower blood fats \n• clopidogrel: a medicine that reduces the chances of getting blood clots \n• cimetidine: a medicine to reduce stomach acid \n• efavirenz, nevirapine, ritonavir, saquinavir, indinavir, nelfinavir: medicines to treat HIV \n\ninfection \n• carbamazepine, phenytoin: medicines to treat epilepsy and certain pain conditions \n• cisplatin: a medicine to treat cancer \n \nPregnancy and breast-feeding \n \nTell your doctor before treatment if you are pregnant, think you may be pregnant or are breast-feeding. \n \nApealea is not recommended during pregnancy, as paclitaxel may cause serious birth defects. \nPatients who can become pregnant should use effective contraception during treatment with Apealea \nand for six months afterwards. \n \nStop breast-feeding while being treated, as paclitaxel passes into breast milk and may harm the child. \n \nDriving and using machines \n \nApealea may cause side effects such as tiredness or dizziness that may reduce your ability to drive or \nuse machines. Do not drive or use machines if you have these symptoms. \n \n\n\n\n32 \n\nApealea contains sodium \n \nAfter reconstitution, this medicine contains approximately up to 1.6 g sodium (component of cooking \nsalt) per dose. This is equivalent to 80% of the recommended maximum daily dietary intake of sodium \nfor an adult. \n \n \n3. How Apealea is given \n \nApealea is given to you by a doctor or nurse by a slow drip (infusion) into a vein. This will take about \none hour. The dose is based on your body surface area (worked out from your height and weight) and \nblood test results. The usual dose is 250 mg/m2 body surface area given every three weeks for up to six \ntreatments. \n \nIf you have any further questions on the use of this medicine, ask your doctor or nurse. \n \n \n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. \n \nTell your doctor or nurse immediately if you have any of the following: \n• Very common (may affect more than 1 in 10 people): \n\n− nerve disorder in arms and legs which causes tingling, numbness or burning pain* \n• Common (may affect up to 1 in 10 people): \n\n− fever \n− muscle weakness, cramps or spasms \n− allergic reactions, such as breathing difficulties, fainting, swelling of the face, itching, \n\nfeeling hot, chills, particularly during your infusion. Uncommonly these can lead to \nsevere allergic shock. \n\n \n* Can persist beyond 6 months of paclitaxel discontinuation. \n \nOther side effects and their frequencies include: \nVery common (may affect more than 1 in 10 people): \n• low level of white blood cells called neutrophils \n• lack of appetite \n• diarrhoea, nausea, vomiting \n• hair loss \n• joint or muscle pain or discomfort \n• weakness, tiredness \n• reactions at the infusion site such as pain, inflammation, discolouration, redness, swelling, \n\ntingling, rash, bleeding \n \nCommon (may affect up to 1 in 10 people): \n• low level of white blood cells called leukocytes and granulocytes \n• low level of blood platelets or red blood cells \n• reduced sense of touch or sensation \n• abnormal sensation such as tingling, burning, pricking or numbness of the skin or in the mouth \n• dizziness or feeling of spinning \n• taste disturbance \n• headache \n• rapid heartbeat \n• chest pain or discomfort \n• low blood pressure, flushing, vein inflammation, vein pain, increased blood flow to some parts \n\nof the body \n\n\n\n33 \n\n• breathing difficulties, nasal congestion \n• abdominal pain, constipation, wind \n• dry mouth, inflammation of the inner lining of the mouth \n• skin reddening, rash, itching, nettle-rash \n• pain for instance in arms, legs, breast or at site of tumour \n• back pain, bone pain \n• swelling of ankles, feet, face or fingers \n \nUncommon (may affect up to 1 in 100 people): \n• blood poisoning \n• pus in body tissue \n• lung inflammation, influenza, tonsil inflammation \n• herpes simplex (a viral infection), viral airways infections \n• urinary tract infection, inflammation of the bladder \n• skin infections, including infections at the infusion site \n• disturbed blood clotting mechanisms in the body \n• lack of white and red blood cells, and blood platelets \n• low blood levels of potassium, magnesium or sodium \n• excessive water loss (dehydration) \n• allergic reactions to other medicines, such as penicillin \n• depression, sleeplessness, anxiety \n• epileptic fit lasting longer than five minutes or more than one fit within five minutes \n• coma, feeling very sleepy, drowsy and/or being deeply unresponsive \n• low muscle tone, facial palsy \n• toxicity to the nervous system \n• cognitive disorder (difficulty thinking or processing thoughts, difficulty remembering) \n• brain damage, abnormal fluid accumulation within the brain \n• stroke \n• blurred vision, eye discomfort or irritation, watery eyes \n• deafness, inner ear disorder, ringing in the ears \n• blood vessel disorders, such as: \n\n− formation of blood clots \n− blood vessel inflammation \n− build-up of water in tissue because of blocked lymph vessel \n− hot flushes \n− bleeding \n\n• cardiac arrest, heart failure \n• blue tinged lips or skin \n• a heart rhythm disorder causing irregular rapid activity in the upper heart chambers \n• feeling your heartbeat (palpitations), slow heartbeat \n• blood circulation failure \n• high blood pressure, blood pressure changes, paleness \n• lung failure, narrowing of airways \n• severe lack of oxygen, arising from abnormal breathing \n• difficulty producing voice sounds \n• nosebleed, allergic inflammation inside the nose, runny nose \n• cough \n• mouth and throat pain or discomfort, throat disorder, bleeding gums \n• inflammation of the stomach lining, abdominal discomfort or bloating, lower abdominal pain \n• indigestion, disorder of bowel function, very hard stools, bloody stool \n• liver inflammation or disorder, raised liver enzyme in your blood \n• painful severe swelling of deep skin layers, mainly in the face \n• skin discolouration, pigmentation disorder \n• skin inflammation with blisters \n\n\n\n34 \n\n• increased sweating, cold sweat \n• dry skin, nail disorder \n• bleeding into a joint \n• sensation of heaviness in the legs \n• multi-organ failure which can lead to death \n• tissue swelling caused by excess fluid \n• hernia \n• feeling hot \n• low body temperature \n• vaginal bleeding \n• abnormally high levels of nitrogen-containing compounds in the blood \n\n \nFrequency not known (cannot be estimated from the available data): \n• redness and swelling of the palms of your hands or soles of your feet which may cause your \n\nskin to peel \n \nReporting of side effects \n \nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \neffects not listed in this leaflet. You can also report side effects directly via the national reporting \nsystem listed in Appendix V. By reporting side effects you can help provide more information on the \nsafety of this medicine. \n \n \n5. How to store Apealea \n \nKeep this medicine out of the sight and reach of children. \n \nDo not use this medicine after the expiry date which is stated on the vial label and carton after EXP. \nThe expiry date refers to the last day of that month. \n \nUnopened vials: Store in a refrigerator (2 °C – 8 °C). Keep the vial in the outer carton in order to \nprotect from light. \n \nOnce opened, Apealea is recommended to be used immediately. \n \nAny unused medicine or waste material should be disposed of in accordance with local requirements. \nDo not throw away any medicines via wastewater or household waste. These measures will help \nprotect the environment. \n \n \n6. Contents of the pack and other information \n \nWhat Apealea contains \n \n• The active substance is paclitaxel. One vial contains 60 mg of paclitaxel. After preparation, each \n\nmillilitre of solution contains 1 mg of paclitaxel (micellar). \n• The other ingredients are: \n\n− N-(all-trans-retinoyl)-L-cysteic acid methyl ester sodium salt \n− N-(13-cis-retinoyl)-L-cysteic acid methyl ester sodium salt \n− sodium hydroxide (for pH adjustment) \n\n See section 2 “Apealea contains sodium”. \n \n\n\n\n35 \n\nWhat Apealea looks like and contents of the pack \n \nApealea is supplied as a greenish-yellow to yellow powder in a glass vial with a rubber stopper and \naluminium seal. \n \nEach carton contains 1 glass vial with powder equivalent to 60 mg of paclitaxel. \n \nMarketing Authorisation Holder and Manufacturer \n \nOasmia Pharmaceutical AB \nVallongatan 1 \nSE-752 28 Uppsala \nSweden \nTel +46 18 50 54 40 \ne-mail: med-info@oasmia.com \n \nFor any information about this medicine, please contact the Marketing Authorisation Holder. \n \nThis leaflet was last revised in \n \nDetailed information on this medicine is available on the European Medicines Agency website: \nhttp://www.ema.europa.eu. \n \n--------------------------------------------------------------------------------------------------------------------------- \n \nThe following information is intended for healthcare professionals only: \n \nAdministration precautions \nPaclitaxel is an antineoplastic medicinal product and as with other potentially toxic compounds, \ncaution should be exercised in handling Apealea. The use of gloves, goggles and protective clothing is \nrecommended. If the solution contacts the skin, the skin should be washed immediately and \nthoroughly with soap and water. If it contacts mucous membranes, the membranes should be flushed \nthoroughly with water. Apealea should only be prepared and administered by personnel appropriately \ntrained in the handling of cytotoxic agents. Pregnant and breast-feeding staff should not handle \nApealea. The reconstituted product should not be diluted. \n \nReconstitution of the medicinal product \nApealea is supplied as a sterile powder for reconstitution before use. After reconstitution, the solution \ncontains 1 mg/mL of paclitaxel formulated as micellar nanoparticles. The reconstituted solution for \ninfusion is a clear, greenish-yellow solution. \n \nProtect from direct and/or bright light throughout the preparation process. The (reconstituted) product \ncan only withstand short-term handling in absence of light protection. \n \nOnly reconstitute Apealea using one of the following commercially available solutions for \nreconstitution: \n\n- sodium chloride 9 mg/mL (0.9%) solution suitable for infusion; \n- lactated Ringer’s solution suitable for infusion; \n- acetated Ringer’s solution suitable for infusion. \n\n \nThe pH of lactated or acetated Ringer’s solution must be in the range of 5.0 to 7.5 and acceptable ion \nconcentrations of calcium and magnesium are listed below (Table 1). \n \n\n\n\n36 \n\nTable 1. Acceptable ion concentrations for calcium and magnesium in lactated and acetated \nRinger’s solutions suitable for reconstitution \n\nIon Range (mmol/L) \nCa2+ 1.0–3.5* \nMg2+ 0.0–2.5* \n\n* Solutions containing both Ca2+ and Mg2+ should have a total (combined) concentration of Ca2+ and \nMg2+ within the range of 1.0 to 3.5 mmol/L. \n \nApealea should be reconstituted using either one of the three suitable solutions for reconstitution and \naccording to the following steps: \n \n1. Take the desired number of vials from the refrigerator. The powder should be greenish-yellow \n\nto yellow. In case of discolouration (orange), discard the vial. To reach room temperature, let \nthe vials stand protected from light for approximately 15 to 20 minutes not above 25 °C. \n\n2. Due to negative pressure in the vial, pressure must be equilibrated by a needle or a spike before \nand during injection of the solution for reconstitution. Using a sterile syringe, inject 60 mL of \nsolution for reconstitution per vial. The solution should be injected during approximately one \nminute towards the inner wall of the vial and not directly onto the powder as this will result in \nfoaming. \n\n3. Swirl the vial in an upright position for approximately for 20 seconds. To keep the generation of \nfoam to a minimum, do not shake the vial. \n\n4. Protect from light and allow the vial to stand for three to five minutes. \n5. Swirl the vial again in upright position for approximately 20 seconds, then gently invert it five \n\ntimes. Do not shake. \n6. Continue to swirl the vial until the powder is completely dissolved. Alternatively, the vial may \n\nbe placed on a shaker and rotated for up to 20 minutes, while being protected from light (orbital \nshake pattern; 200–250 rpm). Steps 3 to 6 should not be more than 30 minutes. \n\n7. The solution should be clear and greenish-yellow without visible particles or precipitates. If \nparticles, precipitates, discolouration (orange) or opalescence are observed, the solution should \nbe discarded. \n\n8. Inject the required amount of reconstituted Apealea into an empty, sterile ethylene-vinyl acetate \n(EVA) bag. Ensure that the solution is clear and place a light protective-bag over the EVA \ninfusion bag. \n\n \nShelf life after reconstitution \nChemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 8 °C in lactated \nand acetated Ringer’s solution and for 4 hours at 2 °C to 8 °C in sodium chloride 9 mg/mL (0.9%) \nsolution when protected from light. From a microbiological point of view, unless the method of \nopening and reconstituting precludes the risks of microbial contamination, the product should be used \nimmediately. If not used immediately, in-use storage times and conditions are the responsibility of the \nuser. \n \nIntravenous administration \nCompatibility with administration sets made of DEHP-free PVC (i.e. polyvinyl chloride without the \nplasticizer di-(2-ethylhexyl) phthalate) has been demonstrated. However, compatibility with \nDEHP-containing administration sets has not been demonstrated. Administration sets containing a \n15 µm polyamide fluid filter should be used. It is important to flush the infusion set and \ncatheter/cannula before and after the administration using the solution for reconstitution in order to \navoid accidental administration into the surrounding tissue and to ensure administration of the \ncomplete dose. \n \nDisposal \nAny unused medicinal product or waste material should be disposed of in accordance with local \nrequirements. \n \n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. PACKAGE LEAFLET"},"Section_1":{"kind":"string","value":"{'Title': '1. what apealea is and what it is used for', 'Section_Content': \"apealea is a cancer medicine containing the active substance paclitaxel, which belongs to a group of medicines called taxanes. paclitaxel affects or stops growth of rapidly dividing cells, such as tumour cells. apealea is used to treat the following cancers in adults, in combination with another medicine called carboplatin: epithelial ovarian cancer a cancer of the ovary, the organ that produces a woman's egg cells primary peritoneal cancer a cancer of the cells lining the space between the wall of the belly and the internal organs cancer of the fallopian tubes (the connection between the ovaries and the womb) it is used when other therapies have not worked.\", 'Entity_Recognition': [{'Text': 'apealea', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'a cancer medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 28}, 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'TREATMENT', 'BeginOffset': 634, 'EndOffset': 649}]}"},"Section_2":{"kind":"string","value":"{'Title': '2. what you need to know before you are given apealea', 'Section_Content': 'do not use apealea if you: are allergic to paclitaxel or any of the other ingredients of this medicine (listed in section 6) are breast-feeding have a count of white blood cells called neutrophils below 1.5 × 109/l before start of the therapy talk to your doctor or nurse, if you are not sure if any of the above applies to you. warnings and precautions talk to your doctor or nurse before you are given apealea if you have: reduced liver, kidney or heart function apealea is not recommended for patients with severely reduced liver or kidney function. previously had nausea, vomiting and diarrhoea during cancer treatment 31 contact your doctor immediately, if during treatment you develop: fever, pain, chills, weakness or other signs of infection severe nausea, vomiting or diarrhoea severe reactions at the site of infusion an allergic reaction numbness, tingling, pricking sensation, sensitivity to touch or muscle weakness you may need additional medicines if you develop any of these symptoms. your doctor may wish to delay further treatment with apealea or reduce the dose. ask your doctor or nurse about hair loss and what can be done to avoid it. you will be observed closely during treatment: regular blood tests to ensure it is safe for you to continue treatment symptoms of allergic reaction during the infusion, such as: − reddening and swelling at the site of infusion − low blood pressure − breathing difficulties − puffing of the face children and adolescents apealea is not recommended for children and adolescents under 18 years, because it has not been studied in this age group. other medicines and apealea tell your doctor if you are using, have recently used or might use any other medicines. in particular, tell your doctor or nurse before you are given apealea if you are using: ketoconazole, or other medicines to treat fungal infections erythromycin, rifampicin: medicines to treat bacterial infections fluoxetine: a medicine to treat depression gemfibrozil: a medicine to lower blood fats clopidogrel: a medicine that reduces the chances of getting blood clots cimetidine: a medicine to reduce stomach acid efavirenz, nevirapine, ritonavir, saquinavir, indinavir, nelfinavir: medicines to treat hiv infection carbamazepine, phenytoin: medicines to treat epilepsy and certain pain conditions cisplatin: a medicine to treat cancer pregnancy and breast-feeding tell your doctor before treatment if you are pregnant, think you may be pregnant or are breast-feeding. apealea is not recommended during pregnancy, as paclitaxel may cause serious birth defects. patients who can become pregnant should use effective contraception during treatment with apealea and for six months afterwards. stop breast-feeding while being treated, as paclitaxel passes into breast milk and may harm the child. driving and using machines apealea may cause side effects such as tiredness or dizziness that may reduce your ability to drive or use machines. do not drive or use machines if you have these symptoms. apealea contains sodium after reconstitution, this medicine contains approximately up to 1.6 g sodium (component of cooking salt) per dose. this is equivalent to 80% of the recommended maximum daily dietary intake of sodium for an adult.', 'Entity_Recognition': [{'Text': 'apealea', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 31, 'EndOffset': 39}, {'Id': 8, 'BeginOffset': 43, 'EndOffset': 53, 'Score': 0.9988049268722534, 'Text': 'paclitaxel', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.5245382785797119}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 89, 'EndOffset': 102}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 122, 'EndOffset': 123}, {'Id': 49, 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'3. how apealea is given', 'Section_Content': 'apealea is given to you by a doctor or nurse by a slow drip (infusion) into a vein. this will take about one hour. the dose is based on your body surface area (worked out from your height and weight) and blood test results. the usual dose is 250 mg/m2 body surface area given every three weeks for up to six treatments. if you have any further questions on the use of this medicine, ask your doctor or nurse.', 'Entity_Recognition': [{'Text': 'apealea', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'a slow drip (infusion', 'Type': 'TREATMENT', 'BeginOffset': 48, 'EndOffset': 69}, {'Id': 0, 'BeginOffset': 78, 'EndOffset': 82, 'Score': 0.8337357640266418, 'Text': 'vein', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'your body surface area', 'Type': 'TREATMENT', 'BeginOffset': 136, 'EndOffset': 158}, {'Text': 'your height and weight', 'Type': 'TEST', 'BeginOffset': 176, 'EndOffset': 198}, {'Id': 6, 'BeginOffset': 204, 'EndOffset': 214, 'Score': 0.9880253672599792, 'Text': 'blood test', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 242, 'EndOffset': 245}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 368, 'EndOffset': 381}]}"},"Section_4":{"kind":"string","value":"{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor or nurse immediately if you have any of the following: very common (may affect more than 1 in 10 people): − nerve disorder in arms and legs which causes tingling, numbness or burning pain* common (may affect up to 1 in 10 people): − fever − muscle weakness, cramps or spasms − allergic reactions, such as breathing difficulties, fainting, swelling of the face, itching, feeling hot, chills, particularly during your infusion. uncommonly these can lead to severe allergic shock. * can persist beyond 6 months of paclitaxel discontinuation. other side effects and their frequencies include: very common (may affect more than 1 in 10 people): low level of white blood cells called neutrophils lack of appetite diarrhoea, nausea, vomiting hair loss joint or muscle pain or discomfort weakness, tiredness reactions at the infusion site such as pain, inflammation, discolouration, redness, swelling, tingling, rash, bleeding common (may affect up to 1 in 10 people): low level of white blood cells called leukocytes and granulocytes low level of blood platelets or red blood cells reduced sense of touch or sensation abnormal sensation such as tingling, burning, pricking or numbness of the skin or in the mouth dizziness or feeling of spinning taste disturbance headache rapid heartbeat chest pain or discomfort low blood pressure, flushing, vein inflammation, vein pain, increased blood flow to some parts of the body 33 breathing difficulties, nasal congestion abdominal pain, constipation, wind dry mouth, inflammation of the inner lining of the mouth skin reddening, rash, itching, nettle-rash pain for instance in arms, legs, breast or at site of tumour back pain, bone pain swelling of ankles, feet, face or fingers uncommon (may affect up to 1 in 100 people): blood poisoning pus in body tissue lung inflammation, influenza, tonsil inflammation herpes simplex (a viral infection), viral airways infections urinary tract infection, inflammation of the bladder skin infections, including infections at the infusion site disturbed blood clotting mechanisms in the body lack of white and red blood cells, and blood platelets low blood levels of potassium, magnesium or sodium excessive water loss (dehydration) allergic reactions to other medicines, such as penicillin depression, sleeplessness, anxiety epileptic fit lasting longer than five minutes or more than one fit within five minutes coma, feeling very sleepy, drowsy and/or being deeply unresponsive low muscle tone, facial palsy toxicity to the nervous system cognitive disorder (difficulty thinking or processing thoughts, difficulty remembering) brain damage, abnormal fluid accumulation within the brain stroke blurred vision, eye discomfort or irritation, watery eyes deafness, inner ear disorder, ringing in the ears blood vessel disorders, such as: − formation of blood clots − blood vessel inflammation − build-up of water in tissue because of blocked lymph vessel − hot flushes − bleeding cardiac arrest, heart failure blue tinged lips or skin a heart rhythm disorder causing irregular rapid activity in the upper heart chambers feeling your heartbeat (palpitations), slow heartbeat blood circulation failure high blood pressure, blood pressure changes, paleness lung failure, narrowing of airways severe lack of oxygen, arising from abnormal breathing difficulty producing voice sounds nosebleed, allergic inflammation inside the nose, runny nose cough mouth and throat pain or discomfort, throat disorder, bleeding gums inflammation of the stomach lining, abdominal discomfort or bloating, lower abdominal pain indigestion, disorder of bowel function, very hard stools, bloody stool liver inflammation or disorder, raised liver enzyme in your blood painful severe swelling of deep skin layers, mainly in the face skin discolouration, pigmentation disorder skin inflammation with blisters 34 increased sweating, cold sweat dry skin, nail disorder bleeding into a joint sensation of heaviness in the legs multi-organ failure which can lead to death tissue swelling caused by excess fluid hernia feeling hot low body temperature vaginal bleeding abnormally high levels of nitrogen-containing compounds in the blood frequency not known (cannot be estimated from the available data): redness and swelling of the palms of your hands or soles of your feet which may cause your skin to peel reporting of side effects if you get any side effects, talk to your doctor, pharmacist or 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'high blood pressure', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9736668467521667}]}, {'Id': 218, 'BeginOffset': 3305, 'EndOffset': 3327, 'Score': 0.9710058569908142, 'Text': 'blood pressure changes', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9737276434898376}]}, {'Text': 'paleness lung failure', 'Type': 'PROBLEM', 'BeginOffset': 3329, 'EndOffset': 3350}, {'Id': 221, 'BeginOffset': 3352, 'EndOffset': 3372, 'Score': 0.6732593178749084, 'Text': 'narrowing of airways', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6076143980026245}]}, {'Text': 'severe lack of oxygen', 'Type': 'PROBLEM', 'BeginOffset': 3373, 'EndOffset': 3394}, {'Id': 224, 'BeginOffset': 3428, 'EndOffset': 3461, 'Score': 0.8429272770881653, 'Text': 'difficulty producing voice sounds', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8870618939399719}]}, {'Text': 'allergic inflammation inside the nose', 'Type': 'PROBLEM', 'BeginOffset': 3473, 'EndOffset': 3510}, {'Id': 228, 'BeginOffset': 3512, 'EndOffset': 3522, 'Score': 0.9475268721580505, 'Text': 'runny nose', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6187651753425598}]}, {'Text': 'cough mouth', 'Type': 'PROBLEM', 'BeginOffset': 3523, 'EndOffset': 3534}, {'Id': 230, 'BeginOffset': 3539, 'EndOffset': 3550, 'Score': 0.6361968517303467, 'Text': 'throat pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9775794148445129}]}, {'Id': 231, 'BeginOffset': 3554, 'EndOffset': 3564, 'Score': 0.9969204664230347, 'Text': 'discomfort', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9870961904525757}]}, {'Id': 232, 'BeginOffset': 3566, 'EndOffset': 3581, 'Score': 0.9636312127113342, 'Text': 'throat disorder', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9723941683769226}]}, {'Text': 'bleeding gums inflammation of the stomach lining', 'Type': 'PROBLEM', 'BeginOffset': 3583, 'EndOffset': 3631}, {'Id': 235, 'BeginOffset': 3633, 'EndOffset': 3653, 'Score': 0.8144292831420898, 'Text': 'abdominal discomfort', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9870883822441101}]}, {'Id': 236, 'BeginOffset': 3657, 'EndOffset': 3665, 'Score': 0.9961691498756409, 'Text': 'bloating', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9770718216896057}]}, {'Text': 'lower abdominal pain indigestion', 'Type': 'PROBLEM', 'BeginOffset': 3667, 'EndOffset': 3699}, {'Id': 239, 'BeginOffset': 3701, 'EndOffset': 3727, 'Score': 0.8598092198371887, 'Text': 'disorder of bowel function', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9614279866218567}]}, {'Id': 152, 'BeginOffset': 3713, 'EndOffset': 3718, 'Score': 0.9302407503128052, 'Text': 'bowel', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'very hard stools', 'Type': 'PROBLEM', 'BeginOffset': 3729, 'EndOffset': 3745}, {'Text': 'bloody stool liver inflammation', 'Type': 'PROBLEM', 'BeginOffset': 3747, 'EndOffset': 3778}, {'Id': 243, 'BeginOffset': 3782, 'EndOffset': 3790, 'Score': 0.9836265444755554, 'Text': 'disorder', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.865816593170166}]}, {'Id': 244, 'BeginOffset': 3792, 'EndOffset': 3811, 'Score': 0.4584360718727112, 'Text': 'raised liver enzyme', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7402383089065552}]}, {'Id': 154, 'BeginOffset': 3799, 'EndOffset': 3804, 'Score': 0.8997893333435059, 'Text': 'liver', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'your blood painful', 'Type': 'PROBLEM', 'BeginOffset': 3815, 'EndOffset': 3833}, {'Text': 'severe swelling', 'Type': 'PROBLEM', 'BeginOffset': 3834, 'EndOffset': 3849}, {'Text': 'deep skin layers', 'Type': 'PROBLEM', 'BeginOffset': 3853, 'EndOffset': 3869}, {'Id': 157, 'BeginOffset': 3885, 'EndOffset': 3889, 'Score': 0.9423086643218994, 'Text': 'face', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'skin discolouration', 'Type': 'PROBLEM', 'BeginOffset': 3890, 'EndOffset': 3909}, {'Id': 248, 'BeginOffset': 3911, 'EndOffset': 3932, 'Score': 0.773968517780304, 'Text': 'pigmentation disorder', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.932033360004425}]}, {'Id': 249, 'BeginOffset': 3933, 'EndOffset': 3950, 'Score': 0.7760549783706665, 'Text': 'skin inflammation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8675609230995178}]}, {'Id': 250, 'BeginOffset': 3956, 'EndOffset': 3964, 'Score': 0.8632832765579224, 'Text': 'blisters', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8960714936256409}]}, {'Text': '34', 'Type': 'NUMBER', 'BeginOffset': 3965, 'EndOffset': 3967}, {'Text': 'increased sweating', 'Type': 'PROBLEM', 'BeginOffset': 3968, 'EndOffset': 3986}, {'Text': 'cold sweat dry skin', 'Type': 'PROBLEM', 'BeginOffset': 3988, 'EndOffset': 4007}, {'Text': 'nail disorder bleeding', 'Type': 'PROBLEM', 'BeginOffset': 4009, 'EndOffset': 4031}, {'Id': 257, 'BeginOffset': 4045, 'EndOffset': 4067, 'Score': 0.20634862780570984, 'Text': 'sensation of heaviness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8896256685256958}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9654280543327332, 'RelationshipScore': 0.8634321689605713, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 162, 'BeginOffset': 4039, 'EndOffset': 4044, 'Text': 'joint', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9696072936058044, 'RelationshipScore': 0.971541702747345, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 163, 'BeginOffset': 4075, 'EndOffset': 4079, 'Text': 'legs', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'the legs multi-organ failure', 'Type': 'PROBLEM', 'BeginOffset': 4071, 'EndOffset': 4099}, {'Text': 'death tissue swelling', 'Type': 'PROBLEM', 'BeginOffset': 4118, 'EndOffset': 4139}, {'Text': 'excess fluid hernia', 'Type': 'PROBLEM', 'BeginOffset': 4150, 'EndOffset': 4169}, {'Id': 262, 'BeginOffset': 4170, 'EndOffset': 4202, 'Score': 0.7335290312767029, 'Text': 'feeling hot low body temperature', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7016527056694031}]}, {'Id': 263, 'BeginOffset': 4203, 'EndOffset': 4219, 'Score': 0.8339182734489441, 'Text': 'vaginal bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.889284074306488}]}, {'Id': 264, 'BeginOffset': 4220, 'EndOffset': 4275, 'Score': 0.3364778757095337, 'Text': 'abnormally high levels of nitrogen-containing compounds', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7386153340339661}]}, {'Id': 274, 'BeginOffset': 4356, 'EndOffset': 4363, 'Score': 0.9848102927207947, 'Text': 'redness', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7707864046096802}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9853330254554749, 'RelationshipScore': 0.6601202487945557, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 268, 'BeginOffset': 4384, 'EndOffset': 4389, 'Text': 'palms', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9979859590530396, 'RelationshipScore': 0.9374656677246094, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 269, 'BeginOffset': 4398, 'EndOffset': 4403, 'Text': 'hands', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.8891689777374268, 'RelationshipScore': 0.7760419249534607, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 270, 'BeginOffset': 4407, 'EndOffset': 4412, 'Text': 'soles', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9956747889518738, 'RelationshipScore': 0.9136489033699036, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 271, 'BeginOffset': 4421, 'EndOffset': 4425, 'Text': 'feet', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'swelling of the palms', 'Type': 'PROBLEM', 'BeginOffset': 4368, 'EndOffset': 4389}, {'Id': 269, 'BeginOffset': 4398, 'EndOffset': 4403, 'Score': 0.9979859590530396, 'Text': 'hands', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 270, 'BeginOffset': 4407, 'EndOffset': 4412, 'Score': 0.8891689777374268, 'Text': 'soles', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 271, 'BeginOffset': 4421, 'EndOffset': 4425, 'Score': 0.9956747889518738, 'Text': 'feet', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'your skin to peel', 'Type': 'PROBLEM', 'BeginOffset': 4442, 'EndOffset': 4459}, {'Id': 276, 'BeginOffset': 4473, 'EndOffset': 4485, 'Score': 0.9095777273178101, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8168026208877563}]}, {'Id': 277, 'BeginOffset': 4501, 'EndOffset': 4513, 'Score': 0.9156547784805298, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7791089415550232}]}, {'Id': 278, 'BeginOffset': 4584, 'EndOffset': 4596, 'Score': 0.952359676361084, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6574267745018005}]}, {'Id': 279, 'BeginOffset': 4645, 'EndOffset': 4657, 'Score': 0.8586530685424805, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7052484750747681}]}, {'Id': 280, 'BeginOffset': 4711, 'EndOffset': 4722, 'Score': 0.3791923522949219, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6152297258377075}]}, {'Id': 281, 'BeginOffset': 4736, 'EndOffset': 4748, 'Score': 0.8554664254188538, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7392748594284058}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 4804, 'EndOffset': 4817}]}"},"Section_5":{"kind":"string","value":"{'Title': '5. how to store apealea', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the vial label and carton after exp. the expiry date refers to the last day of that month. unopened vials: store in a refrigerator (2 8 ). keep the vial in the outer carton in order to protect from light. once opened, apealea is recommended to be used immediately. any unused medicine or waste material should be disposed of in accordance with local requirements. do not throw away any medicines via wastewater or household waste. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'apealea', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 259, 'EndOffset': 260}, {'Text': 'the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 281, 'EndOffset': 297}, {'Text': 'waste material', 'Type': 'TREATMENT', 'BeginOffset': 413, 'EndOffset': 427}]}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': 'what apealea contains the active substance is paclitaxel. one vial contains 60 mg of paclitaxel. after preparation, each millilitre of solution contains 1 mg of paclitaxel (micellar). the other ingredients are: − n-(all-trans-retinoyl)-l-cysteic acid methyl ester sodium salt − n-(13-cis-retinoyl)-l-cysteic acid methyl ester sodium salt − sodium hydroxide (for ph adjustment) see section 2 \"apealea contains sodium\". what apealea looks like and contents of the pack apealea is supplied as a greenish-yellow to yellow powder in a glass vial with a rubber stopper and aluminium seal. each carton contains 1 glass vial with powder equivalent to 60 mg of paclitaxel.', 'Entity_Recognition': [{'Text': 'apealea', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 46, 'EndOffset': 56, 'Score': 0.9991458654403687, 'Text': 'paclitaxel', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8692106008529663, 'RelationshipScore': 0.9999945163726807, 'RelationshipType': 'DOSAGE', 'Id': 1, 'BeginOffset': 58, 'EndOffset': 66, 'Text': 'one vial', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.5139319896697998, 'RelationshipScore': 0.8014750480651855, 'RelationshipType': 'FORM', 'Id': 4, 'BeginOffset': 135, 'EndOffset': 143, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '60', 'Type': 'NUMBER', 'BeginOffset': 76, 'EndOffset': 78}, {'Id': 3, 'BeginOffset': 85, 'EndOffset': 95, 'Score': 0.9992997646331787, 'Text': 'paclitaxel', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8692106008529663, 'RelationshipScore': 0.9287548661231995, 'RelationshipType': 'DOSAGE', 'Id': 1, 'BeginOffset': 58, 'EndOffset': 66, 'Text': 'one vial', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9797617197036743, 'RelationshipScore': 0.9993281364440918, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 76, 'EndOffset': 81, 'Text': '60 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.5139319896697998, 'RelationshipScore': 0.991683840751648, 'RelationshipType': 'FORM', 'Id': 4, 'BeginOffset': 135, 'EndOffset': 143, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'each millilitre of solution', 'Type': 'TREATMENT', 'BeginOffset': 116, 'EndOffset': 143}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 153, 'EndOffset': 154}, {'Text': 'paclitaxel (micellar)', 'Type': 'TREATMENT', 'BeginOffset': 161, 'EndOffset': 182}, {'Id': 8, 'BeginOffset': 213, 'EndOffset': 356, 'Score': 0.8054126501083374, 'Text': 'n-(all-trans-retinoyl)-l-cysteic acid methyl ester sodium salt − n-(13-cis-retinoyl)-l-cysteic acid methyl ester sodium salt − sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ph adjustment', 'Type': 'TREATMENT', 'BeginOffset': 362, 'EndOffset': 375}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 389, 'EndOffset': 390}, {'Text': 'the pack apealea', 'Type': 'TREATMENT', 'BeginOffset': 458, 'EndOffset': 474}, {'Text': 'a rubber stopper and aluminium seal', 'Type': 'TREATMENT', 'BeginOffset': 546, 'EndOffset': 581}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 604, 'EndOffset': 605}, {'Text': 'powder', 'Type': 'TREATMENT', 'BeginOffset': 622, 'EndOffset': 628}, {'Text': '60', 'Type': 'NUMBER', 'BeginOffset': 643, 'EndOffset': 645}, {'Id': 11, 'BeginOffset': 652, 'EndOffset': 662, 'Score': 0.9993017911911011, 'Text': 'paclitaxel', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.47966888546943665, 'RelationshipScore': 0.566891074180603, 'RelationshipType': 'FORM', 'Id': 9, 'BeginOffset': 622, 'EndOffset': 628, 'Text': 'powder', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.978758692741394, 'RelationshipScore': 0.999961256980896, 'RelationshipType': 'DOSAGE', 'Id': 10, 'BeginOffset': 643, 'EndOffset': 648, 'Text': '60 mg', 'Category': 'MEDICATION', 'Traits': []}]}]}"}}},{"rowIdx":1062,"cells":{"ID":{"kind":"string","value":"5CB1F30065ADFE84951D65E10F9A2CCF"},"URL":{"kind":"string","value":"https://www.ema.europa.eu/documents/product-information/pylobactell-epar-product-information_en.pdf"},"Product_Name":{"kind":"string","value":"Pylobactell"},"Full_Content":{"kind":"string","value":"1 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX I \n\n \n\nSUMMARY OF PRODUCT CHARACTERISTICS\n\n\n\n \n\n2 \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nPylobactell, 100 mg, Soluble Tablet \n\n \n\n \n\n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n\n \n\nActive substance Quantity per tablet \n\n \n13C-urea 100 mg \n\n \n\nFor a full list of excipients, see section 6.1. \n\n \n\n \n\n3. PHARMACEUTICAL FORM \n\n \n\nSoluble tablet \n\nA white, biconvex tablet. \n\n \n\n \n\n4. CLINICAL PARTICULARS \n\n \n\n4.1 Therapeutic indications \n\n \n\nThis medicinal product is for diagnostic use only. \n\nFor in vivo diagnosis of gastroduodenal Helicobacter pylori infection. \n\n \n\n4.2 Posology and method of administration \n \n\nPylobactell is not recommended for use in children below the age of 18 years due to \n\ninsufficient data on efficacy. \n\n \n\nThe Pylobactell tablet is for oral administration. \n\n \n\nAdults: The tablet is to be dissolved in water and taken 10 minutes after the start of the breath \n\ntest procedure. \n\n \n\nThe patient should fast for at least 4 hours before the test so that the test is taken on an empty \n\nstomach. If the patient has eaten a heavy meal then it will be necessary to fast for six hours \n\nprior to the test. \n\n \n\nIt is important to follow the instructions for use described in Section 6.6 adequately, otherwise \n\nthe validity of the test result will be questionable. \n\n \n\n4.3 Contraindications \n\n \n\nThe test must not be used in patients with documented or suspected gastric infection that \n\nmight interfere with the urea breath test. \n\nHypersensitivity to the active substance or to any of the excipients listed in section 6.1. \n\n \n\n4.4 Special warnings and precautions for use \n\n \n\nA positive urea breath test alone does not clinically confirm that eradication therapy is \n\nindicated. Alternative diagnosis with invasive endoscopic methods might be indicated in \n\n\n\n \n\n3 \n\norder to examine the presence of any other complicating conditions, eg. gastric ulcer, \n\nautoimmune gastritis and malignancies. \n\n \n\nIn individual cases of atrophic gastritis, the breath test result may have a false positive \n\noutcome and other tests may be required to confirm the presence of H.pylori. \n\n \n\nIf a repeat test is required, it should not be carried out until the following day. \n\nFor patients who do not tolerate the recommended test meal, an alternative test meal should \n\nbe given. Care should be taken in patients where fasting may have medical implications. \n\n \n\nThere are insufficient data on the diagnostic reliability of the Pylobactell test to recommend \n\nits use in patients with partial gastrectomy and in patients younger than 18 years. \n\n \n\n4.5 Interaction with other medicinal products and other forms of interaction \n\n \n\nThe validity of the test result may be affected if the patient is currently being treated with \n\nantibiotics or a proton-pump inhibitor or has completed a course of treatment with these \n\ndrugs. The results may be affected in general by all treatments interfering with H.pylori \n\nstatus or urease activity. \n\n \n\nSuppression of H. pylori might give false negative results. Therefore, the test must not be \n\nused until four weeks without systemic antibacterial therapy and two weeks after last dose of \n\nacid antisecretory agents. This is especially important after eradication therapy. \n\n \n\n4.6 Fertility, pregnancy and lactation \n \n\nThe endogenous production of urea amounts to 25 - 35 g/day. It is therefore unlikely that the \n\ndose of 100 mg urea should cause any adverse effect on pregnancy and lactation. \n\n \n\nThe Pylobactell test is not expected to be harmful during pregnancy or to the health of the \n\nfoetus / newborn child. Pylobactell can be used during pregnancy and lactation. \n\n \n\n4.7 Effects on ability to drive and use machines \n\n \n\nNot relevant. \n\n \n\n4.8 Undesirable effects \n \n\nNone known. \n\n \n\nReporting of suspected adverse reactions \n\nReporting suspected adverse reactions after authorisation of the medicinal product is \n\nimportant. It allows continued monitoring of the benefit/risk balance of the medicinal product. \n\nHealthcare professionals are asked to report any suspected adverse reactions via the national \n\nreporting system listed in Appendix V. \n\n \n\n4.9 Overdose \n\n \n\nOverdose is unlikely to occur in the intended clinical circumstances. No case of overdose has \n\nbeen reported. \n\n \n\n \n\n5. PHARMACOLOGICAL PROPERTIES \n\n \n\n5.1 Pharmacodynamic properties \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n \n\n4 \n\n \n\nPharmacotherapeutic group: Other diagnostic agents \n\n \n\nATC code: V04C X. \n\n \n\nIn the case of infection with H.pylori, orally ingested 13C-urea is metabolised by the enzyme \n\nurease which is present in H.pylori. \n\n \n\nH2N(13CO)NH2 + H2O → 2NH3 + 13CO2 \n \n\nThe carbon dioxide which is liberated diffuses into the blood vessels and is transported as \n\nbicarbonate to the lungs where it is then liberated as 13CO2 in exhaled air. Infection with \n\nH.pylori will significantly change the 13C/12C - carbon isotope ratio. \n\n \n\nThe proportion of 13CO2 in the breath samples may be determined by isotope-ratio-mass \n\nspectrometry (IRMS) or by another suitably-validated method carried out by any qualified \n\nlaboratory, and stated as an absolute difference (excess) in the value between the pre-urea and \n\npost-urea breath samples (see Section 6.6). \n\n \n\nThe cut off point for discriminating between H.pylori negative and positive patients is set to \n\nan excess value of 3.5, i.e. <3.5 is negative and 3.5 is positive. \n\n \n\nIn comparison with biopsy based techniques for diagnosing H.pylori infection, using data \n\nfrom two therapeutic trials, Pylobactell achieved during different conditions (prestudy and \n\nfollow-up visits) sensitivity estimates above 95 % with lower one-sided 95 % confidence limit \n\nranging from 93 % to 98 %. The specificity estimates were all above 90 % with \n\ncorresponding lower confidence limits ranging from 85 % to 90 %. \n\n \n\n5.2 Pharmacokinetic properties \n\n \n\nUrea is rapidly absorbed from the gastro-intestinal tract and distributed into extracellular and \n\nintracellular fluids including lymph, bile, cerebrospinal fluid and blood. It is reported to cross \n\nthe placenta and penetrate the eye. It is excreted unchanged in the urine. \n\n \n\n5.3 Preclinical safety data \n\n \n\nThere are no concerns in relation to the clinical use of the product. \n\n \n\n \n\n6. PHARMACEUTICAL PARTICULARS \n\n \n\n6.1 List of excipients \n\n \n\nPovidone (E1201) \n\nMicrocrystalline Cellulose (E460i) \n\nColloidal Anhydrous Silica \n\nSodium Benzoate (E211) \n\n \n\n6.2 Incompatibilities \n\n \n\nNot applicable. \n\n \n\n6.3 Shelf life \n\n \n\n3 years. The dissolved tablet must be taken immediately. \n\n\n\n \n\n5 \n\n \n\n6.4 Special precautions for storage \n\n \n\nDo not store above 25°C. \n\n \n\n6.5 Nature and contents of container \n \n\nThe Pylobactell 13C-urea breath test kit contains a sachet containing the Pylobactell tablet, six \n\nglass tubes with caps and bar code labels, three additional bar code labels, a 30 ml mixing and \n\nadministration glass vial with cap, two straws, a package leaflet and an Analysis Request \n\nForm. A security label for re-sealing the kit is also provided. \n\n \n\nThe Pylobactell breath test procedure includes the administering of a suitable test meal. This \n\nis not supplied within the box. \n\nThe Pylobactell tablet container is a heat-sealed PET/aluminium foil/LDPE laminated sachet. \n\n \n\n6.6 Special precautions for disposal and other handling \n\n \n\nThe patient should fast for at least 4 hours before the test so that the test is taken on an empty \n\nstomach. If the patient has eaten a heavy meal then it will be necessary to fast for six hours \n\nprior to the test. \n\n \n\nIt is recommended that the breath test is performed while the patient is in a seated position. \n\n \n\nSampling instructions \n\n \n\nt = 0 minutes Note the time the patient drinks the test meal. \n\n \n\nt = 5 minutes Collect pre-urea breath samples. Three tubes of breath are to be taken by \n\nbreathing normally through a straw held at the base of a small tube (white top). The patient \n\nmust expire as the straw is slowly and completely withdrawn from the tube, which is then \n\nimmediately capped. These breath samples are used to measure the natural level of 13C in the \n\ncarbon dioxide of the breath. \n\n \n\nt = 10 minutes The Pylobactell tablet is placed in the 30 ml mixing vial and water added to \n\nthe marked line. The bottle is capped and shaken well to dissolve the tablet. The entire \n\ncontents must be swallowed immediately by the patient, the bottle is refilled with water to the \n\nline and the entire contents are again swallowed by the patient. \n\n \n\nt = 40 minutes Collect post-urea (red top) breath samples. Three tubes of breath are to be \n\ntaken, which are used to measure the presence of excess levels of 13C, which will be present if \n\nthe patient is H.pylori positive. \n\n \n\nOn completion of the test retain one pre-urea sample (white top) and one post-urea sample \n\n(red top). Return two pre-urea and two post-urea samples to the box. Safely discard the 30 ml \n\nmixing vial. Complete the Analysis Request Form; attach one of three spare bar code labels \n\nto the area marked \"AFFIX BAR CODE LABEL HERE\". This bar code is the doctor's \n\nreference number used at the analysing laboratory as a patient identifier; the two spare bar \n\ncode labels are for the doctor's use on the patient notes/files etc. \n\n \n\nAfter placing the four sample tubes and paperwork into the box, use the security label \n\nprovided to seal the lid of the box, and send to a qualified laboratory for analysis. \n\n \n\nThe optimal test meal recommended is 200 ml pure undiluted orange juice. \n\n \n\n\n\n \n\n6 \n\n \n\nAnalysis of breath samples and testing specification \n\n \n\nThe accuracy and precision of the test depends heavily on the quality of the analysis and \n\ntherefore only laboratories having appropriate certification are considered qualified to analyse \n\nthe breath samples. \n\n \n\nSatisfactory specificity and sensitivity have been demonstrated in clinical studies where \n\nbreath was analysed using isotope ratio mass spectrometry (IRMS). \n\n \n\nBreath samples collected during a test must remain in the original containers before analysis \n\nby IRMS. \n\n \n\nIRMS instruments may be of continuous flow or dual inlet configuration. \n\n \n\nA multi-position autosampler and bar code reader should be used to allow samples to be \n\ntracked throughout the analysis. \n\n \n\nIRMS source parameters and tuning must be optimised daily. \n\n \n\nInstruments must be linear over a wide range of CO2 concentrations, typically 1.0 - 6.0%. \n\nThis should be checked routinely. \n\n \n\nInternal analytical precision must be less than + 0.3 ‰ 13C for 20 replicate analyses of the \n\nsame reference gas sample and remain within 3SD’s of the mean for breath analyses. \n\n \n\nTransfer of the breath sample through the analytical system must be accomplished without \n\nisotope fractionation. \n\n \n\nThe IRMS must possess a triple collector to allow the simultaneous detection of the ions at \n\nmass/charge ratio 44, 45 and 46 fluctuations in the oxygen isotope content. \n\n \n\nThere must be provision for correction of instrumental drift during an analysis. \n\n \n\nReference gases must be standardised against an appropriate international standard to allow \n\ninter-laboratory comparison of results. \n\n \n\nAlternatively, any other suitably-validated method may be used, carried out by any \n\nobjectively qualified laboratory. \n\n \n\nExplanation of results:- \n\n \n\n 13C:- Difference in parts per thousand (‰) with respect to an accepted international \n\nstandard. \n\nExcess 13C:- Difference between pre- and post-urea sample measurements. \n\n \n\nH. pylori status: -< 3.5 excess 13C = Negative \n\n > 3.5 excess 13C = Positive \n\n \n\n \n\n \n\n7. MARKETING AUTHORISATION HOLDER \n\n \n\nTorbet Laboratories Ireland Limited \n\n\n\n \n\n7 \n\n20 Holles Street \n\nDublin 2 \n\nIreland \n\n \n\n+44 (0)1953 607856 \n\n+44 (0)1953 713649 \n\nenquiries@torbetlaboratories.co.uk \n\n \n\n \n\n8. MARKETING AUTHORISATION NUMBER \n\n \n\nEU/1/98/064/001 \n\n \n\n \n\n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n\n \n\nDate of first authorisation: 07 May 1998 \n\nDate of latest renewal: 07 May 2008 \n\n \n\n \n\n \n\n10. DATE OF REVISION OF THE TEXT \n\n \n\n \n\n \n\n \n\nDetailed information on this medicinal product is available on the website of the European \n\nMedicines Agency http://www.ema.europa.eu. \n\n \n\n \n\n \n\n \n\nhttp://www.ema.europa.eu/\n\n\n \n\n8 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX II \n\n \n\nA. MANUFACTURER RESPONSIBLE FOR BATCH \n\nRELEASE \n\n \n\nB. CONDITIONS OR RESTRICTIONS REGARDING \n\nSUPPLY AND USE \n\n \n\nC. OTHER CONDITIONS AND REQUIRMENTS OF \n\nTHE MARKETING AUTHORISATION \n\n \n\nD. CONDITIONS OR RESTRICTIONS WITH \n\nREGARD TO THE SAFE AND EFFECTIVE USE OF \n\nTHE MEDICINAL PRODUCT \n\n \n\n \n\n\n\n \n\n9 \n\n \n\nA. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE \n\n \n\nName and address of the manufacturer responsible for batch release \n\n \n\nIdifarma Desarrollo Farmaceutico S.L. \n\nPolígono Mocholí \n\nC/ Noáin, No.1 \n\n31110 Noáin \n\nNavarra, \n\nSpain \n\n \n\n \n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n\n \n\nMedicinal product subject to medical prescription \n\n \n\n \n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n\n \n\n• Periodic Safety Update Reports \n \n\nThe requirements for submission of periodic safety update reports for this medicinal product \n\nare set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) \n\nof Directive 2001/83/EC and any subsequent updates published on the European medicines \n\nweb-portal. \n\n \n\n \n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n\n \n\nNot applicable \n\n \n\n \n\n \n\n \n\n\n\n \n\n10 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX III \n\n \n\nLABELLING AND PACKAGE LEAFLET \n\n\n\n \n\n11 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nA. LABELLING\n\n\n\n \n\n12 \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n\n \n\nOUTER CARTON/CARDBOARD BOX \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nPylobactell, 100 mg, soluble tablet \n13C-urea \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nOne tablet contains: 100 mg 13C-urea \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\nPovidone (E1201), Microcrystalline Cellulose (E460i), Colloidal Anhydrous Silica, Sodium \n\nBenzoate (E211). \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\nThe kit contains: \n\n \n\nA sachet containing one Pylobactell 100 mg soluble tablet. \n\nSix glass tubes, with caps and bar code labels. \n\n30 ml mixing and administration glass vial with cap. \n\nTwo straws. \n\nPackage Leaflet. \n\nAnalysis Request Form. \n\nSecurity Label and three additional bar code labels. \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nDiagnostic test kit \n\nFOR ORAL ADMINISTRATION \n\nRead the package leaflet before use. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE \n\nSTORED OUT OF THE SIGHT AND REACH OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP: {MM/YYYY} \n\n \n\n \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\n\n\n \n\n13 \n\nDo not store above 25C \n\n \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nTorbet Laboratories Ireland Ltd, 20 Holles Street, Dublin 2, Ireland. \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/98/064/001 \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nBN \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\nMedicinal product subject to medical prescription. \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nPylobactell \n\n \n\n17. UNIQUE IDENTIFIER – 2D BARCODE \n\n \n\nNot applicable \n\n \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n\n \n\nNot applicable \n\n \n\n \n\n \n\n \n\n \n\n\n\n \n\n14 \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING \n\nUNITS \n\n \n\nSACHET LABEL \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF \n\nADMINISTRATION \n\n \n\nPylobactell, 100 mg, soluble tablet \n13C-urea \n\nOral \n\n \n\n \n\n2. METHOD OF ADMINISTRATION \n\n \n\nTo be dissolved in water and taken orally. Read the package leaflet before use. \n\n \n\n3. EXPIRY DATE \n\n \n\nEXP {MM/YYYY} \n\n \n\n4. BATCH NUMBER \n\n \n\nBatch \n\n \n\n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n\n \n\nOne tablet \n\n \n\n6. OTHER \n\n \n\nTorbet Laboratories Ireland Limited, 20 Holles Street, Dublin 2, Ireland. \n\n \n\nEU/1/98/064/001 \n\n \n\n \n\n\n\n \n\n15 \n\n \n\nADDITIONAL KIT ITEM: MIXING AND ADMINISTRATION VIAL \n\n \n\nLABEL \n\n \n\nFill to line with water \n\nDissolve tablet from sachet \n\nShake well to dissolve \n\nWhen dissolved, drink entire contents \n\nRefill with water to line, shake bottle and drink \n\nDiscard this bottle after use \n\nDo not return with kit \n\n \n\n \n\nADDITIONAL KIT ITEM: SECURITY LABEL \n\n \n\nLABEL \n\n \n\nSeal lid of box before returning samples for analysis \n\n \n\n \n\n \n\n \n\n \n\n\n\n \n\n16 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nB. PACKAGE LEAFLET\n\n\n\n \n\n17 \n\nPACKAGE LEAFLET: INFORMATION FOR THE USER \n\n \n\nPylobactell 100mg soluble tablet \n13C-Urea \n\n \n\nRead all of this leaflet carefully before you start using this medicine because it contains \n\nimportant information for you. \n\n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor, pharmacist or nurse. \n- This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even \n\nif their symptoms are the same as yours.If you get any side effects, talk to your doctor, \n\npharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section \n\n4. \n\n \n\n \n\nWhat is in this leaflet: \n\n1. What Pylobactell is and what it is used for \n\n2. What you need to know before you use Pylobactell \n\n3. How to use Pylobactell \n\n4. Possible side effects \n\n5. How to store Pylobactell \n6. Contents of the pack and other information \n\n \n\n \n\n1. WHAT PYLOBACTELL IS AND WHAT IT IS USED FOR \n \n\nPylobactell is a breath test for determining the presence of the bacterium, Helicobacter pylori (H. \n\npylori) in the gut (stomach and adjacent bowel) which may be the reason for your stomach (gastric) \n\ncondition. \n\n \n\nYour doctor has recommended that you have a 13C-Urea breath test, for one of the following reasons: \n\n• Your doctor wants to confirm whether you are suffering from H. pylori infection to help diagnose \nyour condition. \n\n• You have already been diagnosed with H. pylori and have been taking medication aimed to clear \nup the infection. Your doctor now wants to find out if the treatment has worked. \n\n \n\nThis medicine is for diagnostic use only. \n\n \n\nHow does the test work? \n\nAll foods contain a substance called carbon 13 (13C), in varying amounts. This 13C can be detected in \n\nthe carbon dioxide that you breathe out of your lungs. The actual amount of 13C in the breath will \n\ndepend on the type of food that you have eaten. \n\n \n\nYou will be asked to drink a \"test meal\". This will help keep the test 13C-urea solution in your \n\nstomach. \n\n \n\nFollowing the meal, 3 samples of your breath will be taken. These samples will be analysed to \n\nmeasure the normal amount of 13C in the carbon dioxide in your breath. \n\n \n\nYou will then drink the Pylobactell 13C-urea solution. If H. pylori is present and active in your \n\nstomach, these bacteria will break down the 13C-urea and this is detected in the carbon dioxide in your \n\nbreath. \n\nA further 3 samples of your breath will then be taken 30 minutes later. \n\n \n\nThe amount of 13C in these samples will be compared to your normal level. If there is a significant \n\nincrease in the amount of 13C, this will let your doctor know that active H. pylori is present. \n\n \n\n\n\n \n\n18 \n\n2. WHAT YOU NEED TO KNOW BEFORE YOU USE PYLOBACTELL \n \n\nDO NOT use Pylobactell if you: \n\n- are allergic to 13C-urea or to any of the other ingredients of this medicine (listed in Section 6). \n\n- suffer from any medical condition that you think may affect, or be affected by, the test. \n\n \n\nWarnings and precautions \n\nTalk to your doctor, pharmacist or nurse before using Pylobactell if: \n\n• part of your stomach has been removed (partial gastrectomy) as the reliability of the test has \n\nnot been proven in these patients \n\n• you have or suspect you have a gastric infection \n\n• you have long term stomach problems (atrophic gastritis) as the breath test may give the \n\nwrong result and other tests may be required to confirm the presence of H. pylori. \n\n• fasting (not taking food) may have medical implications for you \n\n• you are under 18 years. \n \n\nOther medicines and Pylobactell \n\nPlease tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any \n\nother medicines, including medicines obtained without a prescription. \n\n \n\nDo not take the test if: \n\n \n\n• You have taken antibiotics or medication to treat Helicobacter pylori within the last 28 days \n\n \n\n• You have taken proton pump inhibitors in the last 14 days \n\n \n\n• You have taken H2 antagonists or antacids on the same day of the test. \n\n \n\nDo not stop taking medication without the advice of your doctor. \n\n \n\nTaking Pylobactell with food and drink \n\nYou should fast for at least 4 hours before the test so that the test is taken on an empty stomach. If you \n\nhave eaten a heavy meal it will be necessary to fast for six hours before the test. \n\nYou can drink water during the fasting period. \n\nIf fasting is a problem e.g. for diabetic patients, please tell your doctor, pharmacist or nurse. \n\n \n\nPregnancy and breast-feeding \n\nPylobactell can be used during pregnancy and breast-feeding. \n\n \n\nDriving and using machines \n\nThis test should not affect your ability to drive or use machines. \n\n \n\n3. HOW TO USE PYLOBACTELL \n \n\nAlways use this medicine exactly as your doctor, pharmacist or nurse has told you. Check with your \n\ndoctor, pharmacist or nurse if you are not sure. \n\n \n\nThe test will take about 45 minutes. A supply of drinking water will be needed. \n\nIt is recommended that the breath test is performed while you are in a seated position. \n\nYou must not smoke before or during the test. \n\n \n\nThe test procedure involves the following steps: \n\n(A brief form of these instructions is included on the back of the Analysis Request Form) \n\n \n\n1. Fasting: \n\nYou should fast for 4 hours before taking the test (See Section 2 Taking Pylobactell with food \n\nand drink) \n\n\n\n \n\n19 \n\n \n\n2. Test Meal: \n\nDrink the recommended test meal. This is not included in this kit but may have been supplied \n\nseparately. If no test meal has been supplied, the most suitable test meal is 200 ml of pure \n\nundiluted orange juice. If you cannot take the recommended test meal, an alternative test meal \n\nshould be taken. Your doctor will advise you. \n\n \n\n3. Wait 5 minutes \n\n \n\n4. Pre-test Breath Samples (3 White Capped Tubes) \n\n \n\n i. Remove the cap from the tube \n\n ii. Breathe out through your mouth, using a straw, into the sample tube. \n\n iii. Gradually remove the straw from the tube as you breathe out. \n\n iv. Immediately replace the cap. \n\n v. Repeat with remaining white capped tubes. \n\n \n\n It is not necessary to blow hard into the tubes, just breathe normally and cap them quickly. \n\n Try to avoid getting saliva in the tubes. \n\n \n\n5. Preparing the 13Carbon-urea solution \n\n Open the tablet sachet and empty the tablet into the mixer vial. \n\n Add water to the mark on the vial and replace the cap. \n\n Gently shake the vial to dissolve the tablet. \n\n Drink the solution. Note the time upon drinking. \n\n Fill the vial to the mark again with water and drink. \n\n \n\n6. Wait 30 minutes from the time of drinking the Pylobactell 13C-urea solution. Do not smoke, \n\neat or drink during this time. This is important for the proper functioning of the test. \n\n \n\n7. Post-test Breath Samples (3 Red Capped Tubes) \n\n Using the red-capped, take samples of your breath as before (see step 4). \n\n \n\n8. Analysis Request Form \n\n Fill out the analysis request form with patient details on the left hand side of the form and the \n\ndoctor’s name and address on the right hand side. \n\n \n\n9. Test is now complete \n\n Put your breath samples and the completed Analysis Request Form back into the carton and \n\nsend to the address supplied by your doctor. Your doctor will tell you when the results of your \n\ntest will be available and who to contact for these results. \n\n \n\nDispose of the empty sachet, mixing vial and straws as normal waste, but keep this leaflet for \n\nreference. \n\n \n\nIf a repeat test is required, it should not be carried out until the following day. \n\nIf you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. \n\n \n\n \n\n4. POSSIBLE SIDE EFFECTS \n\n \n\nNo side effects to Pylobactell have been reported. 13C and urea are harmless naturally occurring \n\nsubstances which are found in your body. \n\n \n\nReporting of side effects \n\nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \n\neffects not listed in this leaflet. You can also report side effects directly via the national reporting \n\n\n\n \n\n20 \n\nsystem listed in Appendix V. By reporting side effects you can help provide more information on the \n\nsafety of this medicine. \n\n \n\n \n\n5. HOW TO STORE PYLOBACTELL \n\n \n\nKeep out of the sight and reach of children. \n\nDo not store the kit above 25°C. \n\nThe tablet must be taken when dissolved. \n\nDo not use Pylobactell after the expiry date which is stated on the carton after EXP. The expiry date \n\nrefers to the last day of that month. \n\n \n\n6. CONTENTS OF THE PACK AND OTHER INFORMATION \n\n \n\nWhat the Pylobactell tablet contains \n\n \n\n- The active substance is 13C-urea. Each tablet contains 100 mg of 13C-urea \n- The other ingredients are povidone (E1201), microcrystalline cellulose (E460i), colloidal \n\nanhydrous silica and sodium benzoate (E211). \n\n \n\nEach Pylobactell Breath Test kit contains: \n\n• 1 Sachet containing 1 tablet. \n\n• 6 glass tubes, 3 with white caps and 3 with red caps. \n\n• 30 ml glass mixing tube with cap. \n\n• 2 straws. \n\n• Package Leaflet \n\n• Analysis Request Form. \n\n• Security Label and 3 additional bar code labels. \n \n\nThe contents of this kit are sufficient for a single test. If you need to repeat the test, a new kit will be \n\nrequired and it should not be carried out until the following day. \n\n \n\nMarketing Authorisation Holder \n\n \n\nTorbet Laboratories Ireland Limited, 20 Holles Street, Dublin 2, Ireland \n\nTel. +44 (0)1953 607856 \n\nFax. +44 (0)1953 713649 \n\nE-mail enquiries@torbetlaboratories.co.uk \n\n \n\n \n\n \n\nManufacturer \n\n \n\nIdifarma Desarrollo Farmaceutico S.L., Polígono Mocholí, C/ Noáin, No.1, 31110 Noáin, Navarra, , \n\nSpain. \n\n \n\nFor any information about this medicine, please contact the Marketing Authorisation Holder: \n\n \n\nThis leaflet was last revised in \n\n \n\nDetailed information on this medicine is available on the European Medicines Agency web site: \n\nhttp://www.ema.europa.eu. \n\n \n\n \n\n \n\n \n\n \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n \n\n21 \n\n \n\nAnalysis of breath samples and testing specification \n\n \n\nThe accuracy and precision of the test depends heavily on the quality of the analysis and therefore only \n\nlaboratories having appropriate certification are considered qualified to analyse the breath samples. \n\n \n\nSatisfactory specificity and sensitivity have been demonstrated in clinical studies where breath was \n\nanalysed using isotope ratio mass spectrometry (IRMS). \n\n \n\nBreath samples collected during a test must remain in the original containers before analysis by IRMS. \n\n \n\nIRMS instruments may be of continuous flow or dual inlet configuration. \n\n \n\nA multi-position autosampler and bar code reader should be used to allow samples to be tracked \n\nthroughout the analysis. \n\n \n\nIRMS source parameters and tuning must be optimised daily. \n\n \n\nInstruments must be linear over a wide range of CO2 concentrations, typically 1.0 - 6.0%. This should \n\nbe checked routinely. \n\n \n\nInternal analytical precision must be less than + 0.3 ‰ 13C for 20 replicate analyses of the same \n\nreference gas sample and remain within 3SD’s of the mean for breath analyses. \n\n \n\nTransfer of the breath sample through the analytical system must be accomplished without isotope \n\nfractionation. \n\n \n\nThe IRMS must possess a triple collector to allow the simultaneous detection of the ions at \n\nmass/charge ratio 44, 45 and 46 to allow for fluctuations in the oxygen isotope content. \n\n \n\nThere must be provision for correction of instrumental drift during an analysis. \n\n \n\nReference gases must be standardised against an appropriate international standard to allow inter-\n\nlaboratory comparison of results. \n\n \n\nAlternatively, any other suitably-validated method may be used, carried out by any objectively \n\nqualified laboratory. \n\n \n\nExplanation of results:- \n\n \n\n 13C:- Difference in parts per thousand (‰) with respect to an accepted international \n\nstandard \n\nExcess 13C:- Difference between pre- and post-urea sample measurements \n\n \n\nH. pylori status: - < 3.5 excess 13C = Negative \n\n > 3.5 excess 13C = Positive \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n\n\n \n\n22 \n\nANALYSIS REQUEST FORM: \n\n \n\nPylobactell [13Carbon] -UREA BREATH TEST (13C-UBT) for Helicobacter pylori \n\n \n\nANALYSIS REQUEST FORM - Please complete in block capitals \n\nPlease state clearly address for return of results: \n\nCentre: \n\nPatient Name: \n\nDate of Birth: \n\nPatient Reference: \n\nDate of Test: \n\nReferring Doctor: \n\n \n\nAFFIX BAR-CODE LABEL HERE \n\nPLEASE PLACE BAR-CODE LABEL ON PATIENT RECORDS, IF APPLICABLE \n\n \n\nM.A. Number: EU/1/98/064/001 \n\nMarketing Authorisation Holder: Torbet Laboratories Ireland Limited, 20 Holles Street, Dublin 2, \n\nIreland \n\n \nMEDICATION RECORD TEST CHECK LIST \nMedical History - has the patient \ntaken : \n \n\nType \n&Date \n\nMins \n \n\nTest Check List Time \n \n\n(i) antibiotics in the last 28 days? \nIf so, please indicate type and \nwhen last taken \n\n t = 0 \n \n\nNote time patient drinks test \nmeal \n \n\n \n\n \n(ii) proton pump inhibitors (PPIs) \nin the last 14 days? \nIf so, please indicate type and \nwhen last taken. \n \n\n t = 5 \n \n\nCollect Pre-Urea samples \n(White Caps - 3 times) \n \n\n \n\n(iii) eradication therapy in the last \n28 days? \nIf so, please indicate when \ntreatment ended \n\n t = 10 \n \n\nPatient to drink urea solution, \nthen fill bottle to line again and \ndrink. \n\n \n\n \n(iv) other medication (if \napplicable) \n \n\n t = 40 \n \n\nCollect Post-Urea samples (Red \nCaps - 3 times). \n \n\n \n\n(v) patient fasted for hours \n \nPlease note that (i) - (iii) will affect \nresult of test. \n\n Check Bar-code label and all details \nentered on Analysis Request \nForm. \n1 x Pre/Post sample reserved in \nstore. \n2 x Pre/Post samples + this \nform for return to a qualified \nlaboratory. \n\n \n\nLaboratory use only \nDate received: \nAnalytical file reference: \nLaboratory code: \nSamples logged on by : \n\n \nComments: \n \n\n \n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. PACKAGE LEAFLET"},"Section_1":{"kind":"string","value":"{'Title': '1. what pylobactell is and what it is used for', 'Section_Content': 'pylobactell is a breath test for determining the presence of the bacterium, helicobacter pylori (h. pylori) in the gut (stomach and adjacent bowel) which may be the reason for your stomach (gastric) condition. your doctor has recommended that you have a 13c-urea breath test, for one of the following reasons: your doctor wants to confirm whether you are suffering from h. pylori infection to help diagnose your condition. you have already been diagnosed with h. pylori and have been taking medication aimed to clear up the infection. your doctor now wants to find out if the treatment has worked. this medicine is for diagnostic use only. how does the test work? all foods contain a substance called carbon 13 (13c), in varying amounts. this 13c can be detected in the carbon dioxide that you breathe out of your lungs. the actual amount of 13c in the breath will depend on the type of food that you have eaten. you will be asked to drink a \"test meal\". this will help keep the test 13c-urea solution in your stomach. following the meal, 3 samples of your breath will be taken. these samples will be analysed to measure the normal amount of 13c in the carbon dioxide in your breath. you will then drink the pylobactell 13c-urea solution. if h. pylori is present and active in your stomach, these bacteria will break down the 13c-urea and this is detected in the carbon dioxide in your breath. a further 3 samples of your breath will then be taken 30 minutes later. the amount of 13c in these samples will be compared to your normal level. if there is a significant increase in the amount of 13c, this will let your doctor know that active h. pylori is present.', 'Entity_Recognition': [{'Text': 'pylobactell', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'a breath test', 'Type': 'TEST', 'BeginOffset': 15, 'EndOffset': 28}, {'Text': 'the bacterium', 'Type': 'PROBLEM', 'BeginOffset': 61, 'EndOffset': 74}, {'Id': 13, 'BeginOffset': 76, 'EndOffset': 95, 'Score': 0.7416208982467651, 'Text': 'helicobacter pylori', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8721893429756165}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9456746578216553, 'RelationshipScore': 0.6997143030166626, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 0, 'BeginOffset': 115, 'EndOffset': 118, 'Text': 'gut', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.975690484046936, 'RelationshipScore': 0.6012564301490784, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 1, 'BeginOffset': 120, 'EndOffset': 127, 'Text': 'stomach', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'h. pylori', 'Type': 'PROBLEM', 'BeginOffset': 97, 'EndOffset': 106}, {'Id': 0, 'BeginOffset': 115, 'EndOffset': 118, 'Score': 0.9456746578216553, 'Text': 'gut', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 1, 'BeginOffset': 120, 'EndOffset': 127, 'Score': 0.975690484046936, 'Text': 'stomach', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 3, 'BeginOffset': 141, 'EndOffset': 146, 'Score': 0.9506751298904419, 'Text': 'bowel', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'your stomach (gastric) condition', 'Type': 'PROBLEM', 'BeginOffset': 176, 'EndOffset': 208}, {'Text': 'a 13c-urea breath test', 'Type': 'TEST', 'BeginOffset': 252, 'EndOffset': 274}, {'Text': 'h. pylori infection', 'Type': 'PROBLEM', 'BeginOffset': 370, 'EndOffset': 389}, {'Id': 15, 'BeginOffset': 460, 'EndOffset': 469, 'Score': 0.6433541178703308, 'Text': 'h. pylori', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8212570548057556}]}, {'Text': 'medication', 'Type': 'TREATMENT', 'BeginOffset': 491, 'EndOffset': 501}, {'Text': 'the infection', 'Type': 'PROBLEM', 'BeginOffset': 520, 'EndOffset': 533}, {'Text': 'the treatment', 'Type': 'TREATMENT', 'BeginOffset': 572, 'EndOffset': 585}, {'Text': '13', 'Type': 'NUMBER', 'BeginOffset': 708, 'EndOffset': 710}, {'Text': 'the carbon dioxide', 'Type': 'TREATMENT', 'BeginOffset': 766, 'EndOffset': 784}, {'Id': 5, 'BeginOffset': 814, 'EndOffset': 819, 'Score': 0.9860138893127441, 'Text': 'lungs', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'the test 13c', 'Type': 'TEST', 'BeginOffset': 975, 'EndOffset': 987}, {'Text': 'urea solution', 'Type': 'TREATMENT', 'BeginOffset': 988, 'EndOffset': 1001}, {'Id': 6, 'BeginOffset': 1010, 'EndOffset': 1017, 'Score': 0.9471197128295898, 'Text': 'stomach', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 1039, 'EndOffset': 1040}, {'Text': 'your breath', 'Type': 'TEST', 'BeginOffset': 1052, 'EndOffset': 1063}, {'Text': 'these samples', 'Type': 'TEST', 'BeginOffset': 1079, 'EndOffset': 1092}, {'Text': 'the carbon dioxide', 'Type': 'TREATMENT', 'BeginOffset': 1149, 'EndOffset': 1167}, {'Text': 'the pylobactell 13c-urea solution', 'Type': 'TREATMENT', 'BeginOffset': 1204, 'EndOffset': 1237}, {'Text': 'h. pylori', 'Type': 'PROBLEM', 'BeginOffset': 1242, 'EndOffset': 1251}, {'Text': 'active in your stomach', 'Type': 'PROBLEM', 'BeginOffset': 1267, 'EndOffset': 1289}, {'Text': 'these bacteria', 'Type': 'PROBLEM', 'BeginOffset': 1291, 'EndOffset': 1305}, {'Id': 12, 'BeginOffset': 1330, 'EndOffset': 1334, 'Score': 0.4822997748851776, 'Text': 'urea', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the carbon dioxide', 'Type': 'TREATMENT', 'BeginOffset': 1359, 'EndOffset': 1377}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 1404, 'EndOffset': 1405}, {'Text': 'your breath', 'Type': 'PROBLEM', 'BeginOffset': 1417, 'EndOffset': 1428}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 1448, 'EndOffset': 1450}, {'Text': 'these samples', 'Type': 'TEST', 'BeginOffset': 1487, 'EndOffset': 1500}, {'Text': 'active h. pylori', 'Type': 'PROBLEM', 'BeginOffset': 1633, 'EndOffset': 1649}]}"},"Section_2":{"kind":"string","value":"{'Title': '2. what you need to know before you use pylobactell', 'Section_Content': 'do not use pylobactell if you: - are allergic to 13c-urea or to any of the other ingredients of this medicine (listed in section 6). - suffer from any medical condition that you think may affect, or be affected by, the test. warnings and precautions talk to your doctor, pharmacist or nurse before using pylobactell if: part of your stomach has been removed (partial gastrectomy) as the reliability of the test has not been proven in these patients you have or suspect you have a gastric infection you have long term stomach problems (atrophic gastritis) as the breath test may give the wrong result and other tests may be required to confirm the presence of h. pylori. fasting (not taking food) may have medical implications for you you are under 18 years. other medicines and pylobactell please tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription. do not take the test if: you have taken antibiotics or medication to treat helicobacter pylori within the last 28 days you have taken proton pump inhibitors in the last 14 days you have taken h2 antagonists or antacids on the same day of the test. do not stop taking medication without the advice of your doctor. taking pylobactell with food and drink you should fast for at least 4 hours before the test so that the test is taken on an empty stomach. if you have eaten a heavy meal it will be necessary to fast for six hours before the test. you can drink water during the fasting period. if fasting is a problem e.g. for diabetic patients, please tell your doctor, pharmacist or nurse. pregnancy and breast-feeding pylobactell can be used during pregnancy and breast-feeding. driving and using machines this test should not affect your ability to drive or use machines.', 'Entity_Recognition': [{'Text': 'pylobactell', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 3, 'BeginOffset': 11, 'EndOffset': 22, 'Score': 0.8098122477531433, 'Text': 'pylobactell', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.837586522102356}]}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 37, 'EndOffset': 45}, {'Text': 'urea', 'Type': 'TREATMENT', 'BeginOffset': 53, 'EndOffset': 57}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 96, 'EndOffset': 109}, {'Text': 'any medical condition', 'Type': 'PROBLEM', 'BeginOffset': 147, 'EndOffset': 168}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 215, 'EndOffset': 223}, {'Id': 0, 'BeginOffset': 333, 'EndOffset': 340, 'Score': 0.8689616918563843, 'Text': 'stomach', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 16, 'BeginOffset': 359, 'EndOffset': 378, 'Score': 0.8602114915847778, 'Text': 'partial gastrectomy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'PROCEDURE_NAME', 'Traits': []}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 402, 'EndOffset': 410}, {'Text': 'a gastric infection', 'Type': 'PROBLEM', 'BeginOffset': 478, 'EndOffset': 497}, {'Text': 'long term stomach problems', 'Type': 'PROBLEM', 'BeginOffset': 507, 'EndOffset': 533}, {'Id': 11, 'BeginOffset': 535, 'EndOffset': 553, 'Score': 0.89921635389328, 'Text': 'atrophic gastritis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8434075117111206}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9264009594917297, 'RelationshipScore': 0.8690347075462341, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 1, 'BeginOffset': 517, 'EndOffset': 524, 'Text': 'stomach', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'the breath test', 'Type': 'TEST', 'BeginOffset': 558, 'EndOffset': 573}, {'Text': 'other tests', 'Type': 'TEST', 'BeginOffset': 604, 'EndOffset': 615}, {'Text': 'h. pylori', 'Type': 'PROBLEM', 'BeginOffset': 659, 'EndOffset': 668}, {'Text': '18', 'Type': 'NUMBER', 'BeginOffset': 748, 'EndOffset': 750}, {'Text': 'other medicines', 'Type': 'TREATMENT', 'BeginOffset': 758, 'EndOffset': 773}, {'Id': 4, 'BeginOffset': 778, 'EndOffset': 789, 'Score': 0.5089054703712463, 'Text': 'pylobactell', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'any other medicines', 'Type': 'TREATMENT', 'BeginOffset': 888, 'EndOffset': 907}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 919, 'EndOffset': 928}, {'Id': 19, 'BeginOffset': 1002, 'EndOffset': 1013, 'Score': 0.6712141036987305, 'Text': 'antibiotics', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'medication', 'Type': 'TREATMENT', 'BeginOffset': 1017, 'EndOffset': 1027}, {'Id': 12, 'BeginOffset': 1037, 'EndOffset': 1056, 'Score': 0.8685731887817383, 'Text': 'helicobacter pylori', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8579849600791931}]}, {'Id': 23, 'BeginOffset': 1068, 'EndOffset': 1080, 'Score': 0.9996623992919922, 'Text': 'last 28 days', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'DX_NAME', 'Score': 0.8685731887817383, 'RelationshipScore': 0.7722228765487671, 'RelationshipType': 'OVERLAP', 'Id': 12, 'BeginOffset': 1037, 'EndOffset': 1056, 'Text': 'helicobacter pylori', 'Category': 'MEDICAL_CONDITION', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8579849600791931}]}]}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 1073, 'EndOffset': 1075}, {'Id': 20, 'BeginOffset': 1096, 'EndOffset': 1118, 'Score': 0.9536504745483398, 'Text': 'proton pump inhibitors', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 24, 'BeginOffset': 1126, 'EndOffset': 1138, 'Score': 0.9995330572128296, 'Text': 'last 14 days', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_TREATMENT_NAME', 'Traits': [], 'Attributes': [{'Type': 'TREATMENT_NAME', 'Score': 0.9536504745483398, 'RelationshipScore': 0.8971474170684814, 'RelationshipType': 'OVERLAP', 'Id': 20, 'BeginOffset': 1096, 'EndOffset': 1118, 'Text': 'proton pump inhibitors', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': '14', 'Type': 'NUMBER', 'BeginOffset': 1131, 'EndOffset': 1133}, {'Id': 21, 'BeginOffset': 1154, 'EndOffset': 1180, 'Score': 0.5216602087020874, 'Text': 'h2 antagonists or antacids', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Id': 25, 'BeginOffset': 1188, 'EndOffset': 1196, 'Score': 0.7497363686561584, 'Text': 'same day', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_TREATMENT_NAME', 'Traits': [], 'Attributes': [{'Type': 'TREATMENT_NAME', 'Score': 0.5216602087020874, 'RelationshipScore': 0.8571357131004333, 'RelationshipType': 'OVERLAP', 'Id': 21, 'BeginOffset': 1154, 'EndOffset': 1180, 'Text': 'h2 antagonists or antacids', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 1200, 'EndOffset': 1208}, {'Text': 'medication', 'Type': 'TREATMENT', 'BeginOffset': 1229, 'EndOffset': 1239}, {'Id': 8, 'BeginOffset': 1282, 'EndOffset': 1293, 'Score': 0.8689587712287903, 'Text': 'pylobactell', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 1343, 'EndOffset': 1344}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 1358, 'EndOffset': 1366}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 1375, 'EndOffset': 1383}, {'Id': 2, 'BeginOffset': 1405, 'EndOffset': 1412, 'Score': 0.8374875783920288, 'Text': 'stomach', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 1495, 'EndOffset': 1503}, {'Id': 13, 'BeginOffset': 1585, 'EndOffset': 1593, 'Score': 0.8031885623931885, 'Text': 'diabetic', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7500413060188293}]}, {'Id': 14, 'BeginOffset': 1650, 'EndOffset': 1659, 'Score': 0.9545457363128662, 'Text': 'pregnancy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9317742586135864}]}, {'Text': 'breast-feeding pylobactell', 'Type': 'TREATMENT', 'BeginOffset': 1664, 'EndOffset': 1690}, {'Id': 15, 'BeginOffset': 1710, 'EndOffset': 1719, 'Score': 0.9394713044166565, 'Text': 'pregnancy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9204466938972473}]}, {'Text': 'breast-feeding', 'Type': 'TREATMENT', 'BeginOffset': 1724, 'EndOffset': 1738}]}"},"Section_3":{"kind":"string","value":"{'Title': '3. how to use pylobactell', 'Section_Content': \"always use this medicine exactly as your doctor, pharmacist or nurse has told you. check with your doctor, pharmacist or nurse if you are not sure. the test will take about 45 minutes. a supply of drinking water will be needed. it is recommended that the breath test is performed while you are in a seated position. you must not smoke before or during the test. the test procedure involves the following steps: (a brief form of these instructions is included on the back of the analysis request form) 1. fasting: you should fast for 4 hours before taking the test (see section 2 taking pylobactell with food and drink) 19 2. test meal: drink the recommended test meal. this is not included in this kit but may have been supplied separately. if no test meal has been supplied, the most suitable test meal is 200 ml of pure undiluted orange juice. if you cannot take the recommended test meal, an alternative test meal should be taken. your doctor will advise you. 3. wait 5 minutes 4. pre-test breath samples (3 white capped tubes) i. remove the cap from the tube ii. breathe out through your mouth, using a straw, into the sample tube. iii. gradually remove the straw from the tube as you breathe out. iv. immediately replace the cap. v. repeat with remaining white capped tubes. it is not necessary to blow hard into the tubes, just breathe normally and cap them quickly. try to avoid getting saliva in the tubes. 5. preparing the 13carbon-urea solution open the tablet sachet and empty the tablet into the mixer vial. add water to the mark on the vial and replace the cap. gently shake the vial to dissolve the tablet. drink the solution. note the time upon drinking. fill the vial to the mark again with water and drink. 6. wait 30 minutes from the time of drinking the pylobactell 13c-urea solution. do not smoke, eat or drink during this time. this is important for the proper functioning of the test. 7. post-test breath samples (3 red capped tubes) using the red-capped, take samples of your breath as before (see step 4). 8. analysis request form fill out the analysis request form with patient details on the left hand side of the form and the doctor's name and address on the right hand side. 9. test is now complete put your breath samples and the completed analysis request form back into the carton and send to the address supplied by your doctor. your doctor will tell you when the results of your test will be available and who to contact for these results. dispose of the empty sachet, mixing vial and straws as normal waste, but keep this leaflet for reference. if a repeat test is required, it should not be carried out until the following day. if you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.\", 'Entity_Recognition': [{'Text': 'pylobactell', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 148, 'EndOffset': 156}, {'Text': '45', 'Type': 'NUMBER', 'BeginOffset': 173, 'EndOffset': 175}, {'Text': 'the breath test', 'Type': 'TEST', 'BeginOffset': 251, 'EndOffset': 266}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 352, 'EndOffset': 360}, {'Text': 'the test procedure', 'Type': 'TREATMENT', 'BeginOffset': 362, 'EndOffset': 380}, {'Text': '1.', 'Type': 'NUMBER', 'BeginOffset': 501, 'EndOffset': 503}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 533, 'EndOffset': 534}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 577, 'EndOffset': 578}, {'Text': '19', 'Type': 'NUMBER', 'BeginOffset': 619, 'EndOffset': 621}, {'Text': '2.', 'Type': 'NUMBER', 'BeginOffset': 622, 'EndOffset': 624}, {'Text': '200', 'Type': 'NUMBER', 'BeginOffset': 807, 'EndOffset': 810}, {'Text': 'test meal', 'Type': 'TREATMENT', 'BeginOffset': 881, 'EndOffset': 890}, {'Text': 'an alternative test meal', 'Type': 'TEST', 'BeginOffset': 892, 'EndOffset': 916}, {'Text': '3.', 'Type': 'NUMBER', 'BeginOffset': 963, 'EndOffset': 965}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 971, 'EndOffset': 972}, {'Text': '4.', 'Type': 'NUMBER', 'BeginOffset': 981, 'EndOffset': 983}, {'Text': 'pre-test breath samples', 'Type': 'TEST', 'BeginOffset': 984, 'EndOffset': 1007}, {'Text': '3 white capped tubes)', 'Type': 'TREATMENT', 'BeginOffset': 1009, 'EndOffset': 1030}, {'Text': 'the cap', 'Type': 'TREATMENT', 'BeginOffset': 1041, 'EndOffset': 1048}, {'Id': 0, 'BeginOffset': 1092, 'EndOffset': 1097, 'Score': 0.9099831581115723, 'Text': 'mouth', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'a straw', 'Type': 'TREATMENT', 'BeginOffset': 1105, 'EndOffset': 1112}, {'Text': 'the sample tube', 'Type': 'TREATMENT', 'BeginOffset': 1119, 'EndOffset': 1134}, {'Text': 'the straw', 'Type': 'TREATMENT', 'BeginOffset': 1158, 'EndOffset': 1167}, {'Text': 'the tube', 'Type': 'TREATMENT', 'BeginOffset': 1173, 'EndOffset': 1181}, {'Text': 'iv', 'Type': 'TREATMENT', 'BeginOffset': 1202, 'EndOffset': 1204}, {'Text': 'the cap', 'Type': 'TREATMENT', 'BeginOffset': 1226, 'EndOffset': 1233}, {'Text': 'remaining white capped tubes', 'Type': 'TREATMENT', 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'Type': 'NUMBER', 'BeginOffset': 1907, 'EndOffset': 1909}, {'Text': 'post-test breath samples', 'Type': 'TEST', 'BeginOffset': 1910, 'EndOffset': 1934}, {'Text': '3 red capped tubes', 'Type': 'TREATMENT', 'BeginOffset': 1936, 'EndOffset': 1954}, {'Text': 'the red-capped', 'Type': 'TREATMENT', 'BeginOffset': 1962, 'EndOffset': 1976}, {'Text': 'your breath', 'Type': 'PROBLEM', 'BeginOffset': 1994, 'EndOffset': 2005}, {'Text': '4.', 'Type': 'NUMBER', 'BeginOffset': 2026, 'EndOffset': 2028}, {'Text': '8.', 'Type': 'NUMBER', 'BeginOffset': 2030, 'EndOffset': 2032}, {'Text': 'the analysis', 'Type': 'TEST', 'BeginOffset': 2064, 'EndOffset': 2076}, {'Id': 14, 'BeginOffset': 2123, 'EndOffset': 2127, 'Score': 0.922550618648529, 'Text': 'hand', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 16, 'BeginOffset': 2192, 'EndOffset': 2196, 'Score': 0.9333078265190125, 'Text': 'hand', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': '9.', 'Type': 'NUMBER', 'BeginOffset': 2203, 'EndOffset': 2205}, {'Text': 'your breath samples', 'Type': 'TEST', 'BeginOffset': 2231, 'EndOffset': 2250}, {'Text': 'your test', 'Type': 'TEST', 'BeginOffset': 2407, 'EndOffset': 2416}, {'Text': 'the empty sachet', 'Type': 'TREATMENT', 'BeginOffset': 2484, 'EndOffset': 2500}, {'Text': 'mixing vial and straws', 'Type': 'TREATMENT', 'BeginOffset': 2502, 'EndOffset': 2524}, {'Text': 'a repeat test', 'Type': 'TEST', 'BeginOffset': 2582, 'EndOffset': 2595}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2711, 'EndOffset': 2724}]}"},"Section_4":{"kind":"string","value":"{'Title': '4. possible side effects', 'Section_Content': 'no side effects to pylobactell have been reported. 13c and urea are harmless naturally occurring substances which are found in your body. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting 20 system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'pylobactell', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'side effects to pylobactell', 'Type': 'PROBLEM', 'BeginOffset': 3, 'EndOffset': 30}, {'Id': 0, 'BeginOffset': 132, 'EndOffset': 136, 'Score': 0.4369065761566162, 'Text': 'body', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 4, 'BeginOffset': 151, 'EndOffset': 163, 'Score': 0.9294357299804688, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6918842792510986}]}, {'Id': 5, 'BeginOffset': 179, 'EndOffset': 191, 'Score': 0.9097405076026917, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7081830501556396}]}, {'Id': 6, 'BeginOffset': 262, 'EndOffset': 274, 'Score': 0.9522606730461121, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6006610989570618}]}, {'Id': 7, 'BeginOffset': 323, 'EndOffset': 335, 'Score': 0.8625472187995911, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6883346438407898}]}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 372, 'EndOffset': 374}, {'Id': 8, 'BeginOffset': 392, 'EndOffset': 403, 'Score': 0.3820922374725342, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5346482992172241}, {'Name': 'DIAGNOSIS', 'Score': 0.44238629937171936}]}, {'Id': 9, 'BeginOffset': 417, 'EndOffset': 429, 'Score': 0.8633800745010376, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7070889472961426}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 485, 'EndOffset': 498}]}"},"Section_5":{"kind":"string","value":"{'Title': '5. how to store pylobactell', 'Section_Content': 'keep out of the sight and reach of children. do not store the kit above 25. the tablet must be taken when dissolved. do not use pylobactell after the expiry date which is stated on the carton after exp. the expiry date refers to the last day of that month.', 'Entity_Recognition': [{'Text': 'pylobactell', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the kit', 'Type': 'TEST', 'BeginOffset': 58, 'EndOffset': 65}, {'Text': '25.', 'Type': 'NUMBER', 'BeginOffset': 72, 'EndOffset': 75}, {'Text': 'the tablet', 'Type': 'TREATMENT', 'BeginOffset': 76, 'EndOffset': 86}, {'Id': 0, 'BeginOffset': 128, 'EndOffset': 139, 'Score': 0.8016964197158813, 'Text': 'pylobactell', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.7323630452156067}]}]}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': 'what the pylobactell tablet contains - the active substance is 13c-urea. each tablet contains 100 mg of 13c-urea - the other ingredients are povidone (e1201), microcrystalline cellulose (e460i), colloidal anhydrous silica and sodium benzoate (e211). each pylobactell breath test kit contains: 1 sachet containing 1 tablet. 6 glass tubes, 3 with white caps and 3 with red caps. 30 ml glass mixing tube with cap. 2 straws. package leaflet analysis request form. security label and 3 additional bar code labels. the contents of this kit are sufficient for a single test. if you need to repeat the test, a new kit will be required and it should not be carried out until the following day.', 'Entity_Recognition': [{'Text': 'pylobactell', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the pylobactell tablet', 'Type': 'TEST', 'BeginOffset': 5, 'EndOffset': 27}, {'Id': 2, 'BeginOffset': 63, 'EndOffset': 71, 'Score': 0.47470834851264954, 'Text': '13c-urea', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.7301574349403381, 'RelationshipScore': 0.9998114705085754, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 78, 'EndOffset': 84, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '100', 'Type': 'NUMBER', 'BeginOffset': 94, 'EndOffset': 97}, {'Id': 5, 'BeginOffset': 104, 'EndOffset': 136, 'Score': 0.706516444683075, 'Text': '13c-urea - the other ingredients', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9487869739532471, 'RelationshipScore': 0.9995668530464172, 'RelationshipType': 'DOSAGE', 'Id': 4, 'BeginOffset': 94, 'EndOffset': 100, 'Text': '100 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 6, 'BeginOffset': 141, 'EndOffset': 149, 'Score': 0.855804443359375, 'Text': 'povidone', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 159, 'EndOffset': 185, 'Score': 0.9978887438774109, 'Text': 'microcrystalline cellulose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 187, 'EndOffset': 192, 'Score': 0.24539634585380554, 'Text': 'e460i', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'colloidal anhydrous silica and sodium benzoate', 'Type': 'TREATMENT', 'BeginOffset': 195, 'EndOffset': 241}, {'Text': 'each pylobactell breath test', 'Type': 'TEST', 'BeginOffset': 250, 'EndOffset': 278}, {'Text': '1 sachet containing', 'Type': 'TREATMENT', 'BeginOffset': 293, 'EndOffset': 312}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 313, 'EndOffset': 314}, {'Text': '6 glass tubes', 'Type': 'TREATMENT', 'BeginOffset': 323, 'EndOffset': 336}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 338, 'EndOffset': 339}, {'Text': 'white caps', 'Type': 'TREATMENT', 'BeginOffset': 345, 'EndOffset': 355}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 360, 'EndOffset': 361}, {'Id': 13, 'BeginOffset': 367, 'EndOffset': 375, 'Score': 0.48371946811676025, 'Text': 'red caps', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.7103658318519592, 'RelationshipScore': 0.932563066482544, 'RelationshipType': 'DOSAGE', 'Id': 11, 'BeginOffset': 293, 'EndOffset': 301, 'Text': '1 sachet', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8168942928314209, 'RelationshipScore': 0.966148316860199, 'RelationshipType': 'DOSAGE', 'Id': 12, 'BeginOffset': 313, 'EndOffset': 321, 'Text': '1 tablet', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 377, 'EndOffset': 379}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 411, 'EndOffset': 412}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 479, 'EndOffset': 480}, {'Text': 'a single test', 'Type': 'TEST', 'BeginOffset': 553, 'EndOffset': 566}, {'Text': 'the test', 'Type': 'TEST', 'BeginOffset': 590, 'EndOffset': 598}, {'Text': 'a new kit', 'Type': 'TREATMENT', 'BeginOffset': 600, 'EndOffset': 609}]}"}}},{"rowIdx":1063,"cells":{"ID":{"kind":"string","value":"A1DFAB9F4613067C3DFA5916453A4CC7"},"URL":{"kind":"string","value":"https://www.ema.europa.eu/documents/product-information/novoeight-epar-product-information_en.pdf"},"Product_Name":{"kind":"string","value":"NovoEight"},"Full_Content":{"kind":"string","value":"1 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX I \n \n\nSUMMARY OF PRODUCT CHARACTERISTICS \n\n\n\n2 \n\n1. NAME OF THE MEDICINAL PRODUCT \n \nNovoEight 250 IU powder and solvent for solution for injection \nNovoEight 500 IU powder and solvent for solution for injection \nNovoEight 1000 IU powder and solvent for solution for injection \nNovoEight 1500 IU powder and solvent for solution for injection \nNovoEight 2000 IU powder and solvent for solution for injection \nNovoEight 3000 IU powder and solvent for solution for injection \n \n \n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \nNovoEight 250 IU powder and solvent for solution for injection. \nEach powder vial contains nominally 250 IU human coagulation factor VIII (rDNA), turoctocog alfa. \n \nAfter reconstitution NovoEight contains approximately 62.5 IU/ml of human coagulation factor VIII \n(rDNA), turoctocog alfa. \n \nNovoEight 500 IU powder and solvent for solution for injection. \nEach powder vial contains nominally 500 IU human coagulation factor VIII (rDNA), turoctocog alfa. \n \nAfter reconstitution NovoEight contains approximately 125 IU/ml of human coagulation factor VIII \n(rDNA), turoctocog alfa. \n \nNovoEight 1000 IU powder and solvent for solution for injection. \nEach powder vial contains nominally 1000 IU human coagulation factor VIII (rDNA), turoctocog alfa. \n \nAfter reconstitution NovoEight contains approximately 250 IU/ml of human coagulation factor VIII \n(rDNA), turoctocog alfa. \n \nNovoEight 1500 IU powder and solvent for solution for injection. \nEach powder vial contains nominally 1500 IU human coagulation factor VIII (rDNA), turoctocog alfa. \n \nAfter reconstitution NovoEight contains approximately 375 IU/ml of human coagulation factor VIII \n(rDNA), turoctocog alfa. \n \nNovoEight 2000 IU powder and solvent for solution for injection. \nEach powder vial contains nominally 2000 IU human coagulation factor VIII (rDNA), turoctocog alfa. \n \nAfter reconstitution NovoEight contains approximately 500 IU/ml of human coagulation factor VIII \n(rDNA), turoctocog alfa. \n \nNovoEight 3000 IU powder and solvent for solution for injection. \nEach powder vial contains nominally 3000 IU human coagulation factor VIII (rDNA), turoctocog alfa. \n \nAfter reconstitution NovoEight contains approximately 750 IU/ml of human coagulation factor VIII \n(rDNA), turoctocog alfa. \n \nThe potency (IU) is determined using the European Pharmacopoeia (Ph. Eur) chromogenic assay. The \nspecific activity of NovoEight is approximately 8,300 IU/mg protein. \n \nTuroctocog alfa (human coagulation factor VIII (rDNA)) is a purified protein that has 1,445 amino \nacids with an approximate molecular mass of 166 kDA. It is produced by recombinant DNA \ntechnology in Chinese hamster ovary (CHO) cells, and prepared without the addition of any human or \nanimal derived protein in the cell culture process, purification or final formulation. \n \n\n\n\n3 \n\nTuroctocog alfa is a B-domain truncated recombinant human coagulation factor VIII (B-domain \nconsists of 21 amino acids of the wild type B-domain) without any other modifications in the amino \nacid sequence. \n \nExcipient with known effect \nThe medicinal product contains 30.5 mg sodium per reconstituted vial. \n \nFor the full list of excipients, see section 6.1. \n \n \n3. PHARMACEUTICAL FORM \n \nPowder and solvent for solution for injection. \n \nWhite or slightly yellow powder or friable mass. \n \nClear and colourless solution for injection. \n \n \n4. CLINICAL PARTICULARS \n \n4.1 Therapeutic indications \n \nTreatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII \ndeficiency). \n \nNovoEight can be used for all age groups. \n \n4.2 Posology and method of administration \n \nTreatment should be under the supervision of a doctor experienced in the treatment of haemophilia. \n \nTreatment monitoring \nDuring the course of treatment, appropriate determination of factor VIII levels is advised to guide the \ndose to be administered and the frequency of repeated injections. Individual patients may vary in their \nresponse to factor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweight \nmay require adjustment in underweight or overweight patients. In a single dose pharmacokinetic study \nin adult patients the maximum exposure (Cmax) and the total exposure (AUC) increased with increasing \nbody mass index (BMI) indicating that dose adjustments may be required. An increase in dose may be \nrequired for underweight patients (BMI <18.5 kg/m2) and a decrease in dose may be required for obese \npatients (BMI ≥30 kg/m2), but there is insufficient data to recommend specific dose adjustments, see \nsection 5.2. \n \nIn the case of major surgical interventions in particular, precise monitoring of the substitution therapy \nby means of coagulation analysis (plasma factor VIII activity) is indispensable. \n \nWhen using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining \nfactor VIII activity in patients’ blood samples, plasma factor VIII activity results can be significantly \naffected by both the type of aPTT reagent and the reference standard used in the assay. Also there can \nbe significant discrepancies between assay results obtained by aPTT-based one stage clotting assay \nand the chromogenic assay according to Ph. Eur. This is of importance particularly when changing the \nlaboratory and/or reagents used in the assay. \n \nPosology \nThe dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, \non the location and extent of the bleeding and the patient’s clinical condition. \n \n\n\n\n4 \n\nThe number of units of factor VIII administered is expressed in International Units (IU), which are \nrelated to the current WHO standard for factor VIII products. The activity of factor VIII in plasma is \nexpressed either as percentage (relative to normal level human plasma) or in International Units \n(relative to an International Standard for factor VIII in plasma). \n \nOne International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one ml \nnormal human plasma. \n \nOn-demand treatment \nThe calculation of the required dose of factor VIII is based on the empirical finding that 1 \nInternational Unit (IU) factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. \nThe required dose is determined using the following formula: \n \nRequired units = body weight (kg) x desired factor VIII rise (%) (IU/dl) x 0.5 (IU/kg per IU/dl). \n \nThe amount to be administered and the frequency of administration should always be oriented to the \nclinical effectiveness in the individual case. \n \nIn the case of the following haemorrhagic events, the factor VIII activity should not fall below the \ngiven plasma activity level (in % of normal or IU/dl) in the corresponding period. The following table \ncan be used to guide dosing in bleeding episodes and surgery: \n \nTable 1 Guide for dosing in bleeding episodes and surgery \nDegree of haemorrhage/Type of \nsurgical procedure \n\nFVIII level required (%) \n(IU/dl) \n\nFrequency of doses \n(hours)/Duration of therapy (days) \n\nHaemorrhage \n \nEarly haemarthrosis, muscle bleeding \nor oral bleeding \n\n \n20–40 \n\n \nRepeat every 12 to 24 hours, at \nleast 1 day, until the bleeding \nepisode as indicated by pain is \nresolved or healing achieved \n\n \n \nMore extensive haemarthrosis, \nmuscle bleeding or haematoma \n\n \n \n30–60 \n\n \n \nRepeat infusion every 12–24 hours \nfor 3–4 days or more until pain and \nacute disability are resolved \n \n\n \nLife threatening haemorrhages \n\n \n60–100 \n\n \nRepeat infusion every 8 to 24 hours \nuntil threat is resolved \n \n\nSurgery \nMinor surgery including tooth \nextraction \n \n\n30–60 Every 24 hours, at least 1 day, until \nhealing is achieved \n \n\nMajor surgery 80–100 \n(pre- and postoperative) \n\nRepeat infusion every 8–24 hours \nuntil adequate wound healing, then \ntherapy for at least another 7 days \nto maintain a factor VIII activity of \n30% to 60% (IU/dl) \n\n \nProphylaxis \nFor long term prophylaxis against bleeding in patients with severe haemophilia A. The usual \nrecommended doses are 20–40 IU of factor VIII per kg body weight every second day or 20–50 IU of \nfactor VIII per kg body weight 3 times weekly. In adults and adolesents (>12 years) a less frequent \n\n\n\n5 \n\nregimen (40-60 IU/kg every third day or twice weekly) may be applicable. In some cases, especially in \nyounger patients, shorter dosage intervals or higher doses may be necessary. \n \nSurgery \nThere is limited experience of surgery in paediatric patients. \n \nElderly \nThere is no experience in patients >65 years. \n \nPaediatric population \nFor long term prophylaxis against bleeding in patients below the age of 12, doses of 25–50 IU of \nfactor VIII per kg body weight every second day or 25–60 IU of factor VIII per kg body weight \n3 times weekly are recommended. For paediatric patients above the age of 12 the dose \nrecommendations are the same as for adults. \n \nMethod of administration \nIntravenous use. \n \nThe recommended infusion rate for NovoEight is 1–2 ml/min. The rate should be determined by the \npatient’s comfort level. \n \nFor instructions on reconstitution of the medicinal product before administration, see section 6.6. \n \n4.3 Contraindications \n \nHypersensitivity to the active substance or to any of the excipients listed in section 6.1. \n \nKnown allergic reaction to hamster proteins. \n \n4.4 Special warnings and precautions for use \n \nTraceability \nIn order to improve traceability of biological medicinal products, the name and the batch number of \nthe administered product should be clearly recorded. \n \nHypersensitivity \nAllergic type hypersensitivity reactions are possible with NovoEight. The product contains traces of \nhamster proteins, which in some patients may cause allergic reactions. If symptoms of hypersensitivity \noccur, patients should be advised to discontinue use of the medicinal product immediately and contact \ntheir physician. Patients should be informed of the early signs of hypersensitivity reactions including \nhives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. \n \nIn case of shock, standard medical treatment for shock should be implemented. \n \nInhibitors \nThe formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the \nmanagement of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins \ndirected against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per \nml of plasma using the modified assay. The risk of developing inhibitors is correlated to the severity of \nthe disease as well as the exposure to factor VIII, this risk being highest within the first 50 exposure \ndays but continues throughout life although the risk is uncommon. \n \nThe clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre \nposing less of a risk of insufficient clinical response than high titre inhibitors. \nIn general, all patients treated with coagulation factor VIII products should be carefully monitored for \nthe development of inhibitors by appropriate clinical observation and laboratory test. If the expected \nfactor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate \n\n\n\n6 \n\ndose, testing for factor VIII inhibitor presence should be performed. In patients with high levels of \ninhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. \nManagement of such patients should be directed by physicians with experience in the care of \nhaemophilia and factor VIII inhibitors. \n \nCardiovascular event \nIn patients with existing cardiovascular risk factors, substitiution therapy with FVIII may increase the \ncardiovascular risk. \n \nCatheter-related complications \nIf a central venous access device (CVAD) is required, risk of CVAD-related complications including \nlocal infections, bacteraemia and catheter site thrombosis should be considered. \n \nIt is strongly recommended that every time that NovoEight is administered to a patient, the name and \nbatch number of the product are recorded in order to maintain a link between the patient and the batch \nof the medicinal product. \n \nPaediatric population \nThe listed warnings and precautions apply both to adults and children. \n \nExcipient related considerations \nThe medicinal product contains 30.5 mg sodium per reconstituted vial, equivalent to 1.5% of the \nWHO recommended maximum daily intake of 2 g sodium for an adult. \n \n4.5 Interaction with other medicinal products and other forms of interaction \n \nNo interactions of human coagulation factor VIII (rDNA) products with other medicinal products have \nbeen reported. \n \n4.6 Fertility, pregnancy and lactation \n \nAnimal reproduction studies have not been conducted with NovoEight. Based on the rare occurrence \nof haemophilia A in women, experience regarding the use of factor VIII during pregnancy and \nbreastfeeding is not available. Therefore, factor VIII should be used during pregnancy and lactation \nonly if clearly indicated. \n \n4.7 Effects on ability to drive and use machines \n \nNovoEight has no influence on the ability to drive and use machines. \n \n4.8 Undesirable effects \n \nSummary of the safety profile \nHypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the \ninfusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, \nrestlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed \nrarely and may in some cases progress to severe anaphylaxis (including shock). \n \nVery rarely development of antibodies to hamster protein with related hypersensitivity reactions has \nbeen observed. \n \nDevelopment of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated \nwith factor VIII, including with NovoEight. If such inhibitors occur, the condition will manifest itself \nas an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia \ncentre is contacted. \n \nTabulated list of adverse reactions \n\n\n\n7 \n\nThe table presented below is according to the MedDRA system organ classification (SOC and \nPreferred Term Level). \n \nFrequencies have been evaluated according to the following convention: very common (≥1/10), \ncommon (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare \n(<1/10,000), and not known (cannot be estimated from the available data). \nWithin each frequency grouping, adverse reactions are presented in order of decreasing seriousness. \n \nTable 2 Frequency of adverse drug reactions in clinical trials \nSystem Organ Class Frequencya in \n\nPTPs \nFrequencya in \nPUPs \n\nAdverse reaction \n\nBlood and lymphatic \nsystem disorders \n\nUncommonb Very commonb FVIII inhibition \n\nPsychiatric disorders Uncommon Insomnia \nNervous system \ndisorders \n\nUncommon Headache, dizziness, burning \nsensation \n\nCardiac disorders Uncommon Sinus tachycardia, acute \nmyocardial infarction \n\nVascular disorders Uncommon Hypertension, lymphoedema, \nhyperaemia \n\n Common Flushing, Thrombophlebitis \nsuperficial \n\nSkin and subcutaneous \ntissue disorders \n\n Common Rash, rash erythematous \nUncommon Rash, lichenoid keratosis, skin \n\nburning sensation \nMusculoskeletal and \nconnective tissue \ndisorders \n\nUncommon Musculoskeletal stiffness, \narthropathy, pain in extremity, \nmusculoskeletal pain \n\n Common Haemarthrosis, Muscle \nhaemorrhage \n\nRespiratory, thoracic \nand mediastinal \ndisorders \n\n Common Cough \n\nGeneral disorders and \nadministration site \nconditions \n\nCommon Injection site reactionsc \n Common Pyrexia, catheter site erythema \nUncommon Fatigue, feeling hot, oedema \n\nperipheral, pyrexia \nInvestigations Common Hepatic enzymes increasedd \n\n Common Anti factor VIII antibody \npositive \n\nUncommon Heart rate increased \nGastrointestinal \ndisorders \n\n Common Vomiting \n\nInjury, poisoning and \nprocedural \ncomplications \n\nCommon Incorrect dose administered \n Common Infusion related reaction \nUncommon Contusion \n\nProduct issues Common Thrombosis in device \na Calculated based on total number of unique patients in all clinical trials (301), of which 242 \n\nwere previously treated patients (PTPs) and 60 were previously untreated patients (PUPs). \nb Frequency is based on studies with all FVIII products which included patients with severe \n\nhaemophilia A. \nc Injection site reactions include injection site erythema, injection site extravasation and injection \n\nsite pruritus. \nd Hepatic enzymes increased include alanine aminotransferase, aspartate aminotransferase, \n\ngamma-glutamyltransferase and bilirubin. \n \n\n\n\n8 \n\nDescription of selected adverse reactions \nDuring all clinical studies with NovoEight in previously treated patients, a total of 35 adverse \nreactions were reported in 23 of 242 patients exposed to NovoEight. The most frequently reported \nadverse reactions were injection site reactions, incorrect dose administered and hepatic enzymes \nincreased. Of the 35 adverse reactions, 2 were reported in 1 out of 31 patients below 6 years of age, \nnone in patients from 6 to ≤12 years of age, 1 event in 1 out of 24 patients (12 to <18 years of age) and \n32 were reported in 21 out of 155 adults (≥18 years). \n \nPaediatric population \nIn clinical trials involving 63 previously treated paediatric patients between 0 and 12 years of age and \n24 adolescents between 12 and 18 years of age with severe haemophilia A no difference in the safety \nprofile of NovoEight was observed between paediatric patients and adults. \n \nIn the trial with previously untreated patients, between 0 and 6 years of age, a total of 46 adverse \nreactions were reported in 33 of 60 patients exposed to NovoEight. The most frequently reported \nadverse reaction was Factor VIII inhibition, see section 4.4. High risk genetic mutations were \nidentified in 92.3% of the overall and 93.8% of the high titre confirmed inhibitors. No other factors \nwere significantly associated with inhibitor development. \n \nReporting of suspected adverse reactions \nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V. \n \n4.9 Overdose \n \nNo symptoms of overdose with recombinant coagulation factor VIII have been reported. \n \n \n5. PHARMACOLOGICAL PROPERTIES \n \n5.1 Pharmacodynamic properties \n \nPharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII, ATC code: B02BD02. \n \nMechanism of action \nNovoEight contains turoctocog alfa, a human coagulation factor VIII (rDNA), with a truncated B-\ndomain. This glycoprotein has the same structure as human factor VIII when activated, and post-\ntranslational modifications that are similar to those of the plasma-derived molecule. The tyrosine \nsulphation site present at Tyr1680 (native full length), which is important for the binding to von \nWillebrand factor, has been found to be fully sulphated in the turoctocog alfa molecule. When infused \ninto a haemophilia patient, factor VIII binds to endogenous von Willebrand Factor in the patient’s \ncirculation. The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and \nvon Willebrand factor) with different physiological functions. Activated factor VIII acts as a co-factor \nfor activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor \nX converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be \nformed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased \nlevels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either \nspontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels \nof factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and \ncorrection of bleeding tendencies. \n \nOf note, annualised bleeding rate (ABR) is not comparable between different factor concentrates and \nbetween different clinical studies. \n \nClinical efficacy \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n9 \n\nFour multi-centre, open-labelled, non-controlled trials have been conducted to evaluate the safety and \nefficacy of NovoEight in the prevention and treatment of bleeds and during surgery in patients with \nsevere haemophilia A (FVIII activity ≤1%). Three of these trials were performed in previously treated \npatients and the fourth in previously untreated patients. The trials included 298 exposed patients; 175 \nadolescents or adult patients without inhibitors from the age of 12 years (≥150 exposure days), 63 \npreviously treated paediatric patients without inhibitors below 12 years of age (≥50 exposure days) \nand 60 previously untreated patients below 6 years of age. \n188 out of 238 previously treated patients continued into the safety extension trial. Treatment with \nNovoEight was shown to be safe and had the intended haemostatic and preventive effect. \nOf the 3,293 reported bleeds observed in 298 of the patients, 2,902 (88.1%) of the bleeds were \nresolved with 1-2 infusions of NovoEight. \n \nTable 3 Consumption of NovoEight and haemostatic success rates in previously untreated \npatients (PUP) and previously treated patients (PTP) \n Younger \n\nchildren \n(0 – \n<6 years) \nPUP \n\nYounger \nchildren \n(0 – \n<6 years) \nPTP \n\nOlder \nchildren \n(6 – \n<12 years) \nPTP \n\nAdolescents \n(12 – \n<18 years) \nPTP \n\nAdults \n(≥18 years) \nPTP \n\nTotal \n\nNumber of \npatients \n\n60 31 32 24 151 298 \n\nDose used for \nprevention \nper patient \n(IU/kg BW) \nMean (SD) \nMin ; Max \n\n \n \n \n \n45.2 (14.4) \n4.5 ; 363.8 \n\n \n \n \n \n41.5 (8.1) \n3.4 ; 196.3. \n\n \n \n \n \n38.4 (9.4) \n3.2 ; 62.5 \n\n \n \n \n \n28.5 (9.3) \n17.4 ; 73.9 \n\n \n \n \n \n28.5 (8.3) \n12.0 ; 97.4 \n\n \n \n \n \n32.8 (10.9) \n3.2 ; 363.8 \n\nDose used for \ntreatment of \nbleed (IU/kg \nBW) \nMean (SD) \nMin ; Max \n\n \n \n \n43.6 (15.2) \n11.9 ; 118.9 \n\n \n \n \n44.0 (12.6) \n21.4 ; 193.8 \n\n \n \n \n40.4 (10.5) \n24.0 ; 71.4 \n\n \n \n \n29.3 (10.3) \n12.4 ; 76.8 \n\n \n \n \n35.0 (12.3) \n6.4 ; 104.0 \n\n \n \n \n37.5 (13.4) \n6.4 ; 193.8 \n\nSuccess ratea \n% \n\n87.0% 92.2% \n \n\n88.4% \n \n\n85.1% \n \n\n89.6% \n \n\n88.9% \n \n\nBW: Body weight, SD: Standard deviation \na Success is defined as either 'Excellent' or 'Good'. \n \nA total of 30 surgeries were performed in 25 patients of which 26 were major surgeries and 4 were \nminor. Haemostasis was successful in all surgeries and no treatment failures were reported. \n \nData on Immune Tolerance Induction (ITI) has been collected in patients with haemophilia A who had \ndeveloped inhibitors to factor VIII. During clinical trial in PUPs, 21 patients were treated with ITI and \n18 (86%) patients completed ITI with a negative inhibitor test result. \n \n5.2 Pharmacokinetic properties \n \nAll pharmacokinetic (PK) studies with NovoEight were conducted after i.v. administration of 50 IU/kg \nNovoEight in previously treated patients with severe haemophilia A (FVIII ≤1%). The analysis of \nplasma samples was conducted using both the one-stage clotting assay and the chromogenic assay. \nThe assay performance of NovoEight in FVIII:C assays was evaluated and compared to a marketed \nfull length recombinant FVIII product. The study showed that comparable and consistent results were \nobtained for both products and that NovoEight can be reliably measured in plasma without the need of \na separate NovoEight standard. \n \nThe single dose pharmacokinetic parameters of NovoEight are listed in Table 4 for the one-stage \nclotting assay and in Table 5 for the chromogenic assay. \n\n\n\n10 \n\n \nTable 4 Single-dose pharmacokinetic parameters of NovoEight (50 IU/kg) by age - one stage \nclotting assay - Mean (SD) \nParameter 0 − <6 years 6 − <12 years ≥12 years \n\nn=14 n=14 n=33 \nIncremental recovery \n(IU/dl)/(IU/kg) \n\n1.8 (0.7) 2.0 (0.4) 2.2 (0.4) \n\nAUC ((IU*h)/dl) 992 (411) 1109(374) 1526 (577) \nCL (ml/h/kg) 6.21 (3.66) 5.02 (1.68) 3.63 (1.09) \nt½ (h) 7.65 (1.84) 8.02 (1.89) 11.00 (4.65) \nVss (ml/kg) 56.68 (26.43) 46.82 (10.63) 47.40 (9.21) \nCmax (IU/dl) 100 (58) 107 (35) 123 (41) \nMean residence time \n(h) \n\n9.63 (2.50) 9.91 (2.57) 14.19 (5.08) \n\nAbbreviations: AUC = area under the factor VIII activity time profile; CL = clearance; t1/2 = terminal \nhalf-life; Vss = volume of distribution at steady-state; Cmax = maximum factor VIII activity. \n \nTable 5 Single-dose pharmacokinetic parameters of NovoEight (50 IU/kg) by age - chromogenic \nassay - Mean (SD) \nParameter 0 − <6 years 6 − <12 years ≥12 years \n\nn=14 n=14 n=33 \nIncremental recovery \n(IU/dl)/(IU/kg) \n\n2.2 (0.6) 2.5 (0.6) 2.9 (0.6) \n\nAUC ((IU*h)/dl) 1223 (436) 1437 (348) 1963 (773) \nCL (ml/h/kg) 4.59 (1.73) 3.70 (1.00) 2.86 (0.94) \nt½ (h) 9.99 (1.71) 9.42 (1.52) 11.22 (6.86) \nVss (ml/kg) 55.46 (23.53) 41.23 (6.00) 38.18 (10.24) \nCmax (IU/dl) 112 (31) 125 (27) 163 (50) \nMean residence time \n(h) \n\n12.06 (1.90) 11.61 (2.32) 14.54 (5.77) \n\nAbbreviations: AUC = area under the factor VIII activity time profile; CL = clearance; t1/2 = terminal \nhalf-life; Vss = volume of distribution at steady-state; Cmax = maximum factor VIII activity. \n \nThe pharmacokinetic parameters were comparable between paediatric patients below 6 years of age \nand the paediatric patients from 6 to below 12 years of age. Some variation was observed in the \npharmacokinetic parameters of NovoEight between paediatric and adult patients. The higher CL and \nthe shorter t½ seen in paediatric patients compared to adult patients with haemophilia A may be due in \npart to the known higher plasma volume per kilogram body weight in younger patients. \n \nA single dose pharmacokinetic trial (50 IU/kg) was performed in 35 haemophilia patients (≥18 years \nof age) in different BMI categories. The maximum exposure (Cmax) and the total exposure (AUC) \nincrease with increasing BMI indicating that dose adjustments may be required for underweight (BMI \n<18.5 kg/m2) and obese patients (BMI ≥30 kg/m2), see section 4.2. \n \nTable 6 Single-dose pharmacokinetic parameters of NovoEight (50 IU/kg) by BMI classesa – \nOne-stage clotting assay - Mean (SD) \nPK parameter Underweight \n\nN=5 \nNormal weight \nN=7 \n\nOverweight \nN=8 \n\nObese class I \nN=7 \n\nObese class II/III \nN=7 \n\nIncremental \nrecovery \n(IU/dl)/(IU/kg) \n\n1.7 (0.2) 2.0 (0.2) 2.4 (0.4) 2.3 (0.3)b 2.6 (0.3) \n\nAUC ((IU*h)/dl) 1510 (360) 1920 (610) 1730 (610) 2030 (840) 2350 (590) \nCL (ml/h/kg) 3.91 (0.94) 3.20 (1.00) 3.63 (1.24) 3.37 (1.79) 2.51 (0.63) \nt½ (h) 11.3 (2.0) 11.7 (3.5) 9.4 (2.9) 11.2 (3.5) 11.1 (2.7) \n\n\n\n11 \n\nVss (ml/kg) 56.8 (5.4) 44.8 (6.5) 39.6 (6.0) 42.0 (9.0) 35.0 (4.6) \nCmax (IU/dl) 100 (11) 121 (10) 144 (26) 140 (21) 161 (32) \nMean residence \ntime (h) \n\n15.1 (3.0) 15.3 (4.8) 11.9 (3.7) 14.4 (4.6) 14.6 (3.7) \n\na BMI groups: Underweight: BMI <18.5 kg/m2, Normal weight: BMI 18.5-24.9 kg/m2, Overweight: \nBMI 25-29.9 kg/m2, Obese class I: BMI 30-34.9 kg/m2, Obese class II/III: BMI ≥35 kg/m2. \nb Based on 6 patients only. \n \nTable 7 Single-dose pharmacokinetic parameters of NovoEight (50 IU/kg) by BMI classesa – \nChromogenic assay - Mean (SD) \nPK parameter Underweight \n\nN=5 \nNormal weight \nN=7 \n\nOverweight \nN=9 \n\nObese class I \nN=7 \n\nObese class \nII/III N=7 \n\nIncremental \nrecovery \n(IU/dl)/(IU/kg) \n\n2.2 (0.4) 2.9 (0.3) 3.0 (0.5) 3.2 (0.5) 3.5 (0.5) \n\nAUC ((IU*h)/dl) 1860 (700) 2730 (860) 2310 (1020) 2780 (1210) 3050 (730) \nCL (ml/h/kg) 3.28 (0.87) 2.25 (0.73) 2.84 (1.09) 2.58 (1.56) 1.94 (0.52) \nt½ (h) 11.7 (2.4) 11.5 (3.6) 9.7 (3.4) 10.4 (3.2) 10.5 (2.5) \nVss (ml/kg) 49.1 (10.4) 31.2 (4.5) 31.6 (5.8) 28.9 (5.1) 25.7 (4.0) \nCmax (IU/dl) 138 (29) 185 (24) 194 (31) 200 (33) 227 (32) \nMean residence \ntime (h) \n\n15.5 (3.2) 15.2 (4.9) 12.6 (4.8) 13.5 (4.6) 13.9 (3.7) \n\na BMI groups: Underweight: BMI <18.5 kg/m2, Normal weight: BMI 18.5-24.9 kg/m2, Overweight: \nBMI 25-29.9 kg/m2, Obese class I: BMI 30-34.9 kg/m2, Obese class II/III: BMI ≥35 kg/m2. \n \n \n5.3 Preclinical safety data \n \nNon-clinical data reveal no special concern for humans based on conventional studies of safety \npharmacology and repeated dose toxicity. \n \n \n6. PHARMACEUTICAL PARTICULARS \n \n6.1 List of excipients \n \nPowder: \nSodium chloride \nL-histidine \nSucrose \nPolysorbate 80 \nL-methionine \nCalcium chloride dihydrate \nSodium hydroxide (for pH adjustment) \nHydrochloric acid (for pH adjustment) \n \nSolvent: \nSodium chloride \nWater for injections \n \n6.2 Incompatibilities \n \nIn the absence of compatibility studies, this medicinal product must not be mixed with other medicinal \nproducts. \n \n6.3 Shelf life \n\n\n\n12 \n\n \nUnopened vial \n30 months when stored in a refrigerator (2°C – 8°C). \n \nDuring the shelf life, the product may be kept at: \n• room temperature (≤ 30°C) for a single period no longer than 9 months \n or \n• above room temperature (30°C up to 40°C) for a single period no longer than 3 months. \n \nOnce the product has been taken out of the refrigerator, the product must not be returned to the \nrefrigerator. \n \nPlease record the beginning of storage and the storage temperature on the product carton. \n \nAfter reconstitution: \nChemical and physical in-use stability have been demonstrated for: \n• 24 hours stored at 2°C – 8°C \n• 4 hours stored at 30°C, for product which has been kept for a single period no longer than \n\n9 months at room temperature (≤30°C) \n• 4 hours stored up to 40°C, for product which has been kept for a single period no longer than \n\n3 months at above room temperature (30°C up to 40°C). \n \nFrom a microbiological point of view, the medicinal product should be used immediately after \nreconstitution. If not used immediately, in-use storage times and conditions prior to use are the \nresponsibility of the user and would normally not be longer than as stated above, unless reconstitution \nhas taken place in controlled and validated aseptic conditions. \n \nAny unused reconstituted product stored at room temperature (≤30°C) or up to 40°C for more than \n4 hours should be discarded. \n \n6.4 Special precautions for storage \n \nStore in refrigerator (2°C – 8°C). \nDo not freeze. \nKeep the vial in the outer carton in order to protect from light. \n \nFor storage at room temperature (≤30°C) or up to 40°C and storage conditions after reconstitution of \nthe medicinal product, see section 6.3. \n \n6.5 Nature and contents of container \n \nEach pack of NovoEight 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU and 3000 IU powder and solvent \nfor solution for injection contains: \n \n– 1 glass vial (type I) with powder and chlorobutyl rubber stopper \n– 1 sterile vial adapter for reconstitution \n– 1 pre-filled syringe of 4 ml solvent with backstop (polypropylene), a rubber plunger \n\n(bromobutyl) and a syringe cap with a stopper (bromobutyl) \n– 1 plunger rod (polypropylene). \n \n6.6 Special precautions for disposal and other handling \n \nNovoEight is to be administered intravenously after reconstitution of the powder with the solvent \nsupplied in the syringe. After reconstitution the solution appears as a clear or slightly opalescent \nsolution. Do not use solutions that are cloudy or have deposits. \n \n\n\n\n13 \n\nYou will also need an infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads and \nplasters. These devices are not included in the NovoEight package. \n \nAlways use an aseptic technique. \n \nReconstitution \n \nA) \nTake the vial, the vial adapter and the pre-filled \nsyringe out of the carton. Leave the plunger rod \nuntouched in the carton. Bring the vial and the \npre-filled syringe to room temperature. You can \ndo this by holding them in your hands until they \nfeel as warm as your hands. Do not use any \nother way to heat the vial and pre-filled syringe. \n \n\n \n \n\n \n\n A \n\n \n \n\nB) \nRemove the plastic cap from the vial. If the \nplastic cap is loose or missing, do not use the \nvial. Wipe the rubber stopper on the vial with a \nsterile alcohol swab and allow it to air dry for a \nfew seconds before use. \n\n \n\n \n\n B \n\n \n \n\nC) \nRemove the protective paper from the vial \nadapter. If the protective paper is not fully \nsealed or if it is broken, do not use the vial \nadapter. \nDo not take the vial adapter out of the protective \ncap with your fingers. \n\n \n\n \n\n C \n\n \n \n\nD) \nTurn over the protective cap and snap the vial \nadapter onto the vial. Once attached do not \nremove the vial adapter from the vial. \n\n \n\n \n\n D \n\n \n \n\n\n\n14 \n\nE) \nLightly squeeze the protective cap with your \nthumb and index finger as shown. Remove the \nprotective cap from the vial adapter. \n\n \n E \n\n \n \n\nF) \nGrasp the plunger rod by the wide top and \nimmediately connect the plunger rod to the \nsyringe by turning it clockwise into the plunger \ninside the pre-filled syringe until resistance is \nfelt. \n \n\n \n\n \n\n F \n\n \n \n\nG) \nRemove the syringe cap from the pre-filled \nsyringe by bending it down until the perforation \nbreaks. Do not touch the syringe tip under the \nsyringe cap. \n\n \n\n \n\n G \n\n \n \n\nH) \nScrew the pre-filled syringe securely onto the \nvial adapter until resistance is felt. \n\n \n\n \n\n H \n\n \n \n\nI) \nHold the pre-filled syringe slightly tilted with \nthe vial pointing downwards. Push the plunger \nrod to inject all the solvent into the vial. \n\n \n\n \n\n I \n\n \n \n\n\n\n15 \n\nJ) \nKeep the plunger rod pressed down and swirl \nthe vial gently until all the powder is dissolved. \nDo not shake the vial as this will cause foaming. \n\n \n\n \n\n J \n\n \n \n\n \nIt is recommended to use NovoEight immediately after reconstitution. For storage conditions of the \nreconstituted medicinal product see section 6.3. \n \nIf a larger dose is needed, repeat steps A to J with additional vials, vial adapters and pre-filled \nsyringes. \n \nAdministration of the reconstituted solution \n \nK) \nKeep the plunger rod pushed completely in. \nTurn the syringe with the vial upside down. Stop \npushing the plunger rod and let it move back on \nits own while the reconstituted solution fills the \nsyringe. Pull the plunger rod slightly downwards \nto draw the reconstituted solution into the \nsyringe. \n \nIn case you only need part of the entire vial, use \nthe scale on the syringe to see how much \nreconstituted solution you withdraw, as \ninstructed by your doctor or nurse. \n \nWhile holding the vial upside down, tap the \nsyringe gently to let any air bubbles rise to the \ntop. Push the plunger rod slowly until all air \nbubbles are gone. \n \n\n \n \n\n \n\n K \n\n \n \n\nL) \nUnscrew the vial adapter with the vial. \n \n \n \n \n \n \n \nNovoEight is now ready for injection. Locate a \nsuitable site and slowly inject NovoEight into \nthe vein over a period of 2-5 minutes. \n\n \n\n \n\n L \n\n \n \n\n \n\n\n\n16 \n\nDisposal \nAfter injection, safely dispose of all unused NovoEight solution, the syringe with the infusion set, the \nvial with the vial adapter and other waste materials as instructed by your pharmacist. \n \nDo not throw it out with the ordinary household waste. \n \n \n7. MARKETING AUTHORISATION HOLDER \n \nNovo Nordisk A/S \nNovo Allé \nDK-2880 Bagsværd \nDenmark \n \n \n8. MARKETING AUTHORISATION NUMBERS \n \nNovoEight 250 IU \nEU/1/13/888/001 \n \nNovoEight 500 IU \nEU/1/13/888/002 \n \nNovoEight 1000 IU \nEU/1/13/888/003 \n \nNovoEight 1500 IU \nEU/1/13/888/004 \n \nNovoEight 2000 IU \nEU/1/13/888/005 \n \nNovoEight 3000 IU \nEU/1/13/888/006 \n \n \n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n \nDate of first authorisation: 13 November 2013 \nDate of latest renewal: 30 July 2018 \n \n \n10. DATE OF REVISION OF THE TEXT \n \nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency http://www.ema.europa.eu. \n\nhttp://www.ema.europa.eu/\nhttp://www.ema.europa.eu/\n\n\n17 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX II \n \n\nA. MANUFACTURERS OF THE BIOLOGICAL ACTIVE \nSUBSTANCE AND MANUFACTURER RESPONSIBLE FOR \nBATCH RELEASE \n\n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY \n\nAND USE \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE \n\nMARKETING AUTHORISATION \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE \n\nSAFE AND EFFECTIVE USE OF THE MEDICINAL \nPRODUCT \n\n \n \n\n\n\n18 \n\nA. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND \nMANUFACTURER RESPONSIBLE FOR BATCH RELEASE \n\n \nName and address of the manufacturers of the biological active substance \n \nBioReliance Ltd \nTodd Campus, West of Scotland Science Park, \nGlasgow, G20 0XA \nUnited Kingdom \n \nNovo Nordisk US Bio Production Inc. \n9 Technology Drive \nWest Lebanon \nNH 03784 \nUSA \n \nName and address of the manufacturer responsible for batch release \n \nNovo Nordisk A/S \nNovo Allé \nDK-2880 Bagsværd \nDenmark \n \n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n \nMedicinal product subject to restricted medical prescription (See Annex I: Summary of Product \nCharacteristics, section 4.2). \n \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n \n• Periodic Safety Update Reports (PSUR) \n \nThe requirements for submission of periodic safety update reports for this medicinal product are set \nout in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive \n2001/83/EC and any subsequent updates published on the European medicines web-portal. \n \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n \n• Risk Management Plan (RMP) \n \nThe MAH shall perform the required pharmacovigilance activities and interventions detailed in the \nagreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent \nupdates of the RMP. \n \nAn updated RMP should be submitted: \n• At the request of the European Medicines Agency; \n• Whenever the risk management system is modified, especially as the result of new information \n\nbeing received that may lead to a significant change to the benefit/risk profile or as the result of \nan important (pharmacovigilance or risk minimisation) milestone being reached. \n\n\n\n19 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX III \n \n\nLABELLING AND PACKAGE LEAFLET \n\n\n\n20 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nA. LABELLING \n \n\n\n\n21 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCarton \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nNovoEight 250 IU powder and solvent for solution for injection \n \nturoctocog alfa (human coagulation factor VIII (rDNA)) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE \n \nOne ml of NovoEight contains approximately 62.5 IU of human coagulation factor VIII (rDNA), \nturoctocog alfa after reconstitution \n \n \n3. LIST OF EXCIPIENTS \n \nPowder: Sodium chloride, L-histidine, sucrose, polysorbate 80, L-methionine, calcium chloride \ndihydrate, sodium hydroxide, hydrochloric acid \nSolvent: Sodium chloride, water for injections \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nPowder and solvent for solution for injection \n \nPack contains: 1 powder vial, 4 ml solvent in pre-filled syringe, plunger rod and vial adapter \n \n \n5. METHOD AND ROUTE OF ADMINISTRATION \n \nIntravenous use \n \nRead the package leaflet before use \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children \n \n \n7. OTHER SPECIAL WARNINGS, IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \n\n\n\n22 \n\nStore in a refrigerator. Do not freeze \n \nDuring storage, the product may be kept at: \n• room temperature (≤ 30°C) for a single period no longer than 9 months or \n• above room temperature (30°C up to 40°C) for a single period no longer than 3 months \n \nTaken out of refrigerator: _____________Stored at ≤30°C __ Stored at 30°C up to 40°C __ \n \nStore in the original package in order to protect from light \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nNovo Nordisk A/S \nNovo Allé \nDK-2880 Bagsværd \nDenmark \n \n \n12. MARKETING AUTHORISATION NUMBERS \n \nEU/1/13/888/001 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \nMedicinal product subject to medical prescription \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nNovoEight 250 IU \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: \nSN: \n\n\n\n23 \n\nNN:\n\n\n\n24 \n\n \nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVial \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION \n \nNovoEight 250 IU powder for solution for injection \n \nturoctocog alfa \n \nIntravenous use \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n250 IU \n \n \n6. OTHER \n \nNovo Nordisk A/S \n\n\n\n25 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCarton \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nNovoEight 500 IU powder and solvent for solution for injection \n \nturoctocog alfa (human coagulation factor VIII (rDNA)) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE \n \nOne ml of NovoEight contains approximately 125 IU of human coagulation factor VIII (rDNA), \nturoctocog alfa after reconstitution \n \n \n3. LIST OF EXCIPIENTS \n \nPowder: Sodium chloride, L-histidine, sucrose, polysorbate 80, L-methionine, calcium chloride \ndihydrate, sodium hydroxide, hydrochloric acid \nSolvent: Sodium chloride, water for injections \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nPowder and solvent for solution for injection \n \nPack contains: 1 powder vial, 4 ml solvent in pre-filled syringe, plunger rod and vial adapter \n \n \n5. METHOD AND ROUTE OF ADMINISTRATION \n \nIntravenous use \n \nRead the package leaflet before use \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children \n \n \n7. OTHER SPECIAL WARNINGS, IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \n\n\n\n26 \n\nStore in a refrigerator. Do not freeze \n \nDuring storage, the product may be kept at: \n• room temperature (≤ 30°C) for a single period no longer than 9 months or \n• above room temperature (30°C up to 40°C) for a single period no longer than 3 months \n \nTaken out of refrigerator: _____________Stored at ≤30°C __ Stored at 30°C up to 40°C __ \n \nStore in the original package in order to protect from light \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nNovo Nordisk A/S \nNovo Allé \nDK-2880 Bagsværd \nDenmark \n \n \n12. MARKETING AUTHORISATION NUMBERS \n \nEU/1/13/888/002 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \nMedicinal product subject to medical prescription \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nNovoEight 500 IU \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: \nSN: \n\n\n\n27 \n\nNN: \n\n\n\n28 \n\n \nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVial \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION \n \nNovoEight 500 IU powder for solution for injection \n \nturoctocog alfa \n \nIntravenous use \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n500 IU \n \n \n6. OTHER \n \nNovo Nordisk A/S \n\n\n\n29 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCarton \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nNovoEight 1000 IU powder and solvent for solution for injection \n \nturoctocog alfa (human coagulation factor VIII (rDNA)) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE \n \nOne ml of NovoEight contains approximately 250 IU of human coagulation factor VIII (rDNA), \nturoctocog alfa after reconstitution \n \n \n3. LIST OF EXCIPIENTS \n \nPowder: Sodium chloride, L-histidine, sucrose, polysorbate 80, L-methionine, calcium chloride \ndihydrate, sodium hydroxide, hydrochloric acid \nSolvent: Sodium chloride, water for injections \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nPowder and solvent for solution for injection \n \nPack contains: 1 powder vial, 4 ml solvent in pre-filled syringe, plunger rod and vial adapter \n \n \n5. METHOD AND ROUTE OF ADMINISTRATION \n \nIntravenous use \n \nRead the package leaflet before use \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children \n \n \n7. OTHER SPECIAL WARNINGS, IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \n\n\n\n30 \n\nStore in a refrigerator. Do not freeze \n \nDuring storage, the product may be kept at: \n• room temperature (≤ 30°C) for a single period no longer than 9 months or \n• above room temperature (30°C up to 40°C) for a single period no longer than 3 months \n \nTaken out of refrigerator: _____________Stored at ≤30°C __ Stored at 30°C up to 40°C __ \n \nStore in the original package in order to protect from light \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nNovo Nordisk A/S \nNovo Allé \nDK-2880 Bagsværd \nDenmark \n \n \n12. MARKETING AUTHORISATION NUMBERS \n \nEU/1/13/888/003 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \nMedicinal product subject to medical prescription \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nNovoEight 1000 IU \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: \nSN: \n\n\n\n31 \n\nNN: \n\n\n\n32 \n\n \nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVial \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION \n \nNovoEight 1000 IU powder for solution for injection \n \nturoctocog alfa \n \nIntravenous use \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n1000 IU \n \n \n6. OTHER \n \nNovo Nordisk A/S \n\n\n\n33 \n\n \n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCarton \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nNovoEight 1500 IU powder and solvent for solution for injection \n \nturoctocog alfa (human coagulation factor VIII (rDNA)) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE \n \nOne ml of NovoEight contains approximately 375 IU of human coagulation factor VIII (rDNA), \nturoctocog alfa after reconstitution \n \n \n3. LIST OF EXCIPIENTS \n \nPowder: Sodium chloride, L-histidine, sucrose, polysorbate 80, L-methionine, calcium chloride \ndihydrate, sodium hydroxide, hydrochloric acid \nSolvent: Sodium chloride, water for injections \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nPowder and solvent for solution for injection \n \nPack contains: 1 powder vial, 4 ml solvent in pre-filled syringe, plunger rod and vial adapter \n \n \n5. METHOD AND ROUTE OF ADMINISTRATION \n \nIntravenous use \n \nRead the package leaflet before use \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children \n \n \n7. OTHER SPECIAL WARNINGS, IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n\n\n\n34 \n\n \nStore in a refrigerator. Do not freeze \n \nDuring storage, the product may be kept at: \n• room temperature (≤ 30°C) for a single period no longer than 9 months or \n• above room temperature (30°C up to 40°C) for a single period no longer than 3 months \n \nTaken out of refrigerator: _____________Stored at ≤30°C __ Stored at 30°C up to 40°C __ \n \nStore in the original package in order to protect from light \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nNovo Nordisk A/S \nNovo Allé \nDK-2880 Bagsværd \nDenmark \n \n \n12. MARKETING AUTHORISATION NUMBERS \n \nEU/1/13/888/004 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \nMedicinal product subject to medical prescription \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nNovoEight 1500 IU \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: \n\n\n\n35 \n\nSN: \nNN: \n\n\n\n36 \n\n \nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVial \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION \n \nNovoEight 1500 IU powder for solution for injection \n \nturoctocog alfa \n \nIntravenous use \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n1500 IU \n \n \n6. OTHER \n \nNovo Nordisk A/S \n\n\n\n37 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCarton \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nNovoEight 2000 IU powder and solvent for solution for injection \n \nturoctocog alfa (human coagulation factor VIII (rDNA)) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE \n \nOne ml of NovoEight contains approximately 500 IU of human coagulation factor VIII (rDNA), \nturoctocog alfa after reconstitution \n \n \n3. LIST OF EXCIPIENTS \n \nPowder: Sodium chloride, L-histidine, sucrose, polysorbate 80, L-methionine, calcium chloride \ndihydrate, sodium hydroxide, hydrochloric acid \nSolvent: Sodium chloride, water for injections \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nPowder and solvent for solution for injection \n \nPack contains: 1 powder vial, 4 ml solvent in pre-filled syringe, plunger rod and vial adapter \n \n \n5. METHOD AND ROUTE OF ADMINISTRATION \n \nIntravenous use \n \nRead the package leaflet before use \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children \n \n \n7. OTHER SPECIAL WARNINGS, IF NECESSARY \n \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n\n\n\n38 \n\n \nStore in a refrigerator. Do not freeze \n \nDuring storage, the product may be kept at: \n• room temperature (≤ 30°C) for a single period no longer than 9 months or \n• above room temperature (30°C up to 40°C) for a single period no longer than 3 months \n \nTaken out of refrigerator: _____________Stored at ≤30°C __ Stored at 30°C up to 40°C __ \n \nStore in the original package in order to protect from light \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nNovo Nordisk A/S \nNovo Allé \nDK-2880 Bagsværd \nDenmark \n \n \n12. MARKETING AUTHORISATION NUMBERS \n \nEU/1/13/888/005 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \nMedicinal product subject to medical prescription \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nNovoEight 2000 IU \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: \n\n\n\n39 \n\nSN: \nNN:\n\n\n\n40 \n\n \nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVial \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION \n \nNovoEight 2000 IU powder for solution for injection \n \nturoctocog alfa \n \nIntravenous use \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n2000 IU \n \n \n6. OTHER \n \nNovo Nordisk A/S \n\n\n\n41 \n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCarton \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nNovoEight 3000 IU powder and solvent for solution for injection \n \nturoctocog alfa (human coagulation factor VIII (rDNA)) \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE \n \nOne ml of NovoEight contains approximately 750 IU of human coagulation factor VIII (rDNA), \nturoctocog alfa after reconstitution \n \n \n3. LIST OF EXCIPIENTS \n \nPowder: Sodium chloride, L-histidine, sucrose, polysorbate 80, L-methionine, calcium chloride \ndihydrate, sodium hydroxide, hydrochloric acid \nSolvent: Sodium chloride, water for injections \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nPowder and solvent for solution for injection \n \nPack contains: 1 powder vial, 4 ml solvent in pre-filled syringe, plunger rod and vial adapter \n \n \n5. METHOD AND ROUTE OF ADMINISTRATION \n \nIntravenous use \n \nRead the package leaflet before use \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children \n \n \n7. OTHER SPECIAL WARNINGS, IF NECESSARY \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \n\n\n\n42 \n\nStore in a refrigerator. Do not freeze \n \nDuring storage, the product may be kept at: \n• room temperature (≤ 30°C) for a single period no longer than 9 months or \n• above room temperature (30°C up to 40°C) for a single period no longer than 3 months \n \nTaken out of refrigerator: _____________Stored at ≤30°C __ Stored at 30°C up to 40°C __ \n \nStore in the original package in order to protect from light \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nNovo Nordisk A/S \nNovo Allé \nDK-2880 Bagsværd \nDenmark \n \n \n12. MARKETING AUTHORISATION NUMBERS \n \nEU/1/13/888/006 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \nMedicinal product subject to medical prescription \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nNovoEight 3000 IU \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: \nSN: \n\n\n\n43 \n\nNN:\n\n\n\n44 \n\n \nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVial \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION \n \nNovoEight 3000 IU powder for solution for injection \n \nturoctocog alfa \n \nIntravenous use \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n3000 IU \n \n \n6. OTHER \n \nNovo Nordisk A/S \n\n\n\n45 \n\n \nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nPre-filled syringe \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION \n \nSolvent for NovoEight \n \nSodium chloride 9 mg/ml \n \n \n2. METHOD OF ADMINISTRATION \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n4 ml \n \n \n6. OTHER \n \nNovo Nordisk A/S \n\n\n\n46 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nB. PACKAGE LEAFLET \n \n\n\n\n47 \n\nPackage leaflet: Information for the user \n \n\nNovoEight 250 IU powder and solvent for solution for injection \nNovoEight 500 IU powder and solvent for solution for injection \nNovoEight 1000 IU powder and solvent for solution for injection \nNovoEight 1500 IU powder and solvent for solution for injection \nNovoEight 2000 IU powder and solvent for solution for injection \nNovoEight 3000 IU powder and solvent for solution for injection \n\n \nturoctocog alfa (human coagulation factor VIII (rDNA)) \n\n \nRead all of this leaflet carefully before you start using this medicine because it contains \nimportant information for you. \n– Keep this leaflet. You may need to read it again. \n– If you have any further questions, ask your doctor. \n– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n– If you get any side effects, talk to your doctor. This includes any possible side effects not listed \n\nin this leaflet. See section 4. \n \nWhat is in this leaflet \n1. What NovoEight is and what it is used for \n2. What you need to know before you use NovoEight \n3. How to use NovoEight \n4. Possible side effects \n5. How to store NovoEight \n6. Contents of the pack and other information \n \n \n1. What NovoEight is and what it is used for \n \nNovoEight contains the active substance turoctocog alfa, human coagulation factor VIII. Factor VIII is \na protein naturally found in the blood that helps it to clot. \n \nNovoEight is used to treat and prevent bleeding episodes in patients with haemophilia A (inborn factor \nVIII deficiency) and can be used for all age groups. \n \nIn patients with haemophilia A, factor VIII is missing or not working properly. NovoEight replaces \nthis faulty or missing ‘factor VIII’ and helps blood to form clots at the site of bleeding. \n \n \n2. What you need to know before you use NovoEight \n \nDo not use NovoEight: \n• if you are allergic to the active substance or to any of the other ingredients of this medicine \n\n(listed in section 6) \n• if you are allergic to hamster proteins. \n \nDo not use NovoEight if either of the above applies to you. If you are not sure, talk to your doctor \nbefore using this medicine. \n \nWarnings and precautions \n \nTalk to your doctor before using NovoEight. \n \nThere is a rare chance that you may experience an anaphylactic reaction (a severe, sudden allergic \nreaction) to NovoEight. Early signs of allergic reactions are rash, hives, weals, generalised itching, \n\n\n\n48 \n\nswelling of lips and tongue, difficulty in breathing, wheezing, tightness of the chest, general feeling of \nbeing unwell, and dizziness. \n \nIf any of these symptoms occur, stop the injection immediately and contact your doctor. \n \nTalk to your doctor if you think that your bleed is not being controlled with the dose you receive, as \nthere can be several reasons for this. Some people using this medicine can develop antibodies to factor \nVIII (also known as factor VIII inhibitors). Factor VIII inhibitors make NovoEight less effective in \npreventing or controlling bleeding. If this happens you may need a higher dose of NovoEight or a \ndifferent medicine to control your bleed. Do not increase the total dose of NovoEight to control your \nbleed without talking to your doctor. You should tell your doctor if you have been previously treated \nwith factor VIII products, especially if you developed inhibitors, since there might be a higher risk that \nit happens again. \n \nThe formation of inhibitors (antibodies) is a known complication that can occur during treatment with \nall Factor VIII medicines. These inhibitors, especially at high levels, stop the treatment working \nproperly and you or your child will be monitored carefully for the development of these inhibitors. If \nyou or your child´s bleeding is not being controlled with NovoEight, tell your doctor immediately. \n \nOther medicines and NovoEight \nTell your doctor if you are taking, have recently taken or might take any other medicines. \n \nPregnancy and breastfeeding \nIf you are pregnant or breastfeeding, think that you may be pregnant or are planning to have a baby, \nask your doctor for advice before taking this medicine. \n \nDriving and using machines \nNovoEight has no influence on your ability to drive and use machines. \n \nNovoEight contains sodium \nThis medicine contains 30.5 mg sodium (main component of cooking/table salt) per reconstituted vial. \nThis is equivalent to 1.5% of the recommended maximum dietary intake of sodium for an adult. \n \nTalk to your doctor if you are on a controlled sodium diet. \n \n \n3. How to use NovoEight \n \nTreatment with NovoEight will be started by a doctor who is experienced in the care of patients with \nhaemophilia A. Always use this medicine exactly as your doctor has told you. Check with your doctor \nif you are not sure. \n \nYour doctor will calculate your dose for you. This will depend on your weight and what the medicine \nis being used for. \n \nPrevention of bleeding \nThe usual dose of NovoEight is 20 to 50 international units (IU) per kg of body weight. The injection \nis given every 2 to 3 days. In some cases, especially in younger patients, more frequent injections or \nhigher doses may be needed. \n \nTreatment of bleeding \nThe dose of NovoEight is calculated depending on your body weight and the factor VIII levels to be \nachieved. The target factor VIII levels will depend on the severity and location of the bleeding. \n \nUse in children and adolescents \nNovoEight can be used in children of all ages. In children (below the age of 12) higher doses or more \nfrequent injections may be needed. Adolescents (above the age of 12) can use the same dose as adults. \n\n\n\n49 \n\n \nHow NovoEight is given \nNovoEight is given as an injection into a vein. See ‘Instructions on how to use NovoEight’ for more \ninformation. \n \nIf you use more NovoEight than you should \nIf you use more NovoEight than you should, tell your doctor or go to a hospital straight away. \n \nIf you forget to use NovoEight \nYou should contact your doctor if you have missed a dose and do not know how to compensate for \nthis. \n \nIf you stop using NovoEight \nIf you stop using NovoEight you may no longer be protected against bleeding or a current bleed may \nnot stop. Do not stop using NovoEight without talking to your doctor. \n \nIf you have any further questions on the use of this medicine, ask your doctor. \n \n \n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. The \nfollowing side effects may occur with this medicine. \n \nIf severe, sudden allergic reactions (anaphylactic reactions) occur (very rare), the injection must be \nstopped immediately. You must contact your doctor immediately if you have one of the following \nearly symptoms: \n \n• difficulty in breathing, shortness of breath or wheezing \n• chest tightness \n• swelling of the lips and tongue \n• rash, hives, weals or generalised itching \n• feeling dizzy or loss of consciousness \n• low blood pressure (having pale and cold skin, fast heartbeat). \n \nSevere symptoms, including difficulty in swallowing or breathing and red or swollen face or hands, \nrequire prompt emergency treatment. \n \nIf you have a severe allergic reaction, your doctor may change your medicine. \n \nFor children not previously treated with Factor VIII medicines, inhibitor antibodies (see section 2) \nmay form very commonly (more than 1 in 10 patients); however patients who have received previous \ntreatment with Factor VIII (more than 150 days of treatment) the risk is uncommon (less than 1 in 100 \npatients). If this happens to you or your child´s medicines may stop working properly and you or your \nchild may experience persistent bleeding. If this happens, you should contact your doctor immediately. \n \nCommon side effects (may affect up to 1 in 10 people) \n• blood tests showing changes in the way the liver functions \n• reactions (redness and itching) around the site where you injected the medicine. \n \nCommon side effects (may affect up to 1 in 10 people) in patients who have not previously \ntreated with Factor VIII medicines \n• blushing of the skin \n• inflammation of vein \n• bleeding into joint spaces \n• bleeding in muscle tissue \n• cough \n\n\n\n50 \n\n• redness around the site where you placed catheter \n• vomiting. \n \nUncommon side effects (may affect up to 1 in 100 people) \n• feeling tired \n• headache \n• feeling dizzy \n• difficulty sleeping (insomnia) \n• fast heartbeat \n• increased blood pressure \n• rash \n• fever \n• feeling hot \n• stiffness of muscles \n• pain in muscles \n• pain in legs and arms \n• swelling of legs and feet \n• joint disease \n• bruising \n• heart attack. \n \nSide effects in children and adolescents \nThe side effects observed in children and adolescents are the same as observed in adults. \n \nReporting of side effects \nIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side \neffects not listed in this leaflet. You can also report side effects directly via the national reporting \nsystem listed in Appendix V. By reporting side effects you can help provide more information on the \nsafety of this medicine. \n \n \n5. How to store NovoEight \n \nKeep this medicine out of the sight and reach of children. \n \nDo not use this medicine after the expiry date, which is stated after ‘EXP’ on the carton and on the vial \nand the pre-filled syringe labels. The expiry date refers to the last day of that month. \n \nStore in a refrigerator (2°C – 8°C). \nDo not freeze. \nKeep the vial in the outer carton in order to protect from light. \n \nBefore the NovoEight powder is reconstituted it may be kept at: \n \n• room temperature (≤ 30°C) for a single period no longer than 9 months \n or \n• above room temperature (30°C up to 40°C) for a single period no longer than 3 months. \n \nOnce the product has been taken out of the refrigerator, the product must not be returned to the \nrefrigerator. \n \nPlease record the beginning of storage and the storage temperature on the product carton. \n \nOnce you have reconstituted NovoEight it should be used right away. If you cannot use the \nreconstituted NovoEight solution immediately, it should be used within: \n• 24 hours stored at 2°C – 8°C \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n51 \n\n• 4 hours stored at ≤ 30°C, for product which has been kept for a single period no longer than \n9 months at room temperature (≤30°C) \n\n• 4 hours stored up to 40°C, for product which has been kept for a single period no longer than \n3 months at above room temperature (30°C up to 40°C). \n\n \nStore the reconstituted product in the vial. If not used straight away the medicine may no longer be \nsterile and could cause infection. Do not store the solution without your doctor’s advice. \n \nThe powder in the vial appears as a white or slightly yellow powder. Do not use the powder if the \ncolour has changed. \n \nThe reconstituted solution will be clear to slightly opalescent. Do not use this medicine if you notice \nthat it is cloudy or contains visible particles. \n \nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \nthrow away medicines you no longer use. These measures will help protect the environment. \n \n \n6. Contents of the pack and other information \n \nWhat NovoEight contains \n– The active substance is turoctocog alfa (human coagulation factor VIII (rDNA)). Each vial of \n\nNovoEight contains nominally 250, 500, 1000, 1500, 2000 or 3000 IU turoctocog alfa. \n– The other ingredients are L-histidine, sucrose, polysorbate 80, sodium chloride, L-methionine, \n\ncalcium chloride dihydrate, sodium hydroxide and hydrochloric acid. \n– The ingredients in the solvent are sodium chloride and water for injections. \n \nAfter reconstitution with the supplied solvent (sodium chloride 9 mg/ml (0.9%) solution for injection), \nthe prepared solution for injection contains 62.5, 125, 250, 375, 500 or 750 IU turoctocog alfa per ml, \nrespectively, (based on the strength of turoctocog alfa, i.e. 250, 500, 1000, 1500, 2000 or 3000 IU). \n \nWhat NovoEight looks like and contents of the pack \nNovoEight is a powder and solvent for solution for injection. Each pack of NovoEight contains a vial \nwith white or slightly yellow powder, a 4 ml pre-filled syringe with a clear colourless solution, a \nplunger rod and a vial adapter. \n \nMarketing Authorisation Holder and Manufacturer \nNovo Nordisk A/S \nNovo Allé \nDK-2880 Bagsværd, Denmark \n \n \nThis leaflet was last revised in \n \n \nOther sources of information \n \n \nDetailed information on this medicine is available on the European Medicines Agency web site: \nhttp://www.ema.europa.eu. \n\nhttp://www.ema.europa.eu/\nhttp://www.ema.europa.eu/\n\n\n52 \n\n \nInstructions on how to use NovoEight \n \nREAD THESE INSTRUCTIONS CAREFULLY BEFORE USING NOVOEIGHT. \n \nNovoEight is supplied as a powder. Before injection (administration) it must be reconstituted with \nthe solvent supplied in the syringe. The solvent is a sodium chloride 9 mg/ml (0.9%) solution. The \nreconstituted NovoEight must be injected into your vein (intravenous injection). The equipment in \nthis package is designed to reconstitute and inject NovoEight. \n \nYou will also need an infusion set (tubing and butterfly needle), sterile alcohol swabs, gauze pads \nand plasters. These devices are not included in the NovoEight package. \n \nDo not use the equipment without proper training from your doctor or nurse. \n \nAlways wash your hands and ensure that the area around you is clean. \n \nWhen you prepare and inject medicine directly into the veins, it is important to use a clean and \ngerm free (aseptic) technique. Improper technique can introduce germs that can infect the blood. \n \nDo not open the equipment until you are ready to use it. \n \nDo not use the equipment if it has been dropped, or if it is damaged. Use a new package instead. \n \nDo not use the equipment if it is expired. Use a new package instead. The expiry date is printed \nafter ‘EXP’ on the outer carton, on the vial, on the vial adapter, and on the pre-filled syringe. \n \nDo not use the equipment if you suspect it is contaminated. Use a new package instead. \n \nDo not dispose of any of the items until after you have injected the reconstituted solution. \n \nThe equipment is for single use only. \n \nContents \n \nThe package contains: \n \n• 1 vial with NovoEight powder \n• 1 vial adapter \n• 1 pre-filled syringe with solvent \n• 1 plunger rod (placed under the syringe) \n \n \n\n\n\n53 \n\n \n\n \nOverview \nVial with NovoEight powder \n\nPlastic cap \nRubber stopper \n\n(under plastic cap) \n\n \n\n \n\nProtective cap \nVial adapter \n\nSpike \n(under protective paper) \n\nProtective \npaper \n\n \n \n \n\n \n\n \n\nSyringe cap \n\nSyringe tip \n(under syringe \n\ncap) \n\nPre-filled syringe with solvent \n\nScale \n\nPlunger \n\n \n\n \n\nThread \n\nPlunger rod \n\nWide top \nend \n\n \n \n1. Prepare the vial and the syringe \n \n• Take out the number of NovoEight \n\npackages you need. \n \n• Check the expiry date. \n \n• Check the name, strength and \n\ncolour of the package, to make sure it \ncontains the correct product. \n\n \n• Wash your hands and dry them \n\nproperly using a clean towel or air dry. \n \n• Take the vial, the vial adapter and the \n\npre-filled syringe out of the carton. \nLeave the plunger rod untouched in \nthe carton. \n\n \n• Bring the vial and the pre-filled \n\nsyringe to room temperature. You \ncan do this by holding them in your \nhands until they feel as warm as your \nhands. \n\n \n• Do not use any other way to heat the \n\n \n \n \n\n \n\n A \n\n \n\n\n\n54 \n\nvial and pre-filled syringe. \n• Remove the plastic cap from the vial. \n\nIf the plastic cap is loose or missing, \ndo not use the vial. \n\n \n• Wipe the rubber stopper with a \n\nsterile alcohol swab and allow it to air \ndry for a few seconds before use to \nensure that it is as germ free as \npossible. \n\n \n• Do not touch the rubber stopper \n\nwith your fingers as this can transfer \ngerms. \n\n \n\n B \n\n \n \n\n2. Attach the vial adapter \n \n• Remove the protective paper from \n\nthe vial adapter. \n \nIf the protective paper is not fully \nsealed or if it is broken, do not use \nthe vial adapter. \n \nDo not take the vial adapter out of \nthe protective cap with your fingers. \nIf you touch the spike on the vial \nadapter, germs from your fingers can \nbe transferred. \n\n \n \n\n \n\n C \n\n \n\n• Place the vial on a flat and solid \nsurface. \n \n\n• Turn over the protective cap, and \nsnap the vial adapter onto the vial. \n \nOnce attached, do not remove the \nvial adapter from the vial. \n\n \n\n D \n\n \n \n\n• Lightly squeeze the protective cap \nwith your thumb and index finger as \nshown. \n \nRemove the protective cap from the \nvial adapter. \n \nDo not lift the vial adapter from the \nvial when removing the protective cap. \n\n E \n\n \n\n3. Attach the plunger rod and the syringe \n \n• Grasp the plunger rod by the wide top \n\nend and take it out of the carton. Do \nnot touch the sides or the thread of \nthe plunger rod. If you touch the \nsides or the thread, germs from your \nfingers can be transferred. \n\n \n• Immediately connect the plunger rod \n\nto the syringe by turning it clockwise \n\n \n \n\n \n\n F \n\n \n\n\n\n55 \n\ninto the plunger inside the pre-filled \nsyringe until resistance is felt. \n\n• Remove the syringe cap from the pre-\nfilled syringe by bending it down until \nthe perforation breaks. \n\n \n• Do not touch the syringe tip under \n\nthe syringe cap. If you touch the \nsyringe tip, germs from your fingers \ncan be transferred. \n\n \nIf the syringe cap is loose or missing, \ndo not use the pre-filled syringe. \n\n \n\n G \n\n \n\n• Screw the pre-filled syringe securely \nonto the vial adapter until resistance is \nfelt. \n\n \n\n H \n\n \n \n\n4. Reconstitute the powder with the \nsolvent \n \n• Hold the pre-filled syringe slightly \n\ntilted with the vial pointing \ndownwards. \n\n \n• Push the plunger rod to inject all the \n\nsolvent into the vial. \n\n \n\n I \n\n \n\n• Keep the plunger rod pressed down \nand swirl the vial gently until all the \npowder is dissolved. \n \nDo not shake the vial as this will \ncause foaming. \n \n\n• Check the reconstituted solution. It \nmust be clear to slightly opalescent \n(slightly unclear). If you notice visible \nparticles or discolouration, do not \nuse it. Use a new package instead. \n\n \n\n J \n\n \nNovoEight is recommended to be used immediately after it has been reconstituted. This is \nbecause if left, the medicine may no longer be sterile and could cause infections. \n \nIf you cannot use the reconstituted NovoEight solution immediately, it should be used within \n4 hours when stored at room temperature or up to 40°C and within 24 hours when stored at 2°C – \n8°C. Store the reconstituted product in the vial. \n \nDo not freeze reconstituted NovoEight solution or store it in syringes. \nDo not store the solution without your doctor’s advice. \n \nKeep reconstituted NovoEight solution out of direct light. \n \n\n\n\n56 \n\n \nIf your dose requires more than one vial, repeat steps A to J with additional vials, vial adapters and \npre-filled syringes until you have reached your required dose. \n \n• Keep the plunger rod pushed \n\ncompletely in. \n \n• Turn the syringe with the vial upside \n\ndown. \n \n• Stop pushing the plunger rod and let \n\nit move back on its own while the \nreconstituted solution fills the syringe. \n\n \n• Pull the plunger rod slightly \n\ndownwards to draw the reconstituted \nsolution into the syringe. \n\n \n• In case you only need part of the \n\nentire vial, use the scale on the \nsyringe to see how much \nreconstituted solution you withdraw, \nas instructed by your doctor or \nnurse. \n \nIf, at any point, there is too much air in \nthe syringe, inject the air back into the \nvial. \n\n \n• While holding the vial upside down, \n\ntap the syringe gently to let any air \nbubbles rise to the top. \n\n \n• Push the plunger rod slowly until all \n\nair bubbles are gone. \n \n \n\n \n\n K \n\n \n\n• Unscrew the vial adapter with the \nvial. \n\n \n• Do not touch the syringe tip. If you \n\ntouch the syringe tip, germs from your \nfingers can be transferred. \n\n \n\n \n\n L \n\n \n5. Inject the reconstituted solution \n \nNovoEight is now ready to be injected into your vein. \n \n• Inject the reconstituted solution as instructed by your doctor or nurse. \n \n• Inject slowly over 2 to 5 minutes. \n \n• Do not mix NovoEight with any other intravenous infusions or medicines. \n \nInjecting NovoEight via needleless connectors for intravenous (IV) catheters \n \nCaution: The pre-filled syringe is made of glass and is designed to be compatible with standard \n\n\n\n57 \n\nluer-lock connections. Some needleless connectors with an internal spike are incompatible with the \npre-filled syringe. This incompatibility may prevent administration of the medicine and/or result in \ndamage to the needleless connector. \n \nInjecting the solution via a central venous access device (CVAD) such as a central venous catheter \nor a subcutaneous port: \n• Use a clean and germ free (aseptic) technique. Follow the instructions for proper use for your \nconnector and CVAD in consultation with your doctor or nurse. \n• Injecting into a CVAD may require using a sterile 10 ml plastic syringe for withdrawal of the \nreconstituted solution. This should be done right after step J. \n• If the CVAD line needs to be flushed before or after NovoEight injection, use sodium chloride \n9 mg/ml solution for injection. \n \n \nDisposal \n \n• After injection, safely dispose of all \n\nunused NovoEight solution, the \nsyringe with the infusion set, the vial \nwith the vial adapter and other waste \nmaterials as instructed by your \npharmacist. \n \nDo not throw it out with the ordinary \nhousehold waste. \n\n \n\n \n\n M \n\n \n\n \nDo not disassemble the equipment before disposal. \n \nDo not reuse the equipment. \n\n \n\n\n\tANNEX I SUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. PACKAGE LEAFLET"},"Section_1":{"kind":"string","value":"{'Title': '1. what novoeight is and what it is used for', 'Section_Content': \"novoeight contains the active substance turoctocog alfa, human coagulation factor viii. factor viii is a protein naturally found in the blood that helps it to clot. novoeight is used to treat and prevent bleeding episodes in patients with haemophilia a (inborn factor viii deficiency) and can be used for all age groups. in patients with haemophilia a, factor viii is missing or not working properly. novoeight replaces this faulty or missing 'factor viii' and helps blood to form clots at the site of bleeding.\", 'Entity_Recognition': [{'Text': 'novoeight', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'novoeight', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 9}, {'Text': 'the active substance turoctocog alfa', 'Type': 'TREATMENT', 'BeginOffset': 19, 'EndOffset': 55}, {'Text': 'human coagulation factor viii', 'Type': 'TREATMENT', 'BeginOffset': 57, 'EndOffset': 86}, {'Text': 'factor viii', 'Type': 'PROBLEM', 'BeginOffset': 88, 'EndOffset': 99}, {'Text': 'a protein naturally', 'Type': 'PROBLEM', 'BeginOffset': 103, 'EndOffset': 122}, {'Text': 'the blood', 'Type': 'PROBLEM', 'BeginOffset': 132, 'EndOffset': 141}, {'Id': 0, 'BeginOffset': 159, 'EndOffset': 163, 'Score': 0.7891916036605835, 'Text': 'clot', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.47304147481918335}]}, {'Id': 1, 'BeginOffset': 165, 'EndOffset': 174, 'Score': 0.5823735594749451, 'Text': 'novoeight', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'bleeding episodes', 'Type': 'PROBLEM', 'BeginOffset': 204, 'EndOffset': 221}, {'Text': 'haemophilia a (inborn factor viii deficiency', 'Type': 'PROBLEM', 'BeginOffset': 239, 'EndOffset': 283}, {'Id': 5, 'BeginOffset': 338, 'EndOffset': 349, 'Score': 0.5161329507827759, 'Text': 'haemophilia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 353, 'EndOffset': 375, 'Score': 0.7121350765228271, 'Text': 'factor viii is missing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 401, 'EndOffset': 410, 'Score': 0.2092716246843338, 'Text': 'novoeight', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 481, 'EndOffset': 486, 'Score': 0.5697647929191589, 'Text': 'clots', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 502, 'EndOffset': 510, 'Score': 0.9601958394050598, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}]}"},"Section_2":{"kind":"string","value":"{'Title': '2. what you need to know before you use novoeight', 'Section_Content': 'do not use novoeight: if you are allergic to the active substance or to any of the other ingredients of this medicine (listed in section 6) if you are allergic to hamster proteins. do not use novoeight if either of the above applies to you. if you are not sure, talk to your doctor before using this medicine. warnings and precautions talk to your doctor before using novoeight. there is a rare chance that you may experience an anaphylactic reaction (a severe, sudden allergic reaction) to novoeight. early signs of allergic reactions are rash, hives, weals, generalised itching, 48 swelling of lips and tongue, difficulty in breathing, wheezing, tightness of the chest, general feeling of being unwell, and dizziness. if any of these symptoms occur, stop the injection immediately and contact your doctor. talk to your doctor if you think that your bleed is not being controlled with the dose you receive, as there can be several reasons for this. some people using this medicine can develop antibodies to factor viii (also known as factor viii inhibitors). factor viii inhibitors make novoeight less effective in preventing or controlling bleeding. if this happens you may need a higher dose of novoeight or a different medicine to control your bleed. do not increase the total dose of novoeight to control your bleed without talking to your doctor. you should tell your doctor if you have been previously treated with factor viii products, especially if you developed inhibitors, since there might be a higher risk that it happens again. the formation of inhibitors (antibodies) is a known complication that can occur during treatment with all factor viii medicines. these inhibitors, especially at high levels, stop the treatment working properly and you or your child will be monitored carefully for the development of these inhibitors. if you or your child´s bleeding is not being controlled with novoeight, tell your doctor immediately. other medicines and novoeight tell your doctor if you are taking, have recently taken or might take any other medicines. pregnancy and breastfeeding if you are pregnant or breastfeeding, think that you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. driving and using machines novoeight has no influence on your ability to drive and use machines. novoeight contains sodium this medicine contains 30.5 mg sodium (main component of cooking/table salt) per reconstituted vial. this is equivalent to 1.5% of the recommended maximum dietary intake of sodium for an adult. talk to your doctor if you are on a controlled sodium diet.', 'Entity_Recognition': [{'Text': 'novoeight', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 33, 'EndOffset': 41}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 104, 'EndOffset': 117}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 137, 'EndOffset': 138}, {'Id': 3, 'BeginOffset': 151, 'EndOffset': 179, 'Score': 0.5016007423400879, 'Text': 'allergic to hamster proteins', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 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0.44668304920196533}]}, {'Id': 38, 'BeginOffset': 2154, 'EndOffset': 2162, 'Score': 0.9907331466674805, 'Text': 'pregnant', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9522414207458496}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2236, 'EndOffset': 2249}, {'Text': 'machines novoeight', 'Type': 'TREATMENT', 'BeginOffset': 2269, 'EndOffset': 2287}, {'Text': 'novoeight', 'Type': 'TREATMENT', 'BeginOffset': 2348, 'EndOffset': 2357}, {'Text': 'sodium this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2367, 'EndOffset': 2387}, {'Text': '30.5', 'Type': 'NUMBER', 'BeginOffset': 2397, 'EndOffset': 2401}, {'Text': 'cooking/table salt', 'Type': 'TREATMENT', 'BeginOffset': 2431, 'EndOffset': 2449}, {'Text': '1.5', 'Type': 'NUMBER', 'BeginOffset': 2497, 'EndOffset': 2500}, {'Text': 'a controlled sodium diet', 'Type': 'TREATMENT', 'BeginOffset': 2602, 'EndOffset': 2626}]}"},"Section_3":{"kind":"string","value":"{'Title': '3. how to use novoeight', 'Section_Content': \"treatment with novoeight will be started by a doctor who is experienced in the care of patients with haemophilia a. always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure. your doctor will calculate your dose for you. this will depend on your weight and what the medicine is being used for. prevention of bleeding the usual dose of novoeight is 20 to 50 international units (iu) per kg of body weight. the injection is given every 2 to 3 days. in some cases, especially in younger patients, more frequent injections or higher doses may be needed. treatment of bleeding the dose of novoeight is calculated depending on your body weight and the factor viii levels to be achieved. the target factor viii levels will depend on the severity and location of the bleeding. use in children and adolescents novoeight can be used in children of all ages. in children (below the age of 12) higher doses or more frequent injections may be needed. adolescents (above the age of 12) can use the same dose as adults. how novoeight is given novoeight is given as an injection into a vein. see 'instructions on how to use novoeight' for more information. if you use more novoeight than you should if you use more novoeight than you should, tell your doctor or go to a hospital straight away. if you forget to use novoeight you should contact your doctor if you have missed a dose and do not know how to compensate for this. if you stop using novoeight if you stop using novoeight you may no longer be protected against bleeding or a current bleed may not stop. do not stop using novoeight without talking to your doctor. if you have any further questions on the use of this medicine, ask your doctor.\", 'Entity_Recognition': [{'Text': 'novoeight', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 9}, {'Text': 'novoeight', 'Type': 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{'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 481, 'EndOffset': 482}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 486, 'EndOffset': 487}, {'Text': 'frequent injections', 'Type': 'TREATMENT', 'BeginOffset': 546, 'EndOffset': 565}, {'Id': 4, 'BeginOffset': 610, 'EndOffset': 618, 'Score': 0.860314130783081, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.5511850714683533}]}, {'Text': 'novoeight', 'Type': 'TREATMENT', 'BeginOffset': 631, 'EndOffset': 640}, {'Text': 'your body weight', 'Type': 'TEST', 'BeginOffset': 668, 'EndOffset': 684}, {'Text': 'the factor viii levels', 'Type': 'TEST', 'BeginOffset': 689, 'EndOffset': 711}, {'Text': 'the target factor viii levels', 'Type': 'TEST', 'BeginOffset': 728, 'EndOffset': 757}, {'Text': 'the severity', 'Type': 'PROBLEM', 'BeginOffset': 773, 'EndOffset': 785}, {'Text': 'the bleeding', 'Type': 'PROBLEM', 'BeginOffset': 802, 'EndOffset': 814}, {'Id': 8, 'BeginOffset': 925, 'EndOffset': 927, 'Score': 0.8131416440010071, 'Text': '12', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'AGE', 'Traits': []}, {'Text': 'more frequent injections', 'Type': 'TREATMENT', 'BeginOffset': 945, 'EndOffset': 969}, {'Id': 9, 'BeginOffset': 1015, 'EndOffset': 1017, 'Score': 0.8253087997436523, 'Text': '12', 'Category': 'PROTECTED_HEALTH_INFORMATION', 'Type': 'AGE', 'Traits': []}, {'Text': 'novoeight', 'Type': 'TREATMENT', 'BeginOffset': 1075, 'EndOffset': 1084}, {'Id': 14, 'BeginOffset': 1100, 'EndOffset': 1109, 'Score': 0.36333727836608887, 'Text': 'injection', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'PROCEDURE_NAME', 'Traits': []}, {'Id': 0, 'BeginOffset': 1117, 'EndOffset': 1121, 'Score': 0.8430474400520325, 'Text': 'vein', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 6, 'BeginOffset': 1552, 'EndOffset': 1560, 'Score': 0.7792722582817078, 'Text': 'bleeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.43699005246162415}]}, {'Text': 'a current bleed', 'Type': 'PROBLEM', 'BeginOffset': 1564, 'EndOffset': 1579}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1702, 'EndOffset': 1715}]}"},"Section_4":{"kind":"string","value":"{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the following side effects may occur with this medicine. if severe, sudden allergic reactions (anaphylactic reactions) occur (very rare), the injection must be stopped immediately. you must contact your doctor immediately if you have one of the following early symptoms: difficulty in breathing, shortness of breath or wheezing chest tightness swelling of the lips and tongue rash, hives, weals or generalised itching feeling dizzy or loss of consciousness low blood pressure (having pale and cold skin, fast heartbeat). severe symptoms, including difficulty in swallowing or breathing and red or swollen face or hands, require prompt emergency treatment. if you have a severe allergic reaction, your doctor may change your medicine. for children not previously treated with factor viii medicines, inhibitor antibodies (see section 2) may form very commonly (more than 1 in 10 patients); however patients who have received previous treatment with factor viii (more than 150 days of treatment) the risk is uncommon (less than 1 in 100 patients). if this happens to you or your child´s medicines may stop working properly and you or your child may experience persistent bleeding. if this happens, you should contact your doctor immediately. common side effects (may affect up to 1 in 10 people) blood tests showing changes in the way the liver functions reactions (redness and itching) around the site where you injected the medicine. common side effects (may affect up to 1 in 10 people) in patients who have not previously treated with factor viii medicines blushing of the skin inflammation of vein bleeding into joint spaces bleeding in muscle tissue cough 50 redness around the site where you placed catheter vomiting. uncommon side effects (may affect up to 1 in 100 people) feeling tired headache feeling dizzy difficulty sleeping (insomnia) fast heartbeat increased blood pressure rash fever feeling hot stiffness of muscles pain in muscles pain in legs and arms swelling of legs and feet joint disease bruising heart attack. side effects in children and adolescents the side effects observed in children and adolescents are the same as observed in adults. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'novoeight', 'Type': 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'TIME_TO_DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'DX_NAME', 'Score': 0.8768852353096008, 'RelationshipScore': 0.6367756724357605, 'RelationshipType': 'OVERLAP', 'Id': 51, 'BeginOffset': 1628, 'EndOffset': 1658, 'Text': 'factor viii medicines blushing', 'Category': 'MEDICAL_CONDITION', 'Traits': []}]}, {'Id': 51, 'BeginOffset': 1628, 'EndOffset': 1658, 'Score': 0.8768852353096008, 'Text': 'factor viii medicines blushing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9883572459220886, 'RelationshipScore': 0.5096378922462463, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 8, 'BeginOffset': 1666, 'EndOffset': 1670, 'Text': 'skin', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'the skin inflammation', 'Type': 'PROBLEM', 'BeginOffset': 1662, 'EndOffset': 1683}, {'Text': 'vein bleeding into joint spaces bleeding', 'Type': 'PROBLEM', 'BeginOffset': 1687, 'EndOffset': 1727}, {'Text': 'muscle tissue cough', 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'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5982107520103455}, {'Name': 'DIAGNOSIS', 'Score': 0.4030875861644745}]}, {'Id': 94, 'BeginOffset': 2531, 'EndOffset': 2543, 'Score': 0.8637406826019287, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7330866456031799}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 2599, 'EndOffset': 2612}]}"},"Section_5":{"kind":"string","value":"{'Title': '5. how to store novoeight', 'Section_Content': \"keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date, which is stated after 'exp' on the carton and on the vial and the pre-filled syringe labels. the expiry date refers to the last day of that month. store in a refrigerator (2 8). do not freeze. keep the vial in the outer carton in order to protect from light. before the novoeight powder is reconstituted it may be kept at: room temperature (≤ 30) for a single period no longer than 9 months or above room temperature (30 up to 40) for a single period no longer than 3 months. once the product has been taken out of the refrigerator, the product must not be returned to the refrigerator. please record the beginning of storage and the storage temperature on the product carton. once you have reconstituted novoeight it should be used right away. if you cannot use the reconstituted novoeight solution immediately, it should be used within: 24 hours stored at 2 8 51 4 hours stored at ≤ 30, for product which has been kept for a single period no longer than 9 months at room temperature (≤30) 4 hours stored up to 40, for product which has been kept for a single period no longer than 3 months at above room temperature (30 up to 40). store the reconstituted product in the vial. if not used straight away the medicine may no longer be sterile and could cause infection. do not store the solution without your doctor's advice. the powder in the vial appears as a white or slightly yellow powder. do not use the powder if the colour has changed. the reconstituted solution will be clear to slightly opalescent. do not use this medicine if you notice that it is cloudy or contains visible particles. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.\", 'Entity_Recognition': [{'Text': 'novoeight', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 279, 'EndOffset': 280}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 281, 'EndOffset': 282}, {'Text': 'the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 317, 'EndOffset': 333}, {'Text': 'the novoeight powder', 'Type': 'TREATMENT', 'BeginOffset': 373, 'EndOffset': 393}, {'Id': 1, 'BeginOffset': 435, 'EndOffset': 446, 'Score': 0.34675249457359314, 'Text': 'temperature', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 450, 'EndOffset': 452}, {'Text': '9', 'Type': 'NUMBER', 'BeginOffset': 489, 'EndOffset': 490}, {'Id': 2, 'BeginOffset': 512, 'EndOffset': 523, 'Score': 0.614795446395874, 'Text': 'temperature', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 525, 'EndOffset': 527}, {'Text': '40', 'Type': 'NUMBER', 'BeginOffset': 534, 'EndOffset': 536}, {'Text': '3', 'Type': 'NUMBER', 'BeginOffset': 573, 'EndOffset': 574}, {'Text': 'novoeight', 'Type': 'TREATMENT', 'BeginOffset': 812, 'EndOffset': 821}, {'Text': 'the reconstituted novoeight solution', 'Type': 'TREATMENT', 'BeginOffset': 870, 'EndOffset': 906}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 946, 'EndOffset': 948}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 965, 'EndOffset': 966}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 967, 'EndOffset': 968}, {'Text': '51', 'Type': 'NUMBER', 'BeginOffset': 969, 'EndOffset': 971}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 972, 'EndOffset': 973}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 992, 'EndOffset': 994}, {'Text': '9', 'Type': 'NUMBER', 'BeginOffset': 1063, 'EndOffset': 1064}, {'Id': 3, 'BeginOffset': 1080, 'EndOffset': 1091, 'Score': 0.4028875231742859, 'Text': 'temperature', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 1094, 'EndOffset': 1096}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 1098, 'EndOffset': 1099}, {'Text': '40', 'Type': 'NUMBER', 'BeginOffset': 1119, 'EndOffset': 1121}, {'Id': 12, 'BeginOffset': 1190, 'EndOffset': 1198, 'Score': 0.42938292026519775, 'Text': '3 months', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_TEST_NAME', 'Traits': [], 'Attributes': [{'Type': 'TEST_NAME', 'Score': 0.3495110273361206, 'RelationshipScore': 0.5320386290550232, 'RelationshipType': 'OVERLAP', 'Id': 4, 'BeginOffset': 1213, 'EndOffset': 1224, 'Text': 'temperature', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Traits': []}]}, {'Id': 4, 'BeginOffset': 1213, 'EndOffset': 1224, 'Score': 0.3495110273361206, 'Text': 'temperature', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': '30', 'Type': 'NUMBER', 'BeginOffset': 1226, 'EndOffset': 1228}, {'Text': '40', 'Type': 'NUMBER', 'BeginOffset': 1235, 'EndOffset': 1237}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 1311, 'EndOffset': 1323}, {'Id': 0, 'BeginOffset': 1365, 'EndOffset': 1374, 'Score': 0.9303035736083984, 'Text': 'infection', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7958881855010986}]}, {'Text': 'the powder in the vial', 'Type': 'TREATMENT', 'BeginOffset': 1432, 'EndOffset': 1454}, {'Text': 'a white or slightly yellow powder', 'Type': 'PROBLEM', 'BeginOffset': 1466, 'EndOffset': 1499}, {'Text': 'the powder', 'Type': 'TREATMENT', 'BeginOffset': 1512, 'EndOffset': 1522}, {'Text': 'the reconstituted solution', 'Type': 'TREATMENT', 'BeginOffset': 1550, 'EndOffset': 1576}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 1626, 'EndOffset': 1639}, {'Text': 'cloudy', 'Type': 'PROBLEM', 'BeginOffset': 1665, 'EndOffset': 1671}, {'Text': 'visible particles', 'Type': 'PROBLEM', 'BeginOffset': 1684, 'EndOffset': 1701}]}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': 'what novoeight contains the active substance is turoctocog alfa (human coagulation factor viii (rdna)). each vial of novoeight contains nominally 250, 500, 1000, 1500, 2000 or 3000 iu turoctocog alfa. the other ingredients are l-histidine, sucrose, polysorbate 80, sodium chloride, l-methionine, calcium chloride dihydrate, sodium hydroxide and hydrochloric acid. the ingredients in the solvent are sodium chloride and water for injections. after reconstitution with the supplied solvent (sodium chloride 9 mg/ml (0.9%) solution for injection), the prepared solution for injection contains 62.5, 125, 250, 375, 500 or 750 iu turoctocog alfa per ml, respectively, (based on the strength of turoctocog alfa, i.e. 250, 500, 1000, 1500, 2000 or 3000 iu). what novoeight looks like and contents of the pack novoeight is a powder and solvent for solution for injection. each pack of novoeight contains a vial with white or slightly yellow powder, a 4 ml pre-filled syringe with a clear colourless solution, a plunger rod and a vial adapter.', 'Entity_Recognition': [{'Text': 'novoeight', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'turoctocog alfa', 'Type': 'TREATMENT', 'BeginOffset': 48, 'EndOffset': 63}, {'Id': 1, 'BeginOffset': 65, 'EndOffset': 94, 'Score': 0.7205720543861389, 'Text': 'human coagulation factor viii', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 2, 'BeginOffset': 117, 'EndOffset': 149, 'Score': 0.22064784169197083, 'Text': 'novoeight contains nominally 250', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 151, 'EndOffset': 154}, {'Text': '1000', 'Type': 'NUMBER', 'BeginOffset': 156, 'EndOffset': 160}, {'Text': '1500', 'Type': 'NUMBER', 'BeginOffset': 162, 'EndOffset': 166}, {'Text': '2000', 'Type': 'NUMBER', 'BeginOffset': 168, 'EndOffset': 172}, {'Text': '3000', 'Type': 'NUMBER', 'BeginOffset': 176, 'EndOffset': 180}, {'Id': 4, 'BeginOffset': 184, 'EndOffset': 199, 'Score': 0.7704997062683105, 'Text': 'turoctocog alfa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'STRENGTH', 'Score': 0.2617872953414917, 'RelationshipScore': 0.6635030508041382, 'RelationshipType': 'STRENGTH', 'Id': 3, 'BeginOffset': 151, 'EndOffset': 183, 'Text': '500, 1000, 1500, 2000 or 3000 iu', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 5, 'BeginOffset': 227, 'EndOffset': 238, 'Score': 0.969170093536377, 'Text': 'l-histidine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 240, 'EndOffset': 247, 'Score': 0.7384836077690125, 'Text': 'sucrose', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 7, 'BeginOffset': 249, 'EndOffset': 263, 'Score': 0.7122704982757568, 'Text': 'polysorbate 80', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 8, 'BeginOffset': 265, 'EndOffset': 280, 'Score': 0.9995942711830139, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 9, 'BeginOffset': 282, 'EndOffset': 294, 'Score': 0.9910643100738525, 'Text': 'l-methionine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 296, 'EndOffset': 322, 'Score': 0.9992460012435913, 'Text': 'calcium chloride dihydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 324, 'EndOffset': 340, 'Score': 0.9995001554489136, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 345, 'EndOffset': 362, 'Score': 0.9962349534034729, 'Text': 'hydrochloric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.3460555374622345, 'RelationshipScore': 0.6210812926292419, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 14, 'BeginOffset': 429, 'EndOffset': 439, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 13, 'BeginOffset': 399, 'EndOffset': 414, 'Score': 0.986504077911377, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.3460555374622345, 'RelationshipScore': 0.9997187256813049, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 14, 'BeginOffset': 429, 'EndOffset': 439, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'STRENGTH', 'Score': 0.9888399243354797, 'RelationshipScore': 0.7908169031143188, 'RelationshipType': 'STRENGTH', 'Id': 16, 'BeginOffset': 505, 'EndOffset': 512, 'Text': '9 mg/ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'STRENGTH', 'Score': 0.9837172031402588, 'RelationshipScore': 0.9235443472862244, 'RelationshipType': 'STRENGTH', 'Id': 17, 'BeginOffset': 514, 'EndOffset': 518, 'Text': '0.9%', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'FORM', 'Score': 0.9009541273117065, 'RelationshipScore': 0.9591839909553528, 'RelationshipType': 'FORM', 'Id': 18, 'BeginOffset': 520, 'EndOffset': 528, 'Text': 'solution', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 429, 'EndOffset': 439}, {'Text': 'reconstitution', 'Type': 'TREATMENT', 'BeginOffset': 447, 'EndOffset': 461}, {'Text': 'the supplied solvent (sodium chloride', 'Type': 'TREATMENT', 'BeginOffset': 467, 'EndOffset': 504}, {'Text': '9', 'Type': 'NUMBER', 'BeginOffset': 505, 'EndOffset': 506}, {'Text': '9', 'Type': 'NUMBER', 'BeginOffset': 516, 'EndOffset': 517}, {'Text': 'the prepared solution', 'Type': 'TREATMENT', 'BeginOffset': 545, 'EndOffset': 566}, {'Text': '62.5', 'Type': 'NUMBER', 'BeginOffset': 590, 'EndOffset': 594}, {'Text': '125', 'Type': 'NUMBER', 'BeginOffset': 596, 'EndOffset': 599}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 601, 'EndOffset': 604}, {'Text': '375', 'Type': 'NUMBER', 'BeginOffset': 606, 'EndOffset': 609}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 611, 'EndOffset': 614}, {'Text': '750', 'Type': 'NUMBER', 'BeginOffset': 618, 'EndOffset': 621}, {'Id': 21, 'BeginOffset': 625, 'EndOffset': 640, 'Score': 0.6877251863479614, 'Text': 'turoctocog alfa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.5757812261581421, 'RelationshipScore': 0.9997929930686951, 'RelationshipType': 'DOSAGE', 'Id': 20, 'BeginOffset': 611, 'EndOffset': 624, 'Text': '500 or 750 iu', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'ROUTE_OR_MODE', 'Score': 0.15765009820461273, 'RelationshipScore': 0.9992305040359497, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 22, 'BeginOffset': 641, 'EndOffset': 647, 'Text': 'per ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 23, 'BeginOffset': 689, 'EndOffset': 704, 'Score': 0.6806747913360596, 'Text': 'turoctocog alfa', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '250', 'Type': 'NUMBER', 'BeginOffset': 711, 'EndOffset': 714}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 716, 'EndOffset': 719}, {'Text': '1000', 'Type': 'NUMBER', 'BeginOffset': 721, 'EndOffset': 725}, {'Text': '1500', 'Type': 'NUMBER', 'BeginOffset': 727, 'EndOffset': 731}, {'Text': '2000', 'Type': 'NUMBER', 'BeginOffset': 733, 'EndOffset': 737}, {'Text': '3000', 'Type': 'NUMBER', 'BeginOffset': 741, 'EndOffset': 745}, {'Text': 'the pack novoeight', 'Type': 'TREATMENT', 'BeginOffset': 793, 'EndOffset': 811}, {'Text': 'a powder and solvent for solution', 'Type': 'TREATMENT', 'BeginOffset': 815, 'EndOffset': 848}, {'Text': 'slightly yellow powder', 'Type': 'TREATMENT', 'BeginOffset': 917, 'EndOffset': 939}, {'Text': 'a 4 ml pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 941, 'EndOffset': 966}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 943, 'EndOffset': 944}, {'Text': 'a clear colourless solution', 'Type': 'TREATMENT', 'BeginOffset': 972, 'EndOffset': 999}, {'Text': 'a plunger rod', 'Type': 'TREATMENT', 'BeginOffset': 1001, 'EndOffset': 1014}, {'Text': 'a vial adapter', 'Type': 'TREATMENT', 'BeginOffset': 1019, 'EndOffset': 1033}]}"}}},{"rowIdx":1064,"cells":{"ID":{"kind":"string","value":"A1B5CA77B539E285D47E3A64125A95D2"},"URL":{"kind":"string","value":"https://www.ema.europa.eu/documents/product-information/lartruvo-epar-product-information_en.pdf"},"Product_Name":{"kind":"string","value":"Lartruvo"},"Full_Content":{"kind":"string","value":"1 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\n \nANNEX I \n\n \nSUMMARY OF PRODUCT CHARACTERISTICS \n\n \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n2 \n\nThis medicinal product is subject to additional monitoring. This will allow quick identification of \nnew safety information. Healthcare professionals are asked to report any suspected adverse reactions. \nSee section 4.8 for how to report adverse reactions. \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nLartruvo 10 mg/mL concentrate for solution for infusion \n \n \n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \nOne mL of concentrate for solution for infusion contains 10 mg of olaratumab. \n \nEach 19 mL vial contains 190 mg of olaratumab. \nEach 50 mL vial contains 500 mg of olaratumab. \n \nOlaratumab is a human IgG1 monoclonal antibody produced in murine (NS0) cells by recombinant \nDNA technology. \n \nExcipient with known effect \n \nEach 19mL vial contains approximately 22 mg (1 mmol) sodium. \nEach 50 mL vial contains approximately 57 mg (2.5 mmol) sodium. \n \nFor the full list of excipients, see section 6.1. \n \n \n3. PHARMACEUTICAL FORM \n \nConcentrate for solution for infusion (sterile concentrate). \n \nThe concentrate is clear to slightly opalescent and colourless to slightly yellow solution without visible \nparticles. \n \n \n4. CLINICAL PARTICULARS \n \n4.1 Therapeutic indications \n \nLartruvo is indicated in combination with doxorubicin for the treatment of adult patients with \nadvanced soft tissue sarcoma who are not amenable to curative treatment with surgery or radiotherapy \nand who have not been previously treated with doxorubicin (see section 5.1). \n \n4.2 Posology and method of administration \n \nOlaratumab therapy must be initiated and supervised by physicians experienced in oncology. Patients \nshould be monitored during the infusion for signs and symptoms of infusion-related reactions (IRRs) \nin a setting with available resuscitation equipment (see section 4.4). \n \nPosology \n \nThe recommended dose of olaratumab is 15 mg/kg administered by intravenous infusion on days 1 \nand 8 of each 3 week cycle until disease progression or unacceptable toxicity. Lartruvo is administered \nin combination with doxorubicin for up to 8 cycles of treatment, followed by Lartruvo monotherapy in \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n3 \n\npatients whose disease has not progressed. Doxorubicin is given on day 1 of each cycle following the \nLartruvo infusion. \n \nPremedication \nPremedication with an H1 antagonist (e.g., diphenhydramine) and dexamethasone (or equivalent \nmedicinal products) should be given, intravenously, 30–60 minutes prior to the olaratumab doses on \ndays 1 and 8 of cycle 1 in all patients. For subsequent cycles, premedication with an H1 antagonist \n(e.g., diphenhydramine) should be given intravenously 30–60 minutes prior to each dose of \nolaratumab. \n \nFor patients who experience Grade 1 or 2 IRR, the infusion should be interrupted and paracetamol, \nH1 antagonist and dexamethasone (or equivalent medicinal products) administered as needed. For all \nsubsequent infusions, premedication with the following (or equivalent medicinal products) \ndiphenhydramine hydrochloride (intravenously), paracetamol, and dexamethasone, should be given. \n \nIn the event that intravenous administration of an H1 antagonist is not possible, equivalent alternative \npremedication should be given (e.g. oral diphenhydramine hydrochloride at least 90 minutes prior to \nthe infusion). \n \nPosology adjustments for olaratumab \nFor dose adjustment recommendations related to doxorubicin, refer to the current doxorubicin \nprescribing information. \n \nInfusion-related reactions (IRRs) \nRecommendations for the management of olaratumab IRRs are provided in table 1. \n \n\nTable 1 – Management recommendations for infusion-related reactions (IRRs) \n \n\nToxicity \ngradea \n\nManagement recommendations \n(any occurrence) \n\nGrade 1-2 • Stop the infusion \n• Paracetamol, H1 antagonist and dexamethasone should be \n\nadministered as needed (see premedication section) \n• Once the reaction has resolved, resume infusion at a 50 % \n\ndecreased infusion rate.b \n• Monitor patient for worsening of condition. \n• For subsequent infusions, please see premedication section. \n\nGrade 3-4 • Immediately and permanently discontinue treatment with \nolaratumab (see section 4.4). \n\na Grade per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI \nCTCAE), Version 4.03 \nb Once the infusion rate has been reduced for a Grade 1 or 2 infusion-related reaction, it is \nrecommended that the lower infusion rate be utilized for all subsequent infusions. The infusion \nduration should not exceed 2 hours. \n\n \nOther non-haematology toxicities \nFor serious Grade ≥ 3 non-haematologic toxicity deemed related to olaratumab, the dose of olaratumab \nshould be withheld until toxicity is ≤ Grade 1 or has returned to pretreatment baseline. For subsequent \ninfusions, the dose should be reduced to 12 mg/kg for serious Grade 3 toxicities and to 10 mg/kg for \nGrade 4 toxicities. If a Grade 3 toxicity recurs despite the dose reduction, the dose should be reduced \nfurther to 10 mg/kg. In case of recurrence of a Grade 4 toxicity, treatment with olaratumab should be \npermanently discontinued. \n \nNeutropenia \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n4 \n\nIf neutropenic fever/infection or Grade 4 neutropenia lasting longer than 1 week occurs, administration \nof olaratumab should be temporarily discontinued until the absolute neutrophil count is 1,000 / µL or \nhigher and then the dose of olaratumab should be resumed at the reduced dose of 12 mg/kg. If \nneutropenic fever/infection or Grade 4 neutropenia lasting longer than 1 week recurs despite dose \nreduction, the dose should be reduced further to 10 mg/kg. \n \nSpecial populations \n \nElderly (> 65 years) \nData on very elderly patients (> 75 years) are very limited (see sections 4.8 and 5.1). \nNo dose reductions other than those recommended for the general patient population are necessary. \n \nRenal impairment \nThere have been no formal studies with olaratumab in patients with renal impairment. PopPK data \nsuggest that no dose adjustments are required in patients with mild or moderate renal impairment. \nThere are no data regarding olaratumab administration in patients with severe renal impairment \n(calculated creatinine clearance < 30 mL/min) (see section 5.2). \n \nHepatic impairment \nThere have been no formal studies with olaratumab in patients with hepatic impairment. PopPK data \nsuggest that no dose adjustments are required in patients with mild hepatic impairment. There are very \nlimited data regarding olaratumab administration in patients with moderate hepatic impairment. There \nare no data in patients with severe hepatic impairment (see section 5.2). \n \nPaediatric population \nThe safety and efficacy of olaratumab in children aged 0 to 18 years of age have not yet been \nestablished. No data are available. \n \nMethod of administration \n \nAfter dilution in sodium chloride 9 mg/mL (0.9 %) solution for injection, olaratumab is administered \nas an intravenous infusion over approximately 60 minutes. In order to accommodate larger infusion \nvolumes that may be needed for patients requiring higher doses, the duration of infusion should be \nincreased such that the maximum infusion rate of 25 mg/minute is not exceeded. \n \nFor instructions on dilution of the medicinal product before administration, see section 6.6. \n \n4.3 Contraindications \n \nHypersensitivity to the active substance or to any of the excipients listed in section 6.1. \n \n4.4 Special warnings and precautions for use \n \nInfusion-related reactions \nInfusion-related reactions (IRRs), including anaphylactic reactions, were reported in clinical trials with \nolaratumab. The majority of these reactions occurred during or following the first olaratumab infusion. \nSymptoms of IRRs included flushing, shortness of breath, bronchospasm, or fever/chills, and in some \ncases manifested as severe hypotension, anaphylactic shock, or fatal cardiac arrest. Severe IRRs such \nas anaphylactic reactions can occur despite the use of premedication. Patients should be monitored \nduring the infusion for signs and symptoms of IRRs in a setting with available resuscitation \nequipment. For management and dose adjustments in patients who experience Grade 1 or 2 IRR \nduring the infusion, see section 4.2. In patients who have experienced a previous Grade 1 or 2 IRR, \npremedication with diphenhydramine hydrochloride (intravenously), paracetamol, and dexamethasone \nis recommended. Olaratumab should be immediately and permanently discontinued in patients who \nexperience Grade 3 or 4 IRR (see sections 4.2 and 4.8). \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n5 \n\nNeutropenia \nPatients receiving olaratumab and doxorubicin are at risk of neutropenia (see section 4.8). Neutrophil \ncount should be checked prior to Olaratumab dosing on Day 1 and Day 8 of each cycle. Neutrophil \ncount should be monitored during the treatment with olaratumab and doxorubicin and supportive care \nshould be administered such as antibiotics or G-CSF as per local guidelines. For dosage adjustments \nrelated to neutropenia, refer to section 4.2. \n \nHaemorrhagic events \nPatients receiving olaratumab and doxorubicin are at risk of haemorrhagic events (see section 4.8). \nPlatelet counts should be checked prior to olaratumab dosing on Day 1 and Day 8 of each cycle. \nCoagulation parameters should be monitored in patients with conditions predisposing to bleeding, \nsuch as anticoagulant use. In a study of olaratumab in combination with liposomal doxorubicin, there \nwas one case of fatal intracranial haemorrhage in a patient who had experienced a fall while on \ntreatment. \n \nAnthracycline pre-treated patients \nThe risk of cardiac toxicity rises with increasing cumulative doses of anthracyclines, including \ndoxorubicin. There are no data for the combination of olaratumab and doxorubicin in anthracycline \npre-treated patients, including pre-treatment with doxorubicin (see section 4.1). \n \nSodium restricted diet \nThis medicinal product contains 22 mg sodium per each 19 mL vial and 57 mg sodium per each \n50 mL vial. To be taken into consideration by patients on a controlled sodium diet. \n \nCardiac toxicity \nDoxorubicin can cause cardiotoxicity. The risk of toxicity rises with increasing cumulative doses and \nis higher in individuals with a history of cardiomyopathy, mediastinal irradiation or pre-existing \ncardiac disease. To minimise doxorubicin-related cardiotoxicity, the use of appropriate cardio-\nprotective measures (LVEF measurement, such as ECHO or MUGA scan, ECG monitoring, and/or \nuse of cardioprotective agents) should be considered and planned in all patients before the start and \nthroughout the treatment. \n \nPlease refer to doxorubicin SmPC for recommendation on cardiac monitoring. \n \nIn the phase 2 trial, patients in both treatment groups that received 5 or more cycles of doxorubicin \nreceived dexrazoxane prior to each dose of doxorubicin from cycle 5 onwards to minimize the risk of \ndoxorubicin-related cardiotoxicity (see sections 4.8 and 5.1). \n \nHepatic impairment \nAs doxorubicin is rapidly metabolised and predominantly eliminated by the biliary system, the toxicity \nof doxorubicin is enhanced in patients with hepatic impairment. Refer to doxorubicin SmPC for \nappropriate monitoring of hepatic function and doxorubicin dose adjustments in patients with impaired \nliver function. \n \n4.5 Interaction with other medicinal products and other forms of interaction \n \nOlaratumab is a human monoclonal antibody. In a dedicated DDI study, no pharmacokinetic \ninteractions were observed in patients between olaratumab and doxorubicin. \n \nNo other formal DDI studies with olaratumab and medicinal products commonly used in cancer \npatients, including those with STS (e.g. antiemetics, analgesics, anti-diarrheal drugs, oral \ncontraceptives, etc.), have been performed. \n \nAs monoclonal antibodies are not metabolised by cytochrome P450 (CYP) enzymes or other drug \nmetabolising enzymes, inhibition or induction of these enzymes by co-administered medicinal \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n6 \n\nproducts is not anticipated to affect the pharmacokinetics of olaratumab. Conversely, olaratumab is not \nanticipated to affect the pharmacokinetics of co-administered medicinal products. \n \nAdministration of live or live-attenuated vaccines in patients immunocompromised by \nchemotherapeutic agents including doxorubicin may result in serious or fatal infections. Vaccination \nwith a live vaccine should be avoided in patients receiving olaratumab in combination with \ndoxorubicin. \n \n4.6 Fertility, pregnancy and lactation \n \nWomen of childbearing potential/contraception in females \nWomen of childbearing potential should be advised to avoid becoming pregnant while on olaratumab \nand should be informed of the potential hazard to the pregnancy and foetus. Women of childbearing \npotential should be advised to use effective contraception during treatment and for at least 3 months \nfollowing the last dose of olaratumab. \n \nPregnancy \nThere are no or limited amount of data from the use of olaratumab in pregnant women. Reproductive \nand development toxicity study conducted with an anti-murine PDGFRα antibody in mice showed \nfoetal malformations and skeletal alterations (see section 5.3). \nBased on its mechanism of action (see section 5.1), olaratumab has the potential to cause foetal harm. \nOlaratumab is not recommended during pregnancy and in women of childbearing potential not using \ncontraception, unless the potential benefit justifies the potential risk to the foetus. \n \nBreast-feeding \nIt is not known whether olaratumab is excreted in human milk. Human IgG is excreted in human milk, \ntherefore breast-feeding is not recommended during treatment with olaratumab and for at least \n3 months following the last dose. \n \nFertility \nThere are no data on the effect of olaratumab on human fertility. \n \n4.7 Effects on ability to drive and use machines \n \nOlaratumab may have minor influence on the ability to drive and use machines. Due to frequent \noccurrence of fatigue, patients should be advised to use caution when driving or operating machinery. \n \n4.8 Undesirable effects \n \nSummary of the safety profile \n \nOlaratumab-treated patients from Phase 2 study \nIn the olaratumab plus doxorubicin arm, the most serious (Grade ≥3) adverse drug reactions (ADRs) \nobserved were neutropenia (54.7 %) and musculoskeletal pain (7.8 %). \n \nThe most frequently occurring ADRs were nausea, musculoskeletal pain, neutropenia and mucositis. \n \nThe most frequent ADRs associated with permanent treatment discontinuation occurred in 3 (4.7 %) \npatients of which the most frequent were infusion-related reactions (3.1 %) and mucositis (1.6 %). \n \nKnown toxicities reported for doxorubicin, observed in the combination of olaratumab and \ndoxorubicin include fatigue, anaemia, thrombocytopenia and alopecia. Please refer to the doxorubicin \nSmPC for complete descriptions of all adverse events associated with doxorubicin treatment \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n7 \n\nTabulated list of adverse reactions \n \nADRs which were reported in patients with soft tissue sarcoma treated with olaratumab in combination \nwith doxorubicin in the Phase 2 study are listed below in Table 2 in MedDRA body system organ class, \nfrequency and grade of severity. The following convention has been used for classification of frequency: \nVery common (≥ 1/10) \nCommon (≥ 1/100 to < 1/10) \nUncommon (≥ 1/1,000 to < 1/100) \nRare (≥ 1/10,000 to < 1/1,000) \nVery rare (< 1/10,000) \n \nWithin each frequency grouping, ADRs are presented in order of decreasing seriousness. \n \nTable 2: Adverse reactions in patients receiving olaratumab plus doxorubicin for soft tissue \nsarcoma during the Phase 2 portion of a Phase 1b/2 study \n \n\nSystem organ class Adverse Reactiona Frequency overall Grade 3/4 frequency \nBlood and lymphatic \nsystem disorders \n \n\nNeutropenia Very Common Very Common \nLymphopenia Very Common Common \n\nNervous system \ndisorders \n\nHeadache Very Common None reported \n\nGastrointestinal \ndisorders \n\nDiarrhoea Very Common Common \nMucositis Very Common Common \nNausea Very Common Common \nVomiting Very Common None reported \n\nMusculoskeletal and \nconnective tissue \ndisorders \n\nMusculoskeletal \nPainb \n\nVery Common Common \n\nGeneral disorders and \nadministrative site \nconditions \n\nInfusion-related \nReactionsc \n\nVery Common Common \n\na Refer to NCI CTCAE Criteria (Version 4.03) for each Grade of toxicity \nb Musculoskeletal pain includes arthralgia, back pain, bone pain, flank pain, groin pain, \n\nmusculoskeletal chest pain, musculoskeletal pain, myalgia, muscle spasms, neck pain, and pain in \nextremity. \n\nc Infusion-related reactions includes anaphylactic reactions/anaphylactic shock. \n \nDescription of selected ADRs \n \nInfusion-related reactions (IRRs) \nIRRs were reported in 12.5 % of patients and mainly present as chills, fever or dyspnoea. Severe IRRs, \nalso including a fatal case (see section 4.4) were reported in 3.1 % of patients and mainly presented \nwith shortness of breath, loss of consciousness and hypotension. All severe IRRs occurred during or \nimmediately after the first administration of olaratumab. \n \nNeutropenia \nIn the phase 2 trial, the incidence of neutropenia was 59.4 % (all Grades) and 54.7 % (Grade 3) in the \nolaratumab plus doxorubicin arm and 38.5 % (all Grades) and 33.8 % (Grade 3) in the doxorubicin \nalone arm. The rate of febrile neutropenia was 12.5 % in the olaratumab plus doxorubicin arm and \n13.8 % in the doxorubicin alone arm. For dose adjustments, refer to section 4.2 \n \nMusculoskeletal pain \nIn the phase 2 trial the incidence of Musculoskeletal pain was 64.1 % (all Grades) and 7.8 % \n(Grade 3) in the olaratumab plus doxorubicin arm and 24.6 % (all Grades) and 1.5 % (Grade 3) in the \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n8 \n\ndoxorubicin alone arm. In the majority of patients the pain was related to the patients’ underlying \ncancer or metastases or pre-existing or concomitant conditions. The majority of these events occurred \nin the first 4 cycles. The pain can last from few days to up to 200 days. In some patients there was a \nrecurrence of pain .The pain did not worsen with time or during recurrence. \n \nCardiac toxicity \nNo clinically meaningful difference in doxorubicin-related cardiotoxicity was observed between the \ntwo treatment arms of the study. The rate of cardiac arrhythmias was similar in both arms (15.6 % in \nthe Investigational Arm and 15.4 % in the Control Arm). The rate of treatment-emergent cardiac \ndysfunction was comparable between the two treatment arms (7.8 % in the Investigational Arm and \n6.2 % in the Control Arm). \n \nHaemorrhagic events \nIn the phase 2 trial, the frequency of haemorrhagic events considered related to any study drug was \n3.1 % in either treatment arm. All of these events were Grade 1/2 and were confounded by multiple \nfactors. Three Grade ≥3 events, including one fatal, have been reported across the clinical \ndevelopment programme of olaratumab (see section 4.4). \n \nToxicity in the elderly \nThere was a higher incidence of Grade ≥3 adverse reactions, adverse reactions leading to \ndiscontinuation and a higher rate of haematological toxicity in the elderly population compared to the \noverall study population (see section 4.2). The rates of discontinuation were comparable between \ntreatment arms across all age groups. \n \nReporting of suspected adverse reactions \nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V. \n \n4.9 Overdose \n \nThere is no experience with Lartruvo overdose in human clinical trials. Lartruvo has been \nadministered in a Phase 1 study up to 20 mg/kg on days 1 and 8 of a 21 day cycle without reaching a \nmaximum tolerated dose. In case of overdose, use supportive therapy. There is no known antidote to \nLartruvo overdose. \n \n \n5. PHARMACOLOGICAL PROPERTIES \n \n5.1 Pharmacodynamic properties \n \nPharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC27 \n \nMechanism of action \nOlaratumab is an antagonist of platelet derived growth factor receptor-α (PDGFR-α), expressed on \ntumour and stromal cells. Olaratumab is a targeted, recombinant, fully human immunoglobulin G \nsubclass 1 (IgG1) monoclonal antibody that specifically binds PDGFR-α, blocking PDGF AA, -BB, \nand -CC binding and receptor activation. As a result, in vitro olaratumab inhibits PDGFR-α pathway \nsignalling in tumour and stromal cells. In addition, in vivo olaratumab has been shown to disrupt the \nPDGFR-α pathway in tumour cells and inhibit tumour growth. \n \nImmunogenicity \nAs with all therapeutic proteins, there is the potential for immunogenicity. \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n9 \n\nOverall, a low incidence of both treatment emergent anti-drug antibodies and neutralising antibodies \nwere detected in clinical trial samples. \n \nClinical efficacy and safety \n \nThe efficacy and safety of olaratumab was assessed in a Phase 1b/2, multi-centre study in \nanthracycline naïve patients with histologically or cytologically confirmed, advanced soft tissue \nsarcoma not amenable to receive surgery or radiotherapy with curative intent. Patients with \ngastrointestinal stromal tumours (GIST) or Kaposi sarcoma were not enrolled. The Phase 2 portion of \nthe study was a randomised, open label study of olaratumab plus doxorubicin versus doxorubicin \nalone. A total of 133 patients were randomised, of whom 129 received at least one dose of study \ntreatment (64 in the olaratumab plus doxorubicin arm and 65 in the doxorubicin arm). Patients were \nrequired to have histologically or cytologically confirmed, advanced soft tissue sarcoma and ECOG \nperformance status of 0-2. Randomisation was stratified by PDGFR-α expression (positive versus \nnegative), number of previous lines of treatment (0 versus 1 or more lines), histological tumour type \n(leiomyosarcoma, synovial sarcoma, and others) and ECOG performance status (0 or 1 versus 2). \n \nPatients were randomised in a 1:1 ratio to either olaratumab (15 mg/kg) on Day 1 and Day 8 plus \ndoxorubicin (75 mg/m²) on Day 1 of each 21-day cycle for up to 8 cycles or doxorubicin (75 mg/m2) \nalone on Day 1 of each 21-day cycle, also for up to 8 cycles. Olaratumab and doxorubicin were \nadministered by intravenous infusion. During Cycles 5 to 8 on both arms, dexrazoxane (dosed at a \nratio of 10:1 to the administered dose of doxorubicin) could be administered on Day 1 of each cycle at \nthe investigator’s discretion to reduce potential doxorubicin-related cardiotoxicity. All patients \nreceiving more than 4 cycles of doxorubicin received dexrazoxane. Patients in the olaratumab plus \ndoxorubicin arm could continue on olaratumab monotherapy until disease progression, unacceptable \ntoxicity or any other reason for treatment discontinuation occurred. \n \nDemographics and baseline characteristics were quite similar between treatment arms in the phase 2 \nportion of the clinical trial. The median age was 58 years with 42 patients ≥ 65 years of age. 86.4 % of \nthe patients were Caucasian. More than 25 different soft tissue sarcoma subtypes were represented in \nthis trial, the most frequent being leiomyosarcoma (38.4 %), undifferentiated pleomorphic sarcoma \n(18.1 %) and liposarcoma (17.3 %). Other subtypes were infrequently represented. Patients had \nreceived 0-4 previous lines of therapy for treatment of advanced disease but had not previously \nreceived treatment with anthracyclines. The number of patients receiving post-study systemic therapy \nwas similar between arms. Ten patients in the olaratumab plus doxorubicin arm and 5 patients in the \ndoxorubicin arm received post-study radiotherapy only. 3 patients in the olaratumab plus doxorubicin \narm and 1 patient in the doxorubicin arm had post-study surgery only. 2 patients in the olaratumab \nplus doxorubicin arm and none in the doxorubicin arm received both post-study radiotherapy and \nsurgery. \n \nThe median cumulative dose of doxorubicin was 487.6 mg/m2 in the olaratumab plus doxorubicin arm \nand 299.6 mg/m2 in the doxorubicin alone arm. The primary efficacy outcome measure was \nprogression free survival (PFS) by investigator assessment. Key secondary efficacy outcome measures \nwere overall survival (OS) and objective response rate (ORR) (see Table 3). The study met its primary \nendpoint (PFS). PFS according to a post-hoc, blinded, independent assessment was 8.2 months vs \n4.4 months; HR = 0.670; p = 0.1208. A statistically significant improvement in OS was seen in the \nolaratumab plus doxorubicin arm in comparison to treatment with doxorubicin alone in the overall \npopulation. The main analysis was performed in the following two subgroups: Leiomyosarcoma \n(LMS) and non-LMS (other). Subgroups analysis of OS is shown in figure 2. Difference in objective \nresponse rate [complete response (CR) + partial response (PR)] according to investigator assessment \nwas not statistically significant (18.2 % vs 11.9 % in patients randomised to olaratumab plus \ndoxorubicin compared to patients randomized to doxorubicin respectively). \n \nEfficacy results are shown in Table 3 and Figures 1 and 2. \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n10 \n\nTable 3. Summary of survival data – ITT population \n \n\n Lartruvo plus doxorubicin \n(n = 66) \n\nDoxorubicin alone \n(n = 67) \n\nProgression free survival, months* \n Median (95 % CI) 6.6 (4.1, 8.3) 4.1 (2.8, 5.4) \n Hazard ratio (95 % CI) 0.672 (0.442, 1.021) \n p-value 0.0615** \nOverall survival, months \n Median (95 % CI) 26.5 (20.9, 31.7) 14.7 (9.2, 17.1) \n Hazard ratio (95 % CI) 0.463 (0.301, 0.710) \n p-value 0.0003 \n\nAbbreviations: CI = confidence interval \n* By investigator assessment \n**Met phase 2 protocol defined significance level of 0.19 \n \nFigure 1. Kaplan-Meier curves of overall survival for Lartruvo plus doxorubicin versus \ndoxorubicin alone \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\n \n \n \n \n \n \n \n \n \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n11 \n\nFigure 2. Forest plot for subgroup analysis of overall survival (ITT population) \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nPaediatric population \n \nThe European Medicines Agency has deferred the obligation to submit the results of studies with \nolaratumab in one or more subsets of the paediatric population in soft tissue sarcoma (see section 4.2 \nfor information on paediatric use). \n \nThis medicinal product has been authorised under a so-called ‘conditional approval’ scheme. \nThis means that further evidence on this medicinal product is awaited. \nThe European Medicines Agency will review new information on this medicinal product at least every \nyear and this SmPC will be updated as necessary . \n \n5.2 Pharmacokinetic properties \n \nAbsorption \nOlaratumab is administered as an intravenous infusion only. \n \nDistribution \nThe population pharmacokinetic (PopPK) model-based mean (CV %) volume of distribution of \nolaratumab at steady state (Vss) was 7.7 L (16 %). \n \nElimination \nThe PopPK model-based mean (CV %) clearance for olaratumab was 0.56 L/day (33 %). This \ncorresponds to a mean terminal half-life of approximately 11 days. \n \nSpecial populations \nAge, sex, and race had no clinically meaningful effect on the PK of olaratumab based on a PopPK \nanalysis. Clearance and volume of distribution had a positive correlation with body weight. \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n12 \n\nRenal impairment \nNo formal studies have been conducted to evaluate the effect of renal impairment on the PK of \nolaratumab. Based on a PopPK analysis, no clinically meaningful differences in the clearance of \nolaratumab were observed in patients with mild (calculated creatinine clearance [CLcr] 60-89 mL/min, \nn = 43), or moderate (CLcr 30-59 mL/min, n = 15) renal impairment compared to patients with normal \nrenal function (CLcr ≥90 mL/min, n = 85). No data were available from patients with severe renal \nimpairment (CLcr 15-29 mL/min). \n \nHepatic impairment \nNo formal studies have been conducted to evaluate the effect of hepatic impairment on the PK of \nolaratumab. Based on a PopPK analysis, no clinically meaningful differences in the clearance of \nolaratumab were observed in patients with mild (total bilirubin within upper limit of normal [ULN] \nand AST>ULN, or total bilirubin > 1.0-1.5 times ULN and any AST level, n = 16), or moderate (total \nbilirubin > 1.5-3.0 times ULN, n = 1) hepatic impairment compared to patients with normal hepatic \nfunction (total bilirubin and AST ≤ ULN, n = 126). No data were available from patients with severe \nhepatic impairment (total bilirubin > 3.0 times ULN and any AST level). \n \n5.3 Preclinical safety data \n \nNon-clinical data reveal no special hazard for humans based on repeat dose toxicity studies in \nmonkeys. \n \nNo animal studies have been performed to test olaratumab for potential of carcinogenicity, \ngenotoxicity, or fertility impairment. Administration of an anti-murine PDGFR- α surrogate antibody \nto pregnant mice during organogenesis at 50 and 150 mg/kg resulted in increased malformations \n(abnormal eyelid development) and skeletal alterations (frontal/parietal additional ossification site). \nThe foetal effects in mice administered the surrogate antibody occurred at exposures less than the \nAUC exposure at the maximum recommended human dose of 15 mg/kg olaratumab. \n \n \n6. PHARMACEUTICAL PARTICULARS \n \n6.1 List of excipients \n \nMannitol (E421) \nGlycine (E640) \nSodium chloride \nL-Histidine monohydrochloride monohydrate \nL-Histidine \nPolysorbate 20 (E432) \nWater for injections \n \n6.2 Incompatibilities \n \nThe medicinal product should not be administered or mixed with dextrose containing solutions. \n \n6.3 Shelf life \n \nUnopened vial \n2 years. \n \nAfter dilution \nThis product is preservative free. From a microbiological point of view the prepared dosing solution \nshould be used immediately. If not used immediately, the dosing solution should be stored under \nrefrigeration for up to 24 hours at 2 °C to 8 °C and up to an additional 8 hours at room temperature (up \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n13 \n\nto 25 °C) assuming dilution has taken place in controlled and validated aseptic conditions. Storage \ntimes include the duration of infusion. \n \n6.4 Special precautions for storage \n \nStore in a refrigerator (2° C - 8° C). \nDo not freeze. \nKeep the vial in the outer carton in order to protect from light. \nFor storage conditions after dilution of the medicinal product, see section 6.3. \n \n6.5 Nature and contents of container \n \n19 mL solution in a vial (Type I glass) with a chlorobutyl elastomeric stopper, an aluminium seal and \na polypropylene cap. \n50 mL solution in a vial (Type I glass) with a chlorobutyl elastomeric stopper, an aluminium seal and \na polypropylene cap. \n \nPack of 1 vial of 19 mL. \nPack of 2 vials of 19 mL. \nPack of 1 vial of 50 mL. \n \nNot all pack sizes may be marketed. \n \n6.6 Special precautions for disposal and other handling \n \nThe infusion solution should be prepared using aseptic technique to ensure the sterility of the prepared \nsolution. \n \nEach vial is intended for single use only. Do not shake the vial. The content of the vials should be \ninspected for particulate matter and discolouration (the concentrate for solution for infusion should be \nclear to slightly opalescent and colourless to slightly yellow without visible particles) prior to \nadministration. If particulate matter or discolouration is identified, the vial must be discarded. The \ndose and volume of olaratumab needed should be calculated to prepare the infusion solution. Vials \ncontain 190 mg or 500 mg as a 10 mg/mL solution of olaratumab. Only use sodium chloride \n9 mg/mL (0.9 %) solution for injection as a diluent. \n \nIn case of prefilled intravenous infusion container usage \nBased on the calculated volume of olaratumab, the corresponding volume of sodium chloride \n9 mg/mL (0.9 %) solution for injection should be removed from the prefilled 250 mL intravenous \ncontainer. The calculated volume of olaratumab should be aseptically transferred to the intravenous \ncontainer. The final total volume in the container should be 250 mL. The container should be gently \ninverted to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution. \n \nIn case of empty intravenous infusion container usage \nThe calculated volume of olaratumab should be aseptically transferred into an empty intravenous \ninfusion container. A sufficient quantity of sodium chloride 9 mg/mL (0.9 %) solution for injection \nshould be added to the container to make the total volume 250 mL. The container should be gently \ninverted to ensure adequate mixing. DO NOT FREEZE OR SHAKE the infusion solution. \n \nAdminister via an infusion pump. A separate infusion line must be used and the line must be flushed \nwith sodium chloride 9 mg/mL (0.9 %) solution for injection at the end of the infusion. \n \nAny unused portion of olaratumab left in a vial should be discarded, as the product contains no \nantimicrobial preservatives. \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n14 \n\nAny unused medicinal product or waste material should be disposed of in accordance with local \nrequirements. \n \n \n7. MARKETING AUTHORISATION HOLDER \n \nEli Lilly Nederland B.V. \nPapendorpseweg 83 \n3528 BJ Utrecht \nThe Netherlands \n \n \n8. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/16/1143/001-003 \n \n \n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n \nDate of first authorisation: 9 November 2016 \nDate of latest renewal: 21 September 2017 \n \n \n10. DATE OF REVISION OF THE TEXT \n \n \n \nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency http://www.ema.europa.eu. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\nhttp://www.ema.europa.eu/\n\n\n15 \n\n \n \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX II \n \nA. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND \n\nMANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE \n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n \nE. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES \n\nFOR THE CONDITIONAL MARKETING AUTHORISATION \n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n16 \n\nA. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND \nMANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE \n\n \nName and address of the manufacturer(s) of the biological active substance(s) \nImClone Systems LLC \n33 ImClone Drive \nBranchburg \nNew Jersey \nNJ 08876 \nUNITED STATES \n \nName and address of the manufacturer(s) responsible for batch release \nLilly S.A. \nAvda. de la Industria 30 \nAlcobendas \n28108 Madrid \nSPAIN \n\n \n \n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n \n\nMedicinal product subject to restricted medical prescription (see Annex I: Summary of Product \nCharacteristics, section 4.2). \n \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n \n\n• Periodic safety update reports \n \nThe requirements for submission of periodic safety update reports for this medicinal product are set \nout in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive \n2001/83/EC and any subsequent updates published on the European medicines web-portal. \nThe marketing authorisation holder shall submit the first periodic safety update report for this \nproduct within 6 months following authorisation. \n \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n \n\n• Risk Management Plan (RMP) \n \n\nThe MAH shall perform the required pharmacovigilance activities and interventions detailed in the \nagreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent \nupdates of the RMP. \n \nAn updated RMP should be submitted: \n\n• At the request of the European Medicines Agency; \n• Whenever the risk management system is modified, especially as the result of new \n\ninformation being received that may lead to a significant change to the benefit/risk profile or \nas the result of an important (pharmacovigilance or risk minimisation) milestone being \nreached. \n\n \n• Additional risk minimisation measures \n\n \nNot applicable. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n17 \n\nE. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES \nFOR THE CONDITIONAL MARKETING AUTHORISATION \n\n \nThis being a conditional marketing authorisation and pursuant to Article 14(7) of Regulation (EC) \nNo 726/2004, the MAH shall complete, within the stated timeframe, the following measures: \n \n\nDescription Due date \nIn order to further confirm the efficacy and safety of olaratumab in the \ntreatment of patients with advanced soft tissue sarcoma, the MAH should \nsubmit the clinical study report of the phase III study JGDJ comparing \ndoxorubicin plus olaratumab versus doxorubicin in patients with \nadvanced or metastatic STS (including exploratory biomarker data). \n \n\n 31 January 2020 \n \n \n \n \n\n \n \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n18 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\n \n \n\nANNEX III \n \n\nLABELLING AND PACKAGE LEAFLET \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n19 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\n \nA. LABELLING \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n20 \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCARTON – 50 mL vial \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nLartruvo 10 mg/mL concentrate for solution for infusion \nolaratumab \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nOne mL of concentrate contains 10 mg of olaratumab. \nOne vial of 50 mL contains 500 mg olaratumab. \n \n \n3. LIST OF EXCIPIENTS \n \nExcipients: mannitol, glycine, sodium chloride, L-histidine monohydrochloride monohydrate, \nL-histidine, polysorbate 20 and water for injections. See leaflet for further information. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nConcentrate for solution for infusion \n \n500 mg/50 mL \n1 vial \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nRead the package leaflet before use. \nFor intravenous use after dilution. \nFor single use only. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \nDo not shake. \n \n \n8. EXPIRY DATE \n \nEXP \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n21 \n\n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. \nDo not freeze. \nKeep the vial in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nEli Lilly Nederland B.V. \nPapendorpseweg 83, \n3528 BJ Utrecht \nThe Netherlands \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/16/1143/001 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n \n15. INSTRUCTIONS ON USE \n \n \n \n16. INFORMATION IN BRAILLE \n \nJustification for not including Braille accepted. \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \nPC: \nSN: \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n22 \n\nNN: \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n23 \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCARTON – 19 mL vial \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nLartruvo 10 mg/mL concentrate for solution for infusion \nolaratumab \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nOne mL of concentrate contains 10 mg of olaratumab. \nOne vial of 19 mL contains 190 mg olaratumab. \n \n \n3. LIST OF EXCIPIENTS \n \nExcipients: mannitol, glycine, sodium chloride, L-histidine monohydrochloride monohydrate, \nL-histidine, polysorbate 20 and water for injections. See leaflet for further information. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nConcentrate for solution for infusion \n \n190 mg/19 mL \n1 vial \n2 vials \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nRead the package leaflet before use. \nFor intravenous use after dilution. \nFor single use only. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \nDo not shake. \n \n \n8. EXPIRY DATE \n \nEXP \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n24 \n\n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. \nDo not freeze. \nKeep the vial in the outer carton in order to protect from light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nEli Lilly Nederland B.V. \nPapendorpseweg 83, \n3528 BJ Utrecht \nThe Netherlands \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/16/1143/002 – 1 vial of 19 mL. \nEU/1/16/1143/003 – 2 vials of 19 mL. \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n \n15. INSTRUCTIONS ON USE \n \n \n \n16. INFORMATION IN BRAILLE \n \nJustification for not including Braille accepted. \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n25 \n\nPC: \nSN: \nNN: \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n26 \n\n \nPARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING \n \nVIAL LABEL – 50 mL vial \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nLartruvo 10 mg/mL sterile concentrate \nolaratumab \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nOne mL of concentrate contains 10 mg of olaratumab. \nOne vial of 50 mL contains 500 mg olaratumab. \n \n \n3. LIST OF EXCIPIENTS \n \nExcipients: mannitol, glycine, sodium chloride, L-histidine monohydrochloride monohydrate, \nL-histidine, polysorbate 20 and water for injections. See leaflet for further information. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nConcentrate for solution for infusion \n \n500 mg/50 mL \n1 vial \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nRead the package leaflet before use. \nFor IV use after dilution. \nFor single use only. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \nDo not shake. \n \n \n8. EXPIRY DATE \n \nEXP \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n27 \n\n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. \nDo not freeze. \nKeep the vial in the outer carton. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nEli Lilly Nederland B.V. \nPapendorpseweg 83, \n3528 BJ Utrecht \nThe Netherlands \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/16/1143/001 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n \n15. INSTRUCTIONS ON USE \n \n \n \n16. INFORMATION IN BRAILLE \n \nJustification for not including Braille accepted. \n \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n28 \n\nPARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING \n \nVIAL LABEL – 19 mL vial \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nLartruvo 10 mg/mL sterile concentrate \nolaratumab \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nOne mL of concentrate contains 10 mg of olaratumab. \nOne vial of 19 mL contains 190 mg olaratumab. \n \n \n3. LIST OF EXCIPIENTS \n \nExcipients: mannitol, glycine, sodium chloride, L-histidine monohydrochloride monohydrate, \nL-histidine, polysorbate 20 and water for injections. See leaflet for further information. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nConcentrate for solution for infusion \n \n190 mg/19 mL \n1 vial \n2 vials \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nRead the package leaflet before use. \nFor IV use after dilution. \nFor single use only. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \nDo not shake. \n \n \n8. EXPIRY DATE \n \nEXP \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n29 \n\n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in a refrigerator. \nDo not freeze. \nKeep the vial in the outer carton. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nEli Lilly Nederland B.V. \nPapendorpseweg 83, \n3528 BJ Utrecht \nThe Netherlands \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/16/1143/002 – 1 vial of 19 mL. \nEU/1/16/1143/003 – 2 vials of 19 mL. \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n \n15. INSTRUCTIONS ON USE \n \n \n \n16. INFORMATION IN BRAILLE \n \nJustification for not including Braille accepted. \n \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n30 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\n \nB. PACKAGE LEAFLET \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n31 \n\nPackage leaflet: Information for the user \n \n\nLartruvo 10 mg/mL concentrate for solution for infusion \nolaratumab \n\n \nThis medicine is subject to additional monitoring. This will allow quick identification of new \n\nsafety information. You can help by reporting any side effects you may get. See the end of section 4 \nfor how to report side effects. \n \nRead all of this leaflet carefully before you are given this medicine because it contains important \ninformation for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor. \n- If you get any side effects, talk to your doctor. This includes any possible side effects not listed \n\nin this leaflet. See section 4. \n \nWhat is in this leaflet \n \n1. What Lartruvo is and what it is used for \n2. What you need to know before you are given Lartruvo \n3. How you are given Lartruvo \n4. Possible side effects \n5. How to store Lartruvo \n6. Contents of the pack and other information \n \n \n1. What Lartruvo is and what it is used for \n \nLartruvo contains the active substance olaratumab, which belongs to a group of medicines called \nmonoclonal antibodies. \n \nOlaratumab recognises and attaches specifically to a protein known as platelet-derived growth factor \nreceptor-α (PDGFR-α). PDGFR-α is found in large amounts on some cancer cells where it stimulates \nthe cells to grow and divide. When olaratumab attaches to PDGFR-α it may prevent cancer cell growth \nand survival. \n \nLartruvo is used in combination with another anti-cancer medicine called doxorubicin for the \ntreatment of adults with advanced soft tissue sarcoma who have not been previously treated with \ndoxorubicin. Soft tissue sarcoma is a cancer that starts in the soft tissues, such as the muscles, fat, \ncartilage and blood vessels. \n \n \n2. What you need to know before you are given Lartruvo \n \nYou must not be given Lartruvo \n- if you are allergic to olaratumab or any of the other ingredients of this medicine (listed in \n\nsection 6). \n \nWarnings and precautions \nYou should tell your doctor about any of the following: \n- if you are receiving any treatment for heart disease or liver disease \n \nTalk to your doctor or nurse immediately if the following applies to you (or you are not sure): \n \n\n– Infusion-related reaction \nInfusion-related reactions may occur during treatment with Lartruvo. Such reactions may be allergic. \nSymptoms may include back pain, chest pain and/or tightness, chills, fever, flushing, difficulty in \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n32 \n\nbreathing and wheezing. In severe cases, you may experience very low blood pressure, feel faint, and \nexperience breathing distress caused by narrowing of the airways, which could be life-threatening. \nYour doctor will give you other medicines before you receive Lartruvo to reduce the risk of infusion-\nrelated reactions. Your doctor or nurse will check for side effects during and after your infusion. If you \nhave a severe infusion-related reaction, your doctor may recommend reducing the dose of Lartruvo or \nstop your treatment with Lartruvo. See section 4 for more details about infusion-related reactions \nwhich may occur during or after the infusion. \n \n\n– Bleeding \nLartruvo and doxorubicin may decrease your platelet count. Platelets help your blood to clot and a low \nplatelet count may increase the risk of bleeding. If you experience significant bleeding, symptoms may \ninclude extreme tiredness, weakness, dizziness or changes in the colour of your stools. Your doctor \nwill check your platelet count prior to treatment with Lartruvo. \n \n\n– Reduction in the number of white blood cells \nLartruvo and doxorubicin may decrease the number of white blood cells (including neutrophils). \nWhite blood cells are important for fighting infection. A low white blood cell count may increase your \nrisk for infection. Your doctor will check your white blood cell counts prior to treatment with \nLartruvo. \n \nChildren and adolescents \nLartruvo should not be given to patients under the age of 18 years because there is no information \nabout how it works in this age group. \n \nOther medicines and Lartruvo \nTell your doctor if you are taking, have recently taken or might take any other medicines. \n \nPregnancy and breast-feeding \nBefore starting treatment you must tell your doctor if you are pregnant or breast-feeding, think you \nmay be pregnant or are planning to have a baby. \n \nAvoid getting pregnant while receiving this medicine and for at least 3 months after the last dose of \nLartruvo as this medicine may harm your unborn child. Talk to your doctor about the best \ncontraception for you. \n \nIt is not known whether olaratumab gets into breast milk and if the breast-fed infant is at risk of harm. \nAsk your doctor if you can breast-feed during or after treatment with Lartruvo. \n \nDriving and using machines \nIt is not known if Lartruvo will affect your ability to drive. If you get any symptoms that affect your \nability to concentrate and react, such as tiredness, do not drive or use machines until the effect goes \naway. \n \nLartruvo contains sodium \nThis medicine contains 22 mg sodium in each 19 mL vial and 57 mg sodium in each 50 mL vial. This \nshould be taken into consideration if you are on a controlled sodium diet. \n \n \n3. How you are given Lartruvo \n \nA doctor experienced in the use of anti-cancer medicines will supervise your Lartruvo therapy. \n \nPremedication \nYou will be given medicines to reduce the risk of an infusion-related reaction before you receive \nLartruvo. \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n33 \n\nDose and administration \nThe recommended dose of Lartruvo is 15 mg per kilogram of your body weight on days 1 and 8 of \neach 3-week cycle. Lartruvo is given in combination with the medicine doxorubicin for up to 8 cycles \nand then it is given on its own. The number of infusions that you receive will depend on how well and \nfor how long treatment with Lartruvo works and how well you feel. Your doctor will discuss this with \nyou. \n \nThis medicine is given as an infusion into a vein via a drip. The drip lasts about 60 minutes. \n \nDetailed instructions for your doctor or your nurse on how to prepare Lartruvo infusion are included at \nthe end of this package leaflet (see ‘Handling instructions’). \n \nDose adjustments \nDuring each infusion, your doctor or nurse will check for side effects. Your doctor may also give you \na smaller dose or delay your dose of Lartruvo if you get serious side effects including a lowering of \nyour white blood cell counts. If you have an infusion-related reaction during treatment, your doctor or \nnurse may slow down or stop your Lartruvo infusion. \n \n \n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. Your \ndoctor will discuss these with you and will explain the risks and benefits of your treatment. \n \nThe following side effects have been reported: \n \nInfusion reactions \nLartruvo has been associated with infusion reactions (see section 2 “Warnings and precautions”). Tell \nyour doctor or nurse immediately if you feel unwell during infusion. Below is a list of some typical \nsymptoms associated with infusion reactions: \n\n• Feeling faint \n• Fever \n• Chills \n• Flushing \n• Shortness of breath \n\n \nOther symptoms may occur as well (see section 2 “Warnings and precautions”). Your doctor may \nconsider slowing the Lartruvo infusion or interrupting it to manage these symptoms. \n \nVery common (may affect more than 1 in 10 people): \n\n– nausea \n– pain in your muscles, joints or bones (musculoskeletal pain) \n– low white blood cell counts (including neutrophils and lymphocytes which may increase the \n\nrisk of infection) \n– pain or sores in your mouth or throat (mucositis) \n– vomiting \n– diarrhoea \n– headache \n– infusion-related reactions \n\n \nReporting of side effects \nIf you get any side effects, talk to your doctor. This includes any possible side effects not listed in this \nleaflet. You can also report side effects directly via the national reporting system listed in Appendix V. \nBy reporting side effects you can help provide more information on the safety of this medicine. \n \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n34 \n\n5. How to store Lartruvo \n \nKeep this medicine out of the sight and reach of children. \n \nDo not use this medicine after the expiry date which is stated on the outer carton and vial label after \nEXP. The expiry date refers to the last day of that month. \n \nStore in a refrigerator (2 °C – 8 °C). \nDo not freeze or shake the vial. \nKeep the vial in the outer carton to protect from light. \n \nInfusion solution: After dilution and preparation, the medicine must be used immediately. If not used \nimmediately, in-use storage times and conditions before use are the responsibility of the user and \nwould normally not be longer than 24 hours at 2 to 8 ºC and up to an additional 8 hours at room \ntemperature (below 25 ºC). Do not freeze or shake the infusion solution. Do not administer the \nsolution if you notice any particulate matter or discoloration. \n \nThis medicine is for single use only. \n \nDo not store any unused portion of the infusion solution for reuse. Any unused medicine or waste \nmaterial should be disposed of in accordance with local requirements. \n \n \n6. Contents of the pack and other information \n \nWhat Lartruvo contains \n- The active substance is olaratumab. Each millilitre of the concentrate for solution for infusion \n\ncontains 10 mg of olaratumab. \nEach 19 mL vial contains 190 mg of olaratumab. \nEach 50 mL vial contains 500 mg of olaratumab. \n\n- The other ingredients are mannitol, glycine, L-histidine monohydrochloride monohydrate, \nL-histidine, sodium chloride (see section 2 “Lartruvo contains sodium”), polysorbate 20 and \nwater for injections. \n\n \nWhat Lartruvo looks like and contents of the pack \nLartruvo concentrate for solution for infusion (sterile concentrate) is a clear to slightly opalescent and \ncolourless to slightly yellow liquid supplied in a glass vial with an elastomeric stopper. \n \nIt is available in packs of: \n- 1 vial of 19 mL \n- 2 vials of 19 mL \n- 1 vial of 50 mL \n \nNot all pack sizes may be marketed. \n \nMarketing Authorisation Holder \nEli Lilly Nederland B.V. \nPapendorpseweg 83 \n3528 BJ Utrecht \nThe Netherlands. \n \nManufacturer \nLilly S.A. \nAvda de la Industria, 30 \n28108 Alcobendas \nMadrid \nSpain \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n35 \n\n \nFor any information about this medicine, please contact the local representative of the Marketing \nAuthorisation Holder: \n \nBelgië/Belgique/Belgien \nEli Lilly Benelux S.A./N.V. \nTél/Tel: + 32-(0)2 548 84 84 \n\nLietuva \nEli Lilly Holdings Limited atstovybė \nTel. +370 (5) 2649600 \n\nБългария \nТП \"Ели Лили Недерланд\" Б.В. - България \nтел. + 359 2 491 41 40 \n\nLuxembourg/Luxemburg \nEli Lilly Benelux S.A./N.V. \nTél/Tel: + 32-(0)2 548 84 84 \n\nČeská republika \nELI LILLY ČR, s.r.o. \nTel: + 420 234 664 111 \n\nMagyarország \nLilly Hungária Kft. \nTel: + 36 1 328 5100 \n\nDanmark \nEli Lilly Danmark A/S \nTlf: +45 45 26 60 00 \n\nMalta \nCharles de Giorgio Ltd. \nTel: + 356 25600 500 \n\nDeutschland \nLilly Deutschland GmbH \nTel. + 49-(0) 6172 273 2222 \n\nNederland \nEli Lilly Nederland B.V. \nTel: + 31-(0) 30 60 25 800 \n\nEesti \nEli Lilly Holdings Limited Eesti filiaal \nTel: +372 6 817 280 \n\nNorge \nEli Lilly Norge A.S. \nTlf: + 47 22 88 18 00 \n\nΕλλάδα \nΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε. \nΤηλ: +30 210 629 4600 \n\nÖsterreich \nEli Lilly Ges.m.b.H. \nTel: + 43-(0) 1 711 780 \n\nEspaña \nLilly S.A. \nTel: + 34-91 663 50 00 \n\nPolska \nEli Lilly Polska Sp. z o.o. \nTel: +48 22 440 33 00 \n\nFrance \nLilly France SAS \nTél: +33-(0) 1 55 49 34 34 \n\nPortugal \nLilly Portugal Produtos Farmacêuticos, Lda \nTel: + 351-21-4126600 \n\nHrvatska \nEli Lilly Hrvatska d.o.o. \nTel: +385 1 2350 999 \n\nRomânia \nEli Lilly România S.R.L. \nTel: + 40 21 4023000 \n\nIreland \nEli Lilly and Company (Ireland) Limited \nTel: + 353-(0) 1 661 4377 \n\nSlovenija \nEli Lilly farmacevtska družba, d.o.o. \nTel: +386 (0)1 580 00 10 \n\nÍsland \nIcepharma hf. \nSími + 354 540 8000 \n\nSlovenská republika \nEli Lilly Slovakia, s.r.o. \nTel: + 421 220 663 111 \n\nItalia \nEli Lilly Italia S.p.A. \nTel: + 39- 055 42571 \n\nSuomi/Finland \nOy Eli Lilly Finland Ab \nPuh/Tel: + 358-(0) 9 85 45 250 \n\nΚύπρος \nPhadisco Ltd \nΤηλ: +357 22 715000 \n\nSverige \nEli Lilly Sweden AB \nTel: + 46-(0) 8 7378800 \n\nLatvija \nEli Lilly Holdings Limited pārstāvniecība Latvijā \nTel: +371 67364000 \n\nUnited Kingdom \nEli Lilly and Company Limited \nTel: + 44-(0) 1256 315000 \n\n \nThis leaflet was last revised in < {month YYYY}>. \n \nThis medicine has been given ‘conditional approval’. This means that there is more evidence to come \nabout this medicine. \nThe European Medicines Agency will review new information on this medicine at least every year and \nthis leaflet will be updated as necessary. \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n36 \n\nOther sources of information \n \nDetailed information on this medicine is available on the European Medicines Agency web site: \nhttp://www.ema.europa.eu. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\nhttp://www.ema.europa.eu/\n\n\n37 \n\n--------------------------------------------------------------------------------------------------------------------------- \nHandling instructions \nLartruvo 10 mg/mL \n\nconcentrate for solution for infusion \nolaratumab \n\n \nThe following information is intended for healthcare professionals only \n \nPrepare the infusion solution using aseptic technique to ensure the sterility of the prepared solution. \n \nEach vial is intended for single use only. Inspect the contents of the vials for particulate matter and \ndiscolouration. The concentrate for solution for infusion must be clear to slightly opalescent and \ncolourless to slightly yellow prior to dilution. If particulate matter or discolouration is identified, the \nvial must be discarded. \n \nVials contain 190 mg or 500 mg as a 10 mg/mL solution of olaratumab; calculate the dose and volume \nof olaratumab needed to prepare the infusion solution. Only use sodium chloride 9 mg/mL (0.9 %) \nsolution for injection as a diluent. \n \nTo administer using pre-filled intravenous infusion containers \nBased on the calculated volume of olaratumab, aseptically remove the corresponding volume of \nsodium chloride 9 mg/mL (0.9 %) solution for injection from the prefilled 250 mL intravenous \ncontainer and transfer the olaratumab medicine into the container to bring the final volume in the \ncontainer back to 250 mL. Gently invert the container to mix. DO NOT FREEZE OR SHAKE the \ninfusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or \nmedicines. \n \nTo administer using empty intravenous infusion containers \nAseptically transfer the calculated volume of olaratumab into an empty intravenous infusion container. \nAdd a sufficient quantity of sodium chloride 9 mg/mL (0.9 %) solution for injection to the container to \nmake the total volume 250 mL. Gently invert the container to mix. DO NOT FREEZE OR SHAKE \nthe infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or \nmedicines. \n \nAdminister via an infusion pump. A separate infusion line must be used and the line must be flushed \nwith sodium chloride 9 mg/mL (0.9 %) solution for injection at the end of the infusion. \n \nParenteral medicines should be inspected visually for particulate matter prior to administration. If \nparticulate matter is identified, discard the infusion solution. \n \nDiscard any unused portion of olaratumab left in a vial, as the product contains no antimicrobial \npreservatives. \n \nAny unused medicines or waste material should be disposed of in accordance with local requirements. \n Me\n\ndic\nina\n\nl p\nrod\n\nuc\nt n\n\no l\non\n\nge\nr a\n\nuth\nori\n\nse\nd\n\n\n\n38 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nAnnex IV \n \n\nScientific conclusions and grounds for the variation to the terms of the marketing \nauthorisation(s) \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n39 \n\nScientific conclusions \n \nTaking into account the PRAC Assessment Report on the PSUR(s) for olaratumab, the scientific \nconclusions of CHMP are as follows: \n \nBased on cases of anaphylactic reaction and anaphylactic shock reported in the post-marketing setting, \nthese adverse drug reactions should be specifically be mentioned under the category of \ninfusion-related reactions in section 4.8 of the SmPC. The frequency of anaphylactic \nreactions/anaphylactic shock is already calculated as part of grade 3-4 infusion-related reactions in the \ntable of Adverse Drug Reactions (ADRs) in the same section of the SmPC. The current wording of the \nPackage leaflet is considered sufficient to communicate this risk. \n \nThe CHMP agrees with the scientific conclusions made by the PRAC. \n \nGrounds for the variation to the terms of the marketing authorisation(s) \n \nOn the basis of the scientific conclusions for olaratumab the CHMP is of the opinion that the benefit-\nrisk balance of the medicinal product(s) containing olaratumab is unchanged subject to the proposed \nchanges to the product information. \n \nThe CHMP recommends that the terms of the marketing authorisation(s) should be varied. \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION \n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tE. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION \n\tA. LABELLING\n\tB. PACKAGE LEAFLET\n\tScientific conclusions and grounds for the variation to the terms of the marketing authorisation(s)"},"Section_1":{"kind":"string","value":"{'Title': '1. what lartruvo is and what it is used for', 'Section_Content': 'lartruvo contains the active substance olaratumab, which belongs to a group of medicines called monoclonal antibodies. olaratumab recognises and attaches specifically to a protein known as platelet-derived growth factor receptor-α (pdgfr-α). pdgfr-α is found in large amounts on some cancer cells where it stimulates the cells to grow and divide. when olaratumab attaches to pdgfr-α it may prevent cancer cell growth and survival. lartruvo is used in combination with another anti-cancer medicine called doxorubicin for the treatment of adults with advanced soft tissue sarcoma who have not been previously treated with doxorubicin. soft tissue sarcoma is a cancer that starts in the soft tissues, such as the muscles, fat, cartilage and blood vessels.', 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lartruvo', 'Section_Content': 'you must not be given lartruvo - if you are allergic to olaratumab or any of the other ingredients of this medicine (listed in section 6). warnings and precautions you should tell your doctor about any of the following: - if you are receiving any treatment for heart disease or liver disease talk to your doctor or nurse immediately if the following applies to you (or you are not sure): infusion-related reaction infusion-related reactions may occur during treatment with lartruvo. such reactions may be allergic. symptoms may include back pain, chest pain and/or tightness, chills, fever, flushing, difficulty in 32 breathing and wheezing. in severe cases, you may experience very low blood pressure, feel faint, and experience breathing distress caused by narrowing of the airways, which could be life-threatening. your doctor will give you other medicines before you receive lartruvo to reduce the risk of infusion- related reactions. your doctor or nurse will check for side effects during and after your infusion. if you have a severe infusion-related reaction, your doctor may recommend reducing the dose of lartruvo or stop your treatment with lartruvo. see section 4 for more details about infusion-related reactions which may occur during or after the infusion. bleeding lartruvo and doxorubicin may decrease your platelet count. platelets help your blood to clot and a low platelet count may increase the risk of bleeding. if you experience significant bleeding, symptoms may include extreme tiredness, weakness, dizziness or changes in the colour of your stools. your doctor will check your platelet count prior to treatment with lartruvo. reduction in the number of white blood cells lartruvo and doxorubicin may decrease the number of white blood cells (including neutrophils). white blood cells are important for fighting infection. a low white blood cell count may increase your risk for infection. your doctor will check your white blood cell counts prior to treatment with lartruvo. children and adolescents lartruvo should not be given to patients under the age of 18 years because there is no information about how it works in this age group. other medicines and lartruvo tell your doctor if you are taking, have recently taken or might take any other medicines. pregnancy and breast-feeding before starting treatment you must tell your doctor if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby. avoid getting pregnant while receiving this medicine and for at least 3 months after the last dose of lartruvo as this medicine may harm your unborn child. talk to your doctor about the best contraception for you. it is not known whether olaratumab gets into breast milk and if the breast-fed infant is at risk of harm. ask your doctor if you can breast-feed during or after treatment with lartruvo. driving and using machines it is not known if lartruvo will affect your ability to drive. if you get any symptoms that affect your ability to concentrate and react, such as tiredness, do not drive or use machines until the effect goes away. lartruvo contains sodium this medicine contains 22 mg sodium in each 19 ml vial and 57 mg sodium in each 50 ml vial. this should be taken into consideration if you are on a controlled sodium diet.', 'Entity_Recognition': [{'Text': 'lartruvo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 4, 'BeginOffset': 22, 'EndOffset': 30, 'Score': 0.9644026756286621, 'Text': 'lartruvo', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.45464766025543213}]}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 44, 'EndOffset': 52}, {'Id': 5, 'BeginOffset': 56, 'EndOffset': 66, 'Score': 0.9767333269119263, 'Text': 'olaratumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 102, 'EndOffset': 115}, {'Text': 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'Text': '57 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.5452659726142883, 'RelationshipScore': 0.9991436004638672, 'RelationshipType': 'DOSAGE', 'Id': 75, 'BeginOffset': 3207, 'EndOffset': 3212, 'Text': '50 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '50', 'Type': 'NUMBER', 'BeginOffset': 3207, 'EndOffset': 3209}, {'Text': 'a controlled sodium diet', 'Type': 'TREATMENT', 'BeginOffset': 3273, 'EndOffset': 3297}]}"},"Section_3":{"kind":"string","value":"{'Title': '3. how you are given lartruvo', 'Section_Content': \"a doctor experienced in the use of anti-cancer medicines will supervise your lartruvo therapy. premedication you will be given medicines to reduce the risk of an infusion-related reaction before you receive lartruvo. dose and administration the recommended dose of lartruvo is 15 mg per kilogram of your body weight on days 1 and 8 of each 3-week cycle. lartruvo is given in combination with the medicine doxorubicin for up to 8 cycles and then it is given on its own. the number of infusions that you receive will depend on how well and for how long treatment with lartruvo works and how well you feel. your doctor will discuss this with you. this medicine is given as an infusion into a vein via a drip. the drip lasts about 60 minutes. detailed instructions for your doctor or your nurse on how to prepare lartruvo infusion are included at the end of this package leaflet (see 'handling instructions'). dose adjustments during each infusion, your doctor or nurse will check for side effects. your doctor may also give you a smaller dose or delay your dose of lartruvo if you get serious side effects including a lowering of your white blood cell counts. if you have an infusion-related reaction during treatment, your doctor or nurse may slow down or stop your lartruvo infusion.\", 'Entity_Recognition': [{'Text': 'lartruvo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'anti-cancer medicines', 'Type': 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medicine can cause side effects, although not everybody gets them. your doctor will discuss these with you and will explain the risks and benefits of your treatment. the following side effects have been reported: infusion reactions lartruvo has been associated with infusion reactions (see section 2 \"warnings and precautions\"). tell your doctor or nurse immediately if you feel unwell during infusion. below is a list of some typical symptoms associated with infusion reactions: feeling faint fever chills flushing shortness of breath other symptoms may occur as well (see section 2 \"warnings and precautions\"). your doctor may consider slowing the lartruvo infusion or interrupting it to manage these symptoms. very common (may affect more than 1 in 10 people): nausea pain in your muscles, joints or bones (musculoskeletal pain) low white blood cell counts (including neutrophils and lymphocytes which may increase the risk of infection) pain or sores in your mouth or throat (mucositis) vomiting diarrhoea headache infusion-related reactions reporting of side effects if you get any side effects, talk to your doctor. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'lartruvo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 10, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.961088240146637, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6429709792137146}]}, {'Text': 'your treatment', 'Type': 'TREATMENT', 'BeginOffset': 175, 'EndOffset': 189}, {'Id': 11, 'BeginOffset': 205, 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'Text': 'feel unwell', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9304141998291016}]}, {'Text': 'some typical symptoms', 'Type': 'PROBLEM', 'BeginOffset': 447, 'EndOffset': 468}, {'Text': 'infusion reactions', 'Type': 'TREATMENT', 'BeginOffset': 485, 'EndOffset': 503}, {'Text': 'faint fever chills', 'Type': 'PROBLEM', 'BeginOffset': 513, 'EndOffset': 531}, {'Text': 'flushing shortness of breath', 'Type': 'PROBLEM', 'BeginOffset': 532, 'EndOffset': 560}, {'Text': 'other symptoms', 'Type': 'PROBLEM', 'BeginOffset': 561, 'EndOffset': 575}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 607, 'EndOffset': 608}, {'Text': 'the lartruvo infusion', 'Type': 'TREATMENT', 'BeginOffset': 671, 'EndOffset': 692}, {'Text': 'these symptoms', 'Type': 'PROBLEM', 'BeginOffset': 722, 'EndOffset': 736}, {'Id': 18, 'BeginOffset': 755, 'EndOffset': 761, 'Score': 0.3250673711299896, 'Text': 'affect', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 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1407}]}"},"Section_5":{"kind":"string","value":"{'Title': '5. how to store lartruvo', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the outer carton and vial label after exp. the expiry date refers to the last day of that month. store in a refrigerator (2 8 ). do not freeze or shake the vial. keep the vial in the outer carton to protect from light. infusion solution: after dilution and preparation, the medicine must be used immediately. if not used immediately, in-use storage times and conditions before use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 ºc and up to an additional 8 hours at room temperature (below 25 ºc). do not freeze or shake the infusion solution. do not administer the solution if you notice any particulate matter or discoloration. this medicine is for single use only. do not store any unused portion of the infusion solution for reuse. any unused medicine or waste material should be disposed of in accordance with local requirements.', 'Entity_Recognition': [{'Text': 'lartruvo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 247, 'EndOffset': 248}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 249, 'EndOffset': 250}, {'Text': 'the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 304, 'EndOffset': 320}, {'Text': 'infusion solution', 'Type': 'TREATMENT', 'BeginOffset': 344, 'EndOffset': 361}, {'Text': 'the medicine', 'Type': 'TREATMENT', 'BeginOffset': 395, 'EndOffset': 407}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 579, 'EndOffset': 581}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 591, 'EndOffset': 592}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 596, 'EndOffset': 597}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 625, 'EndOffset': 626}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 660, 'EndOffset': 662}, {'Text': 'the infusion solution', 'Type': 'TREATMENT', 'BeginOffset': 691, 'EndOffset': 712}, {'Text': 'the solution', 'Type': 'TREATMENT', 'BeginOffset': 732, 'EndOffset': 744}, {'Text': 'any particulate matter', 'Type': 'PROBLEM', 'BeginOffset': 759, 'EndOffset': 781}, {'Text': 'discoloration', 'Type': 'PROBLEM', 'BeginOffset': 785, 'EndOffset': 798}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 800, 'EndOffset': 813}, {'Text': 'the infusion solution', 'Type': 'TREATMENT', 'BeginOffset': 873, 'EndOffset': 894}, {'Text': 'waste material', 'Type': 'TREATMENT', 'BeginOffset': 929, 'EndOffset': 943}]}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': 'what lartruvo contains - the active substance is olaratumab. each millilitre of the concentrate for solution for infusion contains 10 mg of olaratumab. each 19 ml vial contains 190 mg of olaratumab. each 50 ml vial contains 500 mg of olaratumab. - the other ingredients are mannitol, glycine, l-histidine monohydrochloride monohydrate, l-histidine, sodium chloride (see section 2 \"lartruvo contains sodium\"), polysorbate 20 and water for injections. what lartruvo looks like and contents of the pack lartruvo concentrate for solution for infusion (sterile concentrate) is a clear to slightly opalescent and colourless to slightly yellow liquid supplied in a glass vial with an elastomeric stopper. it is available in packs of: - 1 vial of 19 ml - 2 vials of 19 ml - 1 vial of 50 ml not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'lartruvo', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 13, 'Score': 0.3705810308456421, 'Text': 'lartruvo', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 49, 'EndOffset': 59, 'Score': 0.9909273386001587, 'Text': 'olaratumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.5145581364631653, 'RelationshipScore': 0.99893718957901, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 2, 'BeginOffset': 113, 'EndOffset': 121, 'Text': 'infusion', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8160060048103333, 'RelationshipScore': 0.9796252250671387, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 157, 'EndOffset': 162, 'Text': '19 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'infusion', 'Type': 'TREATMENT', 'BeginOffset': 113, 'EndOffset': 121}, {'Text': '10', 'Type': 'NUMBER', 'BeginOffset': 131, 'EndOffset': 133}, {'Id': 4, 'BeginOffset': 140, 'EndOffset': 150, 'Score': 0.9934309124946594, 'Text': 'olaratumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.5145581364631653, 'RelationshipScore': 0.9923163652420044, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 2, 'BeginOffset': 113, 'EndOffset': 121, 'Text': 'infusion', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9643763303756714, 'RelationshipScore': 0.9999617338180542, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 131, 'EndOffset': 136, 'Text': '10 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8160060048103333, 'RelationshipScore': 0.9993178844451904, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 157, 'EndOffset': 162, 'Text': '19 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9667090177536011, 'RelationshipScore': 0.9492133259773254, 'RelationshipType': 'DOSAGE', 'Id': 8, 'BeginOffset': 204, 'EndOffset': 209, 'Text': '50 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '19', 'Type': 'NUMBER', 'BeginOffset': 157, 'EndOffset': 159}, {'Text': '190', 'Type': 'NUMBER', 'BeginOffset': 177, 'EndOffset': 180}, {'Id': 7, 'BeginOffset': 187, 'EndOffset': 197, 'Score': 0.9954624772071838, 'Text': 'olaratumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8160060048103333, 'RelationshipScore': 0.9014355540275574, 'RelationshipType': 'DOSAGE', 'Id': 5, 'BeginOffset': 157, 'EndOffset': 162, 'Text': '19 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9884341359138489, 'RelationshipScore': 0.9999370574951172, 'RelationshipType': 'DOSAGE', 'Id': 6, 'BeginOffset': 177, 'EndOffset': 183, 'Text': '190 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9667090177536011, 'RelationshipScore': 0.9995555281639099, 'RelationshipType': 'DOSAGE', 'Id': 8, 'BeginOffset': 204, 'EndOffset': 209, 'Text': '50 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '50', 'Type': 'NUMBER', 'BeginOffset': 204, 'EndOffset': 206}, {'Text': '500', 'Type': 'NUMBER', 'BeginOffset': 224, 'EndOffset': 227}, {'Id': 10, 'BeginOffset': 234, 'EndOffset': 244, 'Score': 0.9958981871604919, 'Text': 'olaratumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9667090177536011, 'RelationshipScore': 0.8155466914176941, 'RelationshipType': 'DOSAGE', 'Id': 8, 'BeginOffset': 204, 'EndOffset': 209, 'Text': '50 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9837571978569031, 'RelationshipScore': 0.9999771118164062, 'RelationshipType': 'DOSAGE', 'Id': 9, 'BeginOffset': 224, 'EndOffset': 230, 'Text': '500 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 11, 'BeginOffset': 274, 'EndOffset': 282, 'Score': 0.9018888473510742, 'Text': 'mannitol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 284, 'EndOffset': 291, 'Score': 0.9233996272087097, 'Text': 'glycine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 293, 'EndOffset': 334, 'Score': 0.8956173062324524, 'Text': 'l-histidine monohydrochloride monohydrate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 14, 'BeginOffset': 336, 'EndOffset': 347, 'Score': 0.9571364521980286, 'Text': 'l-histidine', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 15, 'BeginOffset': 349, 'EndOffset': 364, 'Score': 0.9994927644729614, 'Text': 'sodium chloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 378, 'EndOffset': 379}, {'Id': 16, 'BeginOffset': 381, 'EndOffset': 389, 'Score': 0.5540238618850708, 'Text': 'lartruvo', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Id': 17, 'BeginOffset': 409, 'EndOffset': 420, 'Score': 0.3196868300437927, 'Text': 'polysorbate', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.3692972660064697, 'RelationshipScore': 0.9998107552528381, 'RelationshipType': 'DOSAGE', 'Id': 18, 'BeginOffset': 421, 'EndOffset': 423, 'Text': '20', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'ROUTE_OR_MODE', 'Score': 0.44503965973854065, 'RelationshipScore': 0.9999769926071167, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 19, 'BeginOffset': 438, 'EndOffset': 448, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '20', 'Type': 'NUMBER', 'BeginOffset': 421, 'EndOffset': 423}, {'Text': 'injections', 'Type': 'TREATMENT', 'BeginOffset': 438, 'EndOffset': 448}, {'Id': 20, 'BeginOffset': 455, 'EndOffset': 463, 'Score': 0.33027905225753784, 'Text': 'lartruvo', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'ROUTE_OR_MODE', 'Score': 0.44503965973854065, 'RelationshipScore': 0.8042891621589661, 'RelationshipType': 'ROUTE_OR_MODE', 'Id': 19, 'BeginOffset': 438, 'EndOffset': 448, 'Text': 'injections', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'the pack lartruvo concentrate', 'Type': 'TREATMENT', 'BeginOffset': 491, 'EndOffset': 520}, {'Text': 'infusion (sterile concentrate', 'Type': 'TREATMENT', 'BeginOffset': 538, 'EndOffset': 567}, {'Text': 'slightly yellow liquid', 'Type': 'PROBLEM', 'BeginOffset': 621, 'EndOffset': 643}, {'Text': 'an elastomeric stopper', 'Type': 'TREATMENT', 'BeginOffset': 674, 'EndOffset': 696}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 729, 'EndOffset': 730}, {'Text': '19', 'Type': 'NUMBER', 'BeginOffset': 739, 'EndOffset': 741}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 747, 'EndOffset': 748}, {'Text': '19', 'Type': 'NUMBER', 'BeginOffset': 758, 'EndOffset': 760}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 766, 'EndOffset': 767}, {'Text': '50', 'Type': 'NUMBER', 'BeginOffset': 776, 'EndOffset': 778}]}"}}},{"rowIdx":1065,"cells":{"ID":{"kind":"string","value":"84076FDAE8517FC06F70D93160D601E0"},"URL":{"kind":"string","value":"https://www.ema.europa.eu/documents/product-information/solymbic-epar-product-information_en.pdf"},"Product_Name":{"kind":"string","value":"Solymbic"},"Full_Content":{"kind":"string","value":"1 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX I \n\n \n\nSUMMARY OF PRODUCT CHARACTERISTICS \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n2 \n\nThis medicinal product is subject to additional monitoring. This will allow quick identification of \n\nnew safety information. Healthcare professionals are asked to report any suspected adverse reactions. \n\nSee section 4.8 for how to report adverse reactions. \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nSOLYMBIC 20 mg solution for injection in pre-filled syringe. \n\nSOLYMBIC 40 mg solution for injection in pre-filled syringe. \n\nSOLYMBIC 40 mg solution for injection in pre-filled pen. \n\n \n\n \n\n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n\n \n\nSOLYMBIC 20 mg solution for injection in pre-filled syringe \n\nEach single dose pre-filled syringe contains 20 mg of adalimumab in 0.4 mL (50 mg/mL) solution. \n\n \n\nSOLYMBIC 40 mg solution for injection in pre-filled syringe \n\nEach single dose pre-filled syringe contains 40 mg of adalimumab in 0.8 mL (50 mg/mL) solution. \n\n \n\nSOLYMBIC 40 mg solution for injection in pre-filled pen \n\nEach single dose pre-filled pen contains 40 mg of adalimumab in 0.8 mL (50 mg/mL) solution. \n\n \n\nAdalimumab is a recombinant human monoclonal antibody expressed in Chinese Hamster Ovary cells. \n\n \n\nFor the full list of excipients, see section 6.1. \n\n \n\n \n\n3. PHARMACEUTICAL FORM \n\n \n\nSOLYMBIC 20 mg solution for injection in pre-filled syringe \n\nSOLYMBIC 40 mg solution for injection in pre-filled syringe \n\nSolution for injection. \n\n \n\nSOLYMBIC 40 mg solution for injection in pre-filled pen (SureClick) \n\nSolution for injection. \n\n \n\nClear and colourless to slightly yellow solution. \n\n \n\n \n\n4. CLINICAL PARTICULARS \n\n \n\n4.1 Therapeutic indications \n\n \n\nRheumatoid arthritis \n\n \n\nSOLYMBIC in combination with methotrexate, is indicated for: \n\n• the treatment of moderate to severe, active rheumatoid arthritis in adult patients when the \nresponse to disease-modifying anti-rheumatic drugs including methotrexate has been \n\ninadequate. \n\n• the treatment of severe, active and progressive rheumatoid arthritis in adults not previously \ntreated with methotrexate. \n\n \n\nSOLYMBIC can be given as monotherapy in case of intolerance to methotrexate or when continued \n\ntreatment with methotrexate is inappropriate. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n3 \n\nSOLYMBIC reduces the rate of progression of joint damage as measured by x-ray and improves \n\nphysical function, when given in combination with methotrexate. \n\n \n\nJuvenile idiopathic arthritis \n\n \n\nEnthesitis-related arthritis \n\n \n\nSOLYMBIC is indicated for the treatment of active enthesitis-related arthritis in patients, 6 years of \n\nage and older, who have had an inadequate response to, or who are intolerant of, conventional therapy \n\n(see section 5.1). \n\n \n\nAxial spondyloarthritis \n\n \n\nAnkylosing spondylitis (AS) \n\n \n\nSOLYMBIC is indicated for the treatment of adults with severe active ankylosing spondylitis who \n\nhave had an inadequate response to conventional therapy. \n\n \n\nAxial spondyloarthritis without radiographic evidence of AS \n\n \n\nSOLYMBIC is indicated for the treatment of adults with severe axial spondyloarthritis without \n\nradiographic evidence of AS but with objective signs of inflammation by elevated CRP and/or MRI, \n\nwho have had an inadequate response to, or are intolerant to non-steroidal anti-inflammatory drugs. \n\n \n\nPsoriatic arthritis \n\n \n\nSOLYMBIC is indicated for the treatment of active and progressive psoriatic arthritis in adults when \n\nthe response to previous disease-modifying anti-rheumatic drug therapy has been inadequate. \n\nSOLYMBIC reduces the rate of progression of peripheral joint damage as measured by x-ray in \n\npatients with polyarticular symmetrical subtypes of the disease (see section 5.1) and improves physical \n\nfunction. \n\n \n\nPsoriasis \n\n \n\nSOLYMBIC is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult \n\npatients who are candidates for systemic therapy. \n\n \n\nPaediatric plaque psoriasis \n\n \n\nSOLYMBIC is indicated for the treatment of severe chronic plaque psoriasis in children and \n\nadolescents from 4 years of age who have had an inadequate response to or are inappropriate \n\ncandidates for topical therapy and phototherapies. \n\n \n\nHidradenitis suppurativa (HS) \n\n \n\nSOLYMBIC is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne \n\ninversa) in adult patients with an inadequate response to conventional systemic HS therapy. \n\n \n\nCrohn’s disease \n\n \n\nSOLYMBIC is indicated for treatment of moderately to severely active Crohn’s disease, in adult \n\npatients who have not responded despite a full and adequate course of therapy with a corticosteroid \n\nand/or an immunosuppressant; or who are intolerant to or have medical contraindications for such \n\ntherapies. \n\n \n\nPaediatric Crohn's disease \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n4 \n\nSOLYMBIC is indicated for the treatment of moderately to severely active Crohn's disease in \n\npaediatric patients (from 6 years of age) who have had an inadequate response to conventional therapy \n\nincluding primary nutrition therapy, a corticosteroid, and an immunomodulator, or who are intolerant \n\nto or have contraindications for such therapies. \n\n \n\nUlcerative colitis \n\n \n\nSOLYMBIC is indicated for treatment of moderately to severely active ulcerative colitis in adult \n\npatients who have had an inadequate response to conventional therapy including corticosteroids and 6-\n\nmercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical \n\ncontraindications for such therapies. \n\n \n\nUveitis \n\n \n\nSOLYMBIC is indicated for the treatment of non-infectious intermediate, posterior and panuveitis in \n\nadult patients who have had an inadequate response to corticosteroids, in patients in need of \n\ncorticosteroid-sparing, or in whom corticosteroid treatment is inappropriate. \n\n \n\n4.2 Posology and method of administration \n\n \n\nSOLYMBIC treatment should be initiated and supervised by specialist physicians experienced in the \n\ndiagnosis and treatment of conditions for which SOLYMBIC is indicated. Ophthalmologists are \n\nadvised to consult with an appropriate specialist before initiation of treatment with SOLYMBIC (see \n\nsection 4.4). Patients treated with SOLYMBIC should be given the special alert card. \n\n \n\nAfter proper training in injection technique, patients may self-inject with SOLYMBIC if their \n\nphysician determines that it is appropriate and with medical follow-up as necessary. \n\n \n\nDuring treatment with SOLYMBIC, other concomitant therapies (e.g. corticosteroids and/or \n\nimmunomodulatory agents) should be optimised. \n\n \n\nPosology \n\n \n\nRheumatoid arthritis \n\n \n\nThe recommended dose of SOLYMBIC for adult patients with rheumatoid arthritis is 40 mg \n\nadalimumab administered every other week as a single dose via subcutaneous injection. Methotrexate \n\nshould be continued during treatment with SOLYMBIC. \n\n \n\nGlucocorticoids, salicylates, non-steroidal anti-inflammatory drugs, or analgesics can be continued \n\nduring treatment with SOLYMBIC. Regarding combination with disease-modifying anti-rheumatic \n\ndrugs other than methotrexate see sections 4.4 and 5.1. \n\n \n\nIn monotherapy, some patients who experience a decrease in their response may benefit from an \n\nincrease in dose intensity to 40 mg adalimumab every week. \n\n \n\nAvailable adalimumab data suggest that the clinical response is usually achieved within 12 weeks of \n\ntreatment. Continued therapy should be reconsidered in a patient not responding within this time \n\nperiod. \n\n \n\nDose interruption \n\n \n\nThere may be a need for dose interruption, for instance before surgery or if a serious infection occurs. \n\n \n\nRe-introduction of SOLYMBIC after discontinuation for 70 days or longer should result in the same \n\nmagnitudes of clinical response and similar safety profile as before dose interruption. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n5 \n\nAnkylosing spondylitis, axial spondyloarthritis without radiographic evidence of AS and psoriatic \n\narthritis \n\n \n\nThe recommended dose of SOLYMBIC for patients with ankylosing spondylitis, axial \n\nspondyloarthritis without radiographic evidence of AS and for patients with psoriatic arthritis is 40 mg \n\nadalimumab administered every other week as a single dose via subcutaneous injection. \n\n \n\nFor all of the above indications, available data suggest that the clinical response is usually achieved \n\nwithin 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not \n\nresponding within this time period. \n\n \n\nPsoriasis \n\n \n\nThe recommended dose of SOLYMBIC for adult patients is an initial dose of 80 mg administered \n\nsubcutaneously, followed by 40 mg subcutaneously given every other week starting one week after the \n\ninitial dose. \n\n \n\nContinued therapy beyond 16 weeks should be carefully reconsidered in a patient not responding \n\nwithin this time period. \n\n \n\nBeyond 16 weeks, patients with inadequate response may benefit from an increase in dosing frequency \n\nto 40 mg every week. The benefits and risks of continued weekly therapy should be carefully \n\nreconsidered in a patient with an inadequate response after the increase in dosing frequency (see \n\nsection 5.1). If adequate response is achieved with an increased dosing frequency, the dose may \n\nsubsequently be reduced to 40 mg every other week. \n\n \n\nHidradenitis suppurativa \n\n \n\nThe recommended SOLYMBIC dose regimen for adult patients with hidradenitis suppurativa (HS) is \n\n160 mg initially at day 1 (given as four 40 mg injections in one day or as two 40 mg injections per day \n\nfor two consecutive days), followed by 80 mg two weeks later at day 15 (given as two 40 mg \n\ninjections in one day). Two weeks later (day 29) continue with a dose of 40 mg every week. \n\nAntibiotics may be continued during treatment with SOLYMBIC if necessary. It is recommended that \n\nthe patient should use a topical antiseptic wash on their HS lesions on a daily basis during treatment \n\nwith SOLYMBIC. \n\n \n\nContinued therapy beyond 12 weeks should be carefully reconsidered in a patient with no \n\nimprovement within this time period. \n\n \n\nShould treatment be interrupted, SOLYMBIC 40 mg every week may be re-introduced (see \n\nsection 5.1). \n\n \n\nThe benefit and risk of continued long-term treatment should be periodically evaluated (see \n\nsection 5.1). \n\n \n\nCrohn’s disease \n\n \n\nThe recommended SOLYMBIC induction dose regimen for adult patients with moderately to severely \n\nactive Crohn’s disease is 80 mg at week 0 followed by 40 mg at week 2. In case there is a need for a \n\nmore rapid response to therapy, the regimen 160 mg at week 0 (dose can be administered as four \n\ninjections in one day or as two injections per day for two consecutive days), 80 mg at week 2, can be \n\nused with the awareness that the risk for adverse events is higher during induction. \n\n \n\nAfter induction treatment, the recommended dose is 40 mg every other week via subcutaneous \n\ninjection. Alternatively, if a patient has stopped SOLYMBIC and signs and symptoms of disease \n\nrecur, SOLYMBIC may be re-administered. There is little experience from re-administration after \n\nmore than 8 weeks since the previous dose. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n6 \n\n \n\nDuring maintenance treatment, corticosteroids may be tapered in accordance with clinical practice \n\nguidelines. \n\n \n\nSome patients who experience decrease in their response may benefit from an increase in dosing \n\nfrequency to 40 mg SOLYMBIC every week. \n\n \n\nSome patients who have not responded by week 4 may benefit from continued maintenance therapy \n\nthrough week 12. Continued therapy should be carefully reconsidered in a patient not responding \n\nwithin this time period. \n\n \n\nUlcerative colitis \n\n \n\nThe recommended SOLYMBIC induction dose regimen for adult patients with moderate to severe \n\nulcerative colitis is 160 mg at week 0 (dose can be administered as four injections in one day or as two \n\ninjections per day for two consecutive days) and 80 mg at week 2. After induction treatment, the \n\nrecommended dose is 40 mg every other week via subcutaneous injection. \n\n \n\nDuring maintenance treatment, corticosteroids may be tapered in accordance with clinical practice \n\nguidelines. \n\n \n\nSome patients who experience decrease in their response may benefit from an increase in dosing \n\nfrequency to 40 mg SOLYMBIC every week. \n\n \n\nClinical response is usually achieved within 2-8 weeks of treatment. SOLYMBIC therapy should not \n\nbe continued in patients failing to respond within this time period. \n\n \n\nUveitis \n\n \n\nThe recommended dose of SOLYMBIC for adult patients with uveitis is an initial dose of 80 mg, \n\nfollowed by 40 mg given every other week starting one week after the initial dose. There is limited \n\nexperience in the initiation of treatment with adalimumab alone. Treatment with SOLYMBIC can be \n\ninitiated in combination with corticosteroids and/or with other non-biologic immunomodulatory \n\nagents. Concomitant corticosteroids may be tapered in accordance with clinical practice starting two \n\nweeks after initiating treatment with SOLYMBIC. \n\n \n\nIt is recommended that the benefit and risk of continued long-term treatment should be evaluated on a \n\nyearly basis (see section 5.1). \n\n \n\nElderly patients \n\n \n\nNo dose adjustment is required. \n\n \n\nImpaired renal and/or hepatic function \n\n \n\nAdalimumab has not been studied in these patient populations. No dose recommendations can be \n\nmade. \n\n \n\nPaediatric population \n\n \n\nSOLYMBIC is only available as 20 mg and 40 mg pre-filled syringe and 40 mg pre-filled pen. It is not \n\npossible to administer SOLYMBIC to paediatric patients that require less than a full 20 mg or 40 mg \n\ndose. If an alternate dose is required, other adalimumab products offering such an option should be \n\nused. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n7 \n\nEnthesitis-related arthritis \n\n \n\nThe recommended dose of SOLYMBIC for patients with enthesitis-related arthritis 6 years of age and \n\nolder is 24 mg/m² body surface area up to a maximum single dose of 40 mg adalimumab administered \n\nevery other week via subcutaneous injection. The volume for injection is selected based on the \n\npatients' height and weight (table 1). \n\n \n\nAdalimumab has not been studied in patients with enthesitis-related arthritis aged less than 6 years. \n\n \n\nTable 1. SOLYMBIC dose in milligrams (mg) by height and weight of patients for \n\nenthesitis-related arthritis \n\n \n\nHeight \n\n(cm) \n\nTotal body weight (kg) \n\n10 15 20 25 30 35 40 45 50 55 60 65 70 \n\n80 - - - - \n\n90 - - - 20 20 20 \n\n100 - - - 20 20 20 - - \n\n110 - - 20 20 20 - - - - - - \n\n120 - 20 20 20 - - - - - - - - - \n\n130 20 20 - - - - - - - - - - \n\n140 20 20 - - - - - - - - - 40* \n\n150 - - - - - - - - - 40* 40* \n\n160 - - - - - - - 40* 40* 40* 40* \n\n170 - - - - - 40* 40* 40* 40* 40* \n\n180 - - - 40* 40* 40* 40* 40* 40* \n\n* Maximum single dose is 40 mg (0.8 mL) \n- Not applicable, SOLYMBIC is only available as 20 mg and 40 mg pre-filled syringe and 40 mg pre-filled \n\npen \n\n \n\nPaediatric plaque psoriasis \n\n \n\nThe recommended SOLYMBIC dose is 0.8 mg per kg body weight (up to a maximum of 40 mg per \n\ndose) administered subcutaneously weekly for the first two doses and every other week thereafter. \n\nContinued therapy beyond 16 weeks should be carefully considered in a patient not responding within \n\nthis time period. \n\n \n\nIf retreatment with SOLYMBIC is indicated, the above guidance on dose and treatment duration \n\nshould be followed. \n\n \n\nThe safety of adalimumab in paediatric patients with plaque psoriasis has been assessed for a mean of \n\n13 months. \n\n \n\nPatients above 4 years of age but with a weight less than 23 kg or between 29 and 46 kg are not \n\npossible to dose with this product. There is no relevant use of adalimumab in children aged less than 4 \n\nyears in this indication. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n8 \n\n \n\nThe administered dose is selected based on the patients' weight (table 2). \n\n \n\nTable 2 SOLYMBIC dose in milligrams (mg) by weight for patients with paediatric psoriasis \n\n \n\nBody weight (kg) Paediatric psoriasis dose \n\n13–16 - \n\n17–22 - \n\n23–28 20 mg \n\n29–34 - \n\n35–40 - \n\n41–46 - \n\n47+ 40 mg \n- Not applicable, SOLYMBIC is only available as 20 mg and 40 mg pre-filled syringe and 40 mg pre-filled \n\npen. \n\n \n\nPaediatric Crohn's disease \n\n \n\nPaediatric Crohn's disease patients < 40 kg: \n\n \n\nThe recommended SOLYMBIC induction dose regimen for paediatric subjects with severe Crohn's \n\ndisease is 40 mg at week 0 followed by 20 mg at week 2. In case there is a need for a more rapid \n\nresponse to therapy, the regimen 80 mg at week 0 (dose can be administered as two injections in one \n\nday), 40 mg at week 2 can be used, with the awareness that the risk for adverse events may be higher \n\nwith use of the higher induction dose. \n\n \n\nAfter induction treatment, the recommended dose is 20 mg every other week via subcutaneous \n\ninjection. Some subjects who experience insufficient response may benefit from an increase in dosing \n\nfrequency to 20 mg SOLYMBIC every week. \n\n \n\nPaediatric Crohn's disease patients ≥ 40 kg: \n\n \n\nThe recommended SOLYMBIC induction dose regimen for paediatric subjects with severe Crohn's \n\ndisease is 80 mg at week 0 followed by 40 mg at week 2. In case there is a need for a more rapid \n\nresponse to therapy, the regimen 160 mg at week 0 (dose can be administered as four injections in one \n\nday or as two injections per day for two consecutive days), 80 mg at week 2 can be used, with the \n\nawareness that the risk for adverse events may be higher with use of the higher induction dose. \n\n \n\nAfter induction treatment, the recommended dose is 40 mg every other week via subcutaneous \n\ninjection. Some subjects who experience insufficient response may benefit from an increase in dosing \n\nfrequency to 40 mg SOLYMBIC every week. \n\n \n\nContinued therapy should be carefully considered in a subject not responding by week 12. \n\n \n\nThere is no relevant use of adalimumab in children aged less than 6 years in this indication. \n\n \n\nPaediatric hidradenitis suppurativa \n\n \n\nThe safety and efficacy of adalimumab in children aged 12-17 years have not yet been established for \n\nhidradenitis suppurativa. No data are available. There is no relevant use of adalimumab in children \n\naged below 12 years in this indication. \n\n \n\nPaediatric ulcerative colitis \n\n \n\nThe safety and efficacy of adalimumab in children aged 4-17 years have not yet been established. No \n\ndata are available. There is no relevant use of adalimumab in children aged < 4 years in this indication. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n9 \n\nPsoriatic arthritis and axial spondyloarthritis including ankylosing spondylitis \n\n \n\nThere is no relevant use of adalimumab in the paediatric population in the indications, ankylosing \n\nspondylitis and psoriatic arthritis. \n\n \n\nPaediatric uveitis \n\n \n\nThe safety and efficacy of adalimumab in children aged 2-17 years have not yet been established. No \n\ndata are available. \n\n \n\nMethod of administration \n\n \n\nSOLYMBIC is administered by subcutaneous injection. Full instructions for use are provided in the \n\npackage leaflet. \n\n \n\nA 40 mg pen, and a 20 mg and 40 mg pre-filled syringes are available for patients to administer a full \n\n20 mg or 40 mg dose. \n\n \n\n4.3 Contraindications \n\n \n\nHypersensitivity to the active substance or to any of the excipients listed in section 6.1. \n\n \n\nActive tuberculosis or other severe infections such as sepsis, and opportunistic infections (see \n\nsection 4.4). \n\n \n\nModerate to severe heart failure (NYHA class III/IV) (see section 4.4). \n\n \n\n4.4 Special warnings and precautions for use \n\n \n\nIn order to improve traceability of biological medicinal products, the trade name and the batch number \n\nof the administered product should be clearly recorded. \n\n \n\nInfections \n\n \n\nPatients taking TNF-antagonists are more susceptible to serious infections. Impaired lung function \n\nmay increase the risk for developing infections. Patients must therefore be monitored closely for \n\ninfections, including tuberculosis, before, during and after treatment with SOLYMBIC. Because the \n\nelimination of adalimumab may take up to four months, monitoring should be continued throughout \n\nthis period. \n\n \n\nTreatment with SOLYMBIC should not be initiated in patients with active infections including \n\nchronic or localised infections until infections are controlled. In patients who have been exposed to \n\ntuberculosis and patients who have travelled in areas of high risk of tuberculosis or endemic mycoses, \n\nsuch as histoplasmosis, coccidioidomycosis, or blastomycosis, the risk and benefits of treatment with \n\nSOLYMBIC should be considered prior to initiating therapy (see Other opportunistic infections). \n\n \n\nPatients who develop a new infection while undergoing treatment with SOLYMBIC, should be \n\nmonitored closely and undergo a complete diagnostic evaluation. Administration of SOLYMBIC \n\nshould be discontinued if a patient develops a new serious infection or sepsis, and appropriate \n\nantimicrobial or antifungal therapy should be initiated until the infection is controlled. Physicians \n\nshould exercise caution when considering the use of SOLYMBIC in patients with a history of \n\nrecurring infection or with underlying conditions which may predispose patients to infections, \n\nincluding the use of concomitant immunosuppressive medications. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n10 \n\nSerious infections \n\n \n\nSerious infections, including sepsis, due to bacterial, mycobacterial, invasive fungal, parasitic, viral, or \n\nother opportunistic infections such as listeriosis, legionellosis and pneumocystis have been reported in \n\npatients receiving adalimumab. \n\n \n\nOther serious infections seen in clinical trials include pneumonia, pyelonephritis, septic arthritis and \n\nsepticaemia. Hospitalisation or fatal outcomes associated with infections have been reported. \n\n \n\nTuberculosis \n\n \n\nTuberculosis, including reactivation and new onset of tuberculosis, has been reported in patients \n\nreceiving adalimumab. Reports included cases of pulmonary and extra-pulmonary (i.e. disseminated) \n\ntuberculosis. \n\n \n\nBefore initiation of therapy with SOLYMBIC, all patients must be evaluated for both active or \n\ninactive (“latent”) tuberculosis infection. This evaluation should include a detailed medical assessment \n\nof patient history of tuberculosis or possible previous exposure to people with active tuberculosis and \n\nprevious and/or current immunosuppressive therapy. Appropriate screening tests (i.e. tuberculin skin \n\ntest and chest x-ray) should be performed in all patients (local recommendations may apply). It is \n\nrecommended that the conduct and results of these tests are recorded in the patient alert card. \n\nPrescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients \n\nwho are severely ill or immunocompromised. \n\n \n\nIf active tuberculosis is diagnosed, SOLYMBIC therapy must not be initiated (see section 4.3). \n\n \n\nIn all situations described below, the benefit/risk balance of therapy should be very carefully \n\nconsidered. \n\n \n\nIf latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be \n\nconsulted. \n\n \n\nIf latent tuberculosis is diagnosed, appropriate treatment must be started with anti-tuberculosis \n\nprophylaxis treatment before the initiation of SOLYMBIC, and in accordance with local \n\nrecommendations. \n\n \n\nUse of anti-tuberculosis prophylaxis treatment should also be considered before the initiation of \n\nSOLYMBIC in patients with several or significant risk factors for tuberculosis despite a negative test \n\nfor tuberculosis and in patients with a past history of latent or active tuberculosis in whom an adequate \n\ncourse of treatment cannot be confirmed. \n\n \n\nDespite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in \n\npatients treated with adalimumab. Some patients who have been successfully treated for active \n\ntuberculosis have redeveloped tuberculosis while being treated with adalimumab. \n\n \n\nPatients should be instructed to seek medical advice if signs/symptoms suggestive of a tuberculosis \n\ninfection (e.g. persistent cough, wasting/weight loss, low grade fever, listlessness) occur during or \n\nafter therapy with SOLYMBIC. \n\n \n\nOther opportunistic infections \n\n \n\nOpportunistic infections, including invasive fungal infections have been observed in patients receiving \n\nadalimumab. These infections have not consistently been recognised in patients taking TNF-\n\nantagonists and this has resulted in delays in appropriate treatment, sometimes resulting in fatal \n\noutcomes. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n11 \n\nFor patients who develop the signs and symptoms such as fever, malaise, weight loss, sweats, cough, \n\ndyspnoea, and/or pulmonary infiltrates or other serious systemic illness with or without concomitant \n\nshock an invasive fungal infection should be suspected and administration of SOLYMBIC should be \n\npromptly discontinued. Diagnosis and administration of empiric antifungal therapy in these patients \n\nshould be made in consultation with a physician with expertise in the care of patients with invasive \n\nfungal infections. \n\n \n\nHepatitis B reactivation \n\n \n\nReactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including adalimumab, \n\nwho are chronic carriers of this virus (i.e. surface antigen positive). Some cases have had a fatal \n\noutcome. Patients should be tested for HBV infection before initiating treatment with SOLYMBIC. \n\nFor patients who test positive for hepatitis B infection, consultation with a physician with expertise in \n\nthe treatment of hepatitis B is recommended. \n\n \n\nCarriers of HBV who require treatment with SOLYMBIC should be closely monitored for signs and \n\nsymptoms of active HBV infection throughout therapy and for several months following termination \n\nof therapy. Adequate data from treating patients who are carriers of HBV with anti-viral therapy in \n\nconjunction with TNF-antagonist therapy to prevent HBV reactivation are not available. In patients \n\nwho develop HBV reactivation, SOLYMBIC should be stopped and effective anti-viral therapy with \n\nappropriate supportive treatment should be initiated. \n\n \n\nNeurological events \n\n \n\nTNF-antagonists including adalimumab have been associated in rare instances with new onset or \n\nexacerbation of clinical symptoms and/or radiographic evidence of central nervous system \n\ndemyelinating disease including multiple sclerosis and optic neuritis, and peripheral demyelinating \n\ndisease, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use \n\nof SOLYMBIC in patients with pre-existing or recent-onset central or peripheral nervous system \n\ndemyelinating disorders; discontinuation of SOLYMBIC should be considered if any of these \n\ndisorders develop. There is a known association between intermediate uveitis and central \n\ndemyelinating disorders. Neurologic evaluation should be performed in patients with non-infectious \n\nintermediate uveitis prior to the initiation of SOLYMBIC therapy and regularly during treatment to \n\nassess for pre-existing or developing central demyelinating disorders. \n\n \n\nAllergic reactions \n\n \n\nSerious allergic reactions associated with adalimumab were rare during clinical trials. Non-serious \n\nallergic reactions associated with adalimumab were uncommon during clinical trials. Reports of \n\nserious allergic reactions including anaphylaxis have been received following adalimumab \n\nadministration. If an anaphylactic reaction or other serious allergic reaction occurs, administration of \n\nSOLYMBIC should be discontinued immediately and appropriate therapy initiated. \n\n \n\nDry natural rubber \n\n \n\nThe needle cover of the pre-filled syringe or pen is made from dry natural rubber (a derivative of \n\nlatex), which may cause allergic reactions. \n\n \n\nImmunosuppression \n\n \n\nIn a study of 64 patients with rheumatoid arthritis that were treated with adalimumab, there was no \n\nevidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or \n\nchange in enumeration of effector T-, B-, NK-cells, monocyte/macrophages, and neutrophils. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n12 \n\nMalignancies and lymphoproliferative disorders \n\n \n\nIn the controlled portions of adalimumab clinical trials of TNF-antagonists, more cases of \n\nmalignancies including lymphoma have been observed among patients receiving a TNF-antagonist \n\ncompared with control patients. However, the occurrence was rare. In the post-marketing setting, cases \n\nof leukaemia have been reported in patients treated with a TNF-antagonist. There is an increased \n\nbackground risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing \n\nhighly active, inflammatory disease, which complicates the risk estimation. With the current \n\nknowledge, a possible risk for the development of lymphomas, leukaemia, and other malignancies in \n\npatients treated with a TNF-antagonist cannot be excluded. \n\n \n\nMalignancies, some fatal, have been reported among children, adolescents and young adults (up to \n\n22 years of age) treated with TNF-antagonists (initiation of therapy ≤ 18 years of age), including \n\nadalimumab in the post-marketing setting. Approximately half the cases were lymphomas. The other \n\ncases represented a variety of different malignancies and included rare malignancies usually associated \n\nwith immunosuppression. A risk for the development of malignancies in children and adolescents \n\ntreated with TNF-antagonists cannot be excluded. \n\n \n\nRare post-marketing cases of hepatosplenic T-cell lymphoma have been identified in patients treated \n\nwith adalimumab. This rare type of T-cell lymphoma has a very aggressive disease course and is \n\nusually fatal. Some of these hepatosplenic T-cell lymphomas with adalimumab have occurred in \n\nyoung adult patients on concomitant treatment with azathioprine or 6-mercaptopurine used for \n\ninflammatory bowel disease. The potential risk with the combination of azathioprine or \n\n6-mercaptopurine and SOLYMBIC should be carefully considered. A risk for the development of \n\nhepatosplenic T-cell lymphoma in patients treated with SOLYMBIC cannot be excluded (see \n\nsection 4.8). \n\n \n\nNo studies have been conducted that include patients with a history of malignancy or in whom \n\ntreatment with adalimumab is continued following development of malignancy. Thus additional \n\ncaution should be exercised in considering SOLYMBIC treatment of these patients (see section 4.8). \n\n \n\nAll patients, and in particular patients with a medical history of extensive immunosuppressant therapy \n\nor psoriasis patients with a history of PUVA treatment should be examined for the presence of non-\n\nmelanoma skin cancer prior to and during treatment with SOLYMBIC. Melanoma and Merkel cell \n\ncarcinoma have also been reported in patients treated with TNF-antagonists including adalimumab \n\n(see section 4.8). \n\n \n\nIn an exploratory clinical trial evaluating the use of another TNF-antagonist, infliximab, in patients \n\nwith moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, mostly in \n\nthe lung or head and neck, were reported in infliximab-treated patients compared with control patients. \n\nAll patients had a history of heavy smoking. Therefore, caution should be exercised when using any \n\nTNF-antagonist in COPD patients, as well as in patients with increased risk for malignancy due to \n\nheavy smoking. \n\n \n\nWith current data it is not known if adalimumab treatment influences the risk for developing dysplasia \n\nor colon cancer. All patients with ulcerative colitis who are at increased risk for dysplasia or colon \n\ncarcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing \n\ncholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for \n\ndysplasia at regular intervals before therapy and throughout their disease course. This evaluation \n\nshould include colonoscopy and biopsies per local recommendations. \n\n \n\nHaematologic reactions \n\n \n\nRare reports of pancytopenia including aplastic anaemia have been reported with TNF-antagonists. \n\nAdverse events of the haematologic system, including medically significant cytopenia (e.g. \n\nthrombocytopenia, leucopenia) have been reported with adalimumab. All patients should be advised to \n\nseek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n13 \n\n(e.g. persistent fever, bruising, bleeding, pallor) while on SOLYMBIC. Discontinuation of \n\nSOLYMBIC therapy should be considered in patients with confirmed significant haematologic \n\nabnormalities. \n\n \n\nVaccinations \n\n \n\nSimilar antibody responses to the standard 23-valent pneumococcal vaccine and the influenza trivalent \n\nvirus vaccination were observed in a study in 226 adult subjects with rheumatoid arthritis who were \n\ntreated with adalimumab or placebo. No data are available on the secondary transmission of infection \n\nby live vaccines in patients receiving adalimumab. \n\n \n\nIt is recommended that paediatric patients, if possible, be brought up to date with all immunisations in \n\nagreement with current immunisation guidelines prior to initiating SOLYMBIC therapy. \n\n \n\nPatients on SOLYMBIC may receive concurrent vaccinations, except for live vaccines. \n\nAdministration of live vaccines to infants exposed to SOLYMBIC in utero is not recommended for \n\n5 months following the mother’s last SOLYMBIC injection during pregnancy. \n\n \n\nCongestive heart failure \n\n \n\nIn a clinical trial with another TNF-antagonist worsening congestive heart failure and increased \n\nmortality due to congestive heart failure have been observed. Cases of worsening congestive heart \n\nfailure have also been reported in patients receiving adalimumab. SOLYMBIC should be used with \n\ncaution in patients with mild heart failure (NYHA class I/II). SOLYMBIC is contraindicated in \n\nmoderate to severe heart failure (see section 4.3). Treatment with SOLYMBIC must be discontinued \n\nin patients who develop new or worsening symptoms of congestive heart failure. \n\n \n\nAutoimmune processes \n\n \n\nTreatment with SOLYMBIC may result in the formation of autoimmune antibodies. The impact of \n\nlong-term treatment with SOLYMBIC on the development of autoimmune diseases is unknown. If a \n\npatient develops symptoms suggestive of a lupus-like syndrome following treatment with SOLYMBIC \n\nand is positive for antibodies against double-stranded DNA, further treatment with SOLYMBIC \n\nshould not be given (see section 4.8). \n\n \n\nConcurrent administration of biologic DMARDS or TNF-antagonists \n\n \n\nSerious infections were seen in clinical studies with concurrent use of anakinra and another TNF-\n\nantagonist, etanercept, with no added clinical benefit compared to etanercept alone. Because of the \n\nnature of the adverse events seen with the combination of etanercept and anakinra therapy, similar \n\ntoxicities may also result from the combination of anakinra and other TNF-antagonists. Therefore, the \n\ncombination of SOLYMBIC and anakinra is not recommended (see section 4.5). \n\n \n\nConcomitant administration of SOLYMBIC with other biologic DMARDS (e.g. anakinra and \n\nabatacept) or other TNF-antagonists is not recommended based upon the possible increased risk for \n\ninfections, including serious infections and other potential pharmacological interactions (see section \n\n4.5). \n\n \n\nSurgery \n\n \n\nThere is limited safety experience of surgical procedures in patients treated with adalimumab. The \n\nlong half-life of adalimumab should be taken into consideration if a surgical procedure is planned. A \n\npatient who requires surgery while on SOLYMBIC should be closely monitored for infections, and \n\nappropriate actions should be taken. There is limited safety experience in patients undergoing \n\narthroplasty while receiving adalimumab. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n14 \n\nSmall bowel obstruction \n\n \n\nFailure to respond to treatment for Crohn’s disease may indicate the presence of fixed fibrotic stricture \n\nthat may require surgical treatment. Available data suggest that adalimumab does not worsen or cause \n\nstrictures. \n\n \n\nElderly patients \n\n \n\nThe frequency of serious infections among adalimumab-treated subjects over 65 years of age (3.7%) \n\nwas higher than for those under 65 years of age (1.5%). Some of those had a fatal outcome. Particular \n\nattention regarding the risk for infection should be paid when treating the elderly. \n\n \n\nPaediatric population \n\n \n\nSee Vaccinations above. \n\n \n\n4.5 Interaction with other medicinal products and other forms of interaction \n\n \n\nAdalimumab has been studied in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and \n\npsoriatic arthritis patients taking adalimumab as monotherapy and those taking concomitant \n\nmethotrexate. Antibody formation was lower when adalimumab was given together with methotrexate \n\nin comparison with use as monotherapy. Administration of adalimumab without methotrexate resulted \n\nin increased formation of antibodies, increased clearance and reduced efficacy of adalimumab (see \n\nsection 5.1). \n\n \n\nThe combination of SOLYMBIC and anakinra is not recommended (see section 4.4 “Concurrent \n\nadministration of biologic DMARDS or TNF-antagonists”). \n\n \n\nThe combination of SOLYMBIC and abatacept is not recommended (see section 4.4 “Concurrent \n\nadministration of biologic DMARDS or TNF-antagonists”). \n\n \n\n4.6 Fertility, pregnancy and lactation \n\n \n\nWomen of child bearing potential/Contraception in males and females \n\n \n\nWomen of childbearing potential are strongly recommended to use adequate contraception to prevent \n\npregnancy and continue its use for at least five months after the last SOLYMBIC treatment. \n\n \n\nPregnancy \n\n \n\nFor adalimumab, limited clinical data on exposed pregnancies are available. \n\n \n\nIn a developmental toxicity study conducted in monkeys, there was no indication of maternal toxicity, \n\nembryotoxicity or teratogenicity. Preclinical data on postnatal toxicity of adalimumab are not available \n\n(see section 5.3). \n\n \n\nDue to its inhibition of TNFα, adalimumab administered during pregnancy could affect normal \n\nimmune responses in the newborn. Administration of SOLYMBIC is not recommended during \n\npregnancy. \n\n \n\nAdalimumab may cross the placenta into the serum of infants born to women treated with adalimumab \n\nduring pregnancy. Consequently, these infants may be at increased risk for infection. Administration \n\nof live vaccines to infants exposed to adalimumab in utero is not recommended for 5 months following \n\nthe mother’s last adalimumab injection during pregnancy. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n15 \n\nBreast-feeding \n\n \n\nIt is not known whether adalimumab is excreted in human milk or absorbed systemically after \n\ningestion. \n\n \n\nHowever, because human immunoglobulins are excreted in milk, women must not breast-feed for at \n\nleast five months after the last SOLYMBIC treatment. \n\n \n\nFertility \n\n \n\nPreclinical data on fertility effects of adalimumab are not available. \n\n \n\n4.7 Effects on ability to drive and use machines \n\n \n\nSOLYMBIC may have a minor influence on the ability to drive and use machines. Vertigo and visual \n\nimpairment may occur following administration of SOLYMBIC (see section 4.8). \n\n \n\n4.8 Undesirable effects \n\n \n\nSummary of the safety profile \n\n \n\nAdalimumab was studied in 9,506 patients in pivotal controlled and open-label trials for up to \n\n60 months or more. These trials included rheumatoid arthritis patients with short term and long-\n\nstanding disease, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-\n\nrelated arthritis) as well as axial spondyloarthritis (ankylosing spondylitis and axial spondyloarthritis \n\nwithout radiographic evidence of AS), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, \n\nhidradenitis suppurativa and uveitis patients. The pivotal controlled studies involved 6,089 patients \n\nreceiving adalimumab and 3,801 patients receiving placebo or active comparator during the controlled \n\nperiod. \n\n \n\nThe proportion of patients who discontinued treatment due to adverse events during the double-blind, \n\ncontrolled portion of pivotal studies was 5.9% for patients taking adalimumab and 5.4% for control \n\ntreated patients. \n\n \n\nThe most commonly reported adverse reactions are infections (such as nasopharyngitis, upper \n\nrespiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain \n\nor swelling), headache and musculoskeletal pain. \n\n \n\nSerious adverse reactions have been reported for adalimumab. TNF-antagonists, such as SOLYMBIC \n\naffect the immune system and their use may affect the body’s defence against infection and cancer. \n\n \n\nFatal and life-threatening infections (including sepsis, opportunistic infections and TB), HBV \n\nreactivation and various malignancies (including leukaemia, lymphoma and HSTCL) have also been \n\nreported with use of adalimumab. \n\n \n\nSerious haematological, neurological and autoimmune reactions have also been reported. These \n\ninclude rare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events \n\nand reports of lupus, lupus-related conditions and Stevens-Johnson syndrome. \n\n \n\nPaediatric population \n\n \n\nUndesirable effects in paediatric patients \n\n \n\nIn general, the adverse events in paediatric patients were similar in frequency and type to those seen in \n\nadult patients. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n16 \n\nTabulated list of adverse reactions \n\n \n\nThe following list of adverse reactions is based on experience from clinical trials and on post-\n\nmarketing experience and are displayed by system organ class and frequency in table 3 below: very \n\ncommon (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to \n\n< 1/1,000); and not known (cannot be estimated from the available data). Within each frequency \n\ngrouping, undesirable effects are presented in order of decreasing seriousness. The highest frequency \n\nseen among the various indications has been included. An asterisk (*) appears in the SOC column if \n\nfurther information is found elsewhere in sections 4.3, 4.4 and 4.8. \n\n \n\nTable 3 Undesirable effects \n\n \n\nSystem Organ Class Frequency Adverse Reaction \n\nInfections and \n\ninfestations* \n\nVery common Respiratory tract infections (including lower and upper \n\nrespiratory tract infection, pneumonia, sinusitis, pharyngitis, \n\nnasopharyngitis and pneumonia herpes viral) \n\nCommon Systemic infections (including sepsis, candidiasis and \n\ninfluenza), \n\nIntestinal infections (including gastroenteritis viral), \n\nSkin and soft tissue infections (including paronychia, \n\ncellulitis, impetigo, necrotising fasciitis and herpes zoster), \n\nEar infections, \n\nOral infections (including herpes simplex, oral herpes and \n\ntooth infections), \n\nReproductive tract infections (including vulvovaginal \n\nmycotic infection), \n\nUrinary tract infections (including pyelonephritis), \n\nFungal infections, \n\nJoint infection \n\nUncommon Neurological infections (including viral meningitis), \n\nOpportunistic infections and tuberculosis (including \n\ncoccidioidomycosis, histoplasmosis and mycobacterium \n\navium complex infection), \n\nBacterial infections, \n\nEye infections, \n\nDiverticulitis1) \n\nNeoplasms benign, \n\nmalignant and \n\nunspecified (including \n\ncysts and polyps)* \n\nCommon Skin cancer excluding melanoma (including basal cell \n\ncarcinoma and squamous cell carcinoma), \n\nBenign neoplasm \n\nUncommon Lymphoma**, \n\nSolid organ neoplasm (including breast cancer, lung \n\nneoplasm and thyroid neoplasm), \n\nMelanoma** \n\nRare Leukaemia1) \n\nNot known Hepatosplenic T-cell lymphoma1), \n\nMerkel cell carcinoma (neuroendocrine carcinoma of the \n\nskin)1) \n\nBlood and the \n\nlymphatic system \n\ndisorders* \n\n \n\nVery common \n\n \n\nLeucopaenia (including neutropaenia and agranulocytosis), \n\nAnaemia \n\nCommon \n\n \n\nLeucocytosis, \n\nThrombocytopaenia \n\nUncommon Idiopathic thrombocytopaenic purpura \n\nRare Pancytopaenia \n\nImmune system \n\ndisorders* \n\n \n\nCommon \n\n \n\nHypersensitivity, \n\nAllergies (including seasonal allergy) \n\nUncommon \n\n \n\nSarcoidosis1), \n\nVasculitis \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n17 \n\nSystem Organ Class Frequency Adverse Reaction \n\nRare Anaphylaxis1) \n\nMetabolism and \n\nnutrition disorders \n\n \n\nVery common Lipids increased \n\nCommon \n\n \n\nHypokalaemia, \n\nUric acid increased, \n\nBlood sodium abnormal, \n\nHypocalcaemia, \n\nHyperglycaemia, \n\nHypophosphataemia, \n\nDehydration \n\nPsychiatric disorders \n\n \n\nCommon \n\n \n\nMood alterations (including depression), \n\nAnxiety, \n\nInsomnia \n\nNervous system \n\ndisorders* \n\n \n\nVery common Headache \n\nCommon \n\n \n\nParaesthesias (including hypoaesthesia), \n\nMigraine, \n\nNerve root compression \n\nUncommon \n\n \n\nCerebrovascular accident1), \n\nTremor, \n\nNeuropathy \n\nRare \n\n \n\nMultiple sclerosis, \n\nDemyelinating disorders (e.g. optic neuritis, Guillain-Barré \n\nsyndrome)1) \n\nEye disorders \n\n \n\nCommon \n\n \n\nVisual impairment, \n\nConjunctivitis, \n\nBlepharitis, \n\nEye swelling \n\nUncommon Diplopia \n\nEar and labyrinth \n\ndisorders \n\nCommon Vertigo \n\nUncommon Deafness, \n\nTinnitus \n\nCardiac disorders* Common Tachycardia \n\nUncommon Myocardial infarction1), \n\nArrhythmia, \n\nCongestive heart failure \n\nRare Cardiac arrest \n\nVascular disorders Common Hypertension, \n\nFlushing, \n\nHaematoma \n\nUncommon Aortic aneurysm, \n\nVascular arterial occlusion, \n\nThrombophlebitis \n\nRespiratory, thoracic \n\nand mediastinal \n\ndisorders* \n\nCommon Asthma, \n\nDyspnoea, \n\nCough \n\nUncommon Pulmonary embolism1), \n\nInterstitial lung disease, \n\nChronic obstructive pulmonary disease, \n\nPneumonitis, \n\nPleural effusion1) \n\nRare Pulmonary fibrosis1) \n\nGastrointestinal \n\ndisorders \n\nVery common Abdominal pain, \n\nNausea and vomiting \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n18 \n\nSystem Organ Class Frequency Adverse Reaction \n\nCommon GI haemorrhage, \n\nDyspepsia, \n\nGastroesophageal reflux disease, \n\nSicca syndrome \n\nUncommon Pancreatitis, \n\nDysphagia, \n\nFace oedema \n\nRare Intestinal perforation1) \n\nHepato-biliary \n\ndisorders* \n\nVery common Elevated liver enzymes \n\nUncommon Cholecystitis and cholelithiasis, \n\nHepatic steatosis, \n\nBilirubin increased \n\nRare Hepatitis, \n\nReactivation of hepatitis B1), \n\nAutoimmune hepatitis1) \n\nNot known Liver failure1) \n\nSkin and subcutaneous \n\ntissue disorders \n\nVery common Rash (including exfoliative rash) \n\nCommon Worsening or new onset of psoriasis (including palmoplantar \n\npustular psoriasis)1), \n\nUrticaria, \n\nBruising (including purpura), \n\nDermatitis (including eczema), \n\nOnychoclasis, \n\nHyperhidrosis, \n\nAlopecia1), \n\nPruritus \n\nUncommon Night sweats, \n\nScar \n\nRare Erythema multiforme1), \n\nStevens-Johnson syndrome1), \n\nAngioedema1), \n\nCutaneous vasculitis1) \n\nNot known Worsening of symptoms of dermatomyositis1) \n\nMusculoskeletal and \n\nconnective tissue \n\ndisorders \n\nVery common Musculoskeletal pain \n\nCommon Muscle spasms (including blood creatine phosphokinase \n\nincreased) \n\nUncommon Rhabdomyolysis, \n\nSystemic lupus erythematosus \n\nRare Lupus-like syndrome1) \n\nRenal and urinary \n\ndisorders \n\nCommon Renal impairment, \n\nHaematuria \n\nUncommon Nocturia \n\nReproductive system \n\nand breast disorders \n\nUncommon Erectile dysfunction \n\nGeneral disorders and \n\nadministration site \n\nconditions* \n\nVery common Injection site reaction (including injection site erythema) \n\nCommon Chest pain, \n\nOedema, \n\nPyrexia1) \n\nUncommon Inflammation \n\nInvestigations* Common Coagulation and bleeding disorders (including activated \n\npartial thromboplastin time prolonged), \n\nAutoantibody test positive (including double stranded DNA \n\nantibody), \n\nBlood lactate dehydrogenase increased \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n19 \n\nSystem Organ Class Frequency Adverse Reaction \n\nInjury, poisoning and \n\nprocedural \n\ncomplications \n\nCommon \n\n \n\nImpaired healing \n\n \n\n* further information is found elsewhere in sections 4.3, 4.4 and 4.8 \n\n** including open-label extension studies \n1) including spontaneous reporting data \n\n \n\nHidradenitis suppurativa \n\n \n\nThe safety profile for patients with HS treated with adalimumab weekly was consistent with the \n\nknown safety profile of adalimumab. \n\n \n\nUveitis \n\n \n\nThe safety profile for patients with uveitis treated with adalimumab every other week was consistent \n\nwith the known safety profile of adalimumab. \n\n \n\nDescription of selected adverse reactions \n\n \n\nInjection site reactions \n\n \n\nIn the pivotal controlled trials in adults and children, 12.9% of patients treated with adalimumab \n\ndeveloped injection site reactions (erythema and/or itching, haemorrhage, pain or swelling), compared \n\nto 7.2% of patients receiving placebo or active control. Injection site reactions generally did not \n\nnecessitate discontinuation of the medicinal product. \n\n \n\nInfections \n\n \n\nIn the pivotal controlled trials in adults and children, the rate of infection was 1.51 per patient year in \n\nthe adalimumab-treated patients and 1.46 per patient year in the placebo and active control-treated \n\npatients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and \n\nsinusitis. Most patients continued on adalimumab after the infection resolved. \n\n \n\nThe incidence of serious infections was 0.04 per patient year in adalimumab-treated patients and 0.03 \n\nper patient year in placebo and active control-treated patients. \n\n \n\nIn controlled and open-label adult and paediatric studies with adalimumab, serious infections \n\n(including fatal infections, which occurred rarely) have been reported, which include reports of \n\ntuberculosis (including miliary and extra-pulmonary locations) and invasive opportunistic infections \n\n(e.g. disseminated or extrapulmonary histoplasmosis, blastomycosis, coccidioidomycosis, \n\npneumocystis, candidiasis, aspergillosis and listeriosis). Most of the cases of tuberculosis occurred \n\nwithin the first eight months after initiation of therapy and may reflect recrudescence of latent disease. \n\n \n\nMalignancies and lymphoproliferative disorders \n\n \n\nNo malignancies were observed in 249 paediatric patients with an exposure of 655.6 patient-years \n\nduring adalimumab trials in patients with juvenile idiopathic arthritis (polyarticular juvenile idiopathic \n\narthritis and enthesitis-related arthritis). In addition, no malignancies were observed in 192 paediatric \n\npatients with an exposure of 498.1 patient-years during an adalimumab trial in paediatric patients with \n\nCrohn’s disease. No malignancies were observed in 77 paediatric patients with an exposure of 80.0 \n\npatient-years during an adalimumab trial in paediatric patients with chronic plaque psoriasis. \n\n \n\nDuring the controlled portions of pivotal adalimumab trials in adults of at least 12 weeks in duration in \n\npatients with moderately to severely active rheumatoid arthritis, ankylosing spondylitis, axial \n\nspondyloarthritis without radiographic evidence of AS, psoriatic arthritis, psoriasis, hidradenitis \n\nsuppurativa, Crohn’s disease, ulcerative colitis and uveitis, malignancies, other than lymphoma and \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n20 \n\nnon-melanoma skin cancer, were observed at a rate (95% confidence interval) of 6.8 (4.4, 10.5) per \n\n1,000 patient-years among 5,291 adalimumab-treated patients versus a rate of 6.3 (3.4, 11.8) per 1,000 \n\npatient-years among 3,444 control patients (median duration of treatment was 4.0 months for \n\nadalimumab and 3.8 months for control-treated patients). The rate (95% confidence interval) of non-\n\nmelanoma skin cancers was 8.8 (6.0, 13.0) per 1,000 patient-years among adalimumab-treated patients \n\nand 3.2 (1.3, 7.6) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell \n\ncarcinomas occurred at rates (95% confidence interval) of 2.7 (1.4, 5.4) per 1,000 patient-years among \n\nadalimumab-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. The rate \n\n(95% confidence interval) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among \n\nadalimumab-treated patients and 0.6 (0.1, 4.5) per 1,000 patient-years among control patients. \n\n \n\nWhen combining controlled portions of these trials and ongoing and completed open-label extension \n\nstudies of adalimumab, with a median duration of approximately 3.3 years including 6,427 patients \n\nand over 26,439 patient-years of therapy, the observed rate of malignancies, other than lymphoma and \n\nnon-melanoma skin cancers is approximately 8.5 per 1,000 patient-years. The observed rate of non-\n\nmelanoma skin cancers is approximately 9.6 per 1,000 patient-years, and the observed rate of \n\nlymphomas is approximately 1.3 per 1,000 patient-years. \n\n \n\nIn post-marketing experience from January 2003 to December 2010, predominantly in patients with \n\nrheumatoid arthritis, the reported rate of malignancies is approximately 2.7 per 1,000 patient treatment \n\nyears. The reported rates for non-melanoma skin cancers and lymphomas are approximately 0.2 and \n\n0.3 per 1,000 patient treatment years, respectively (see section 4.4). \n\n \n\nRare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated \n\nwith adalimumab (see section 4.4). \n\n \n\nAutoantibodies \n\n \n\nPatients had serum samples tested for autoantibodies at multiple time points in rheumatoid arthritis \n\nstudies I−V. In these trials, 11.9% of patients treated with adalimumab and 8.1% of placebo and active \n\ncontrol-treated patients that had negative baseline anti-nuclear antibody titres reported positive titres at \n\nweek 24. Two patients out of 3,441 treated with adalimumab in all rheumatoid arthritis and psoriatic \n\narthritis studies developed clinical signs suggestive of new onset lupus-like syndrome. The patients \n\nimproved following discontinuation of therapy. No patients developed lupus nephritis or central \n\nnervous system symptoms. \n\n \n\nHepato-biliary events \n\n \n\nIn controlled phase 3 trials of adalimumab in patients with rheumatoid arthritis and psoriatic arthritis \n\nwith a control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in \n\n3.7% of adalimumab-treated patients and 1.6% of control-treated patients. \n\n \n\nIn controlled phase 3 trials of adalimumab in patients with polyarticular juvenile idiopathic arthritis \n\nwho were 4 to 17 years and enthesitis-related arthritis who were 6 to 17 years, ALT elevations \n\n≥ 3 x ULN occurred in 6.1% of adalimumab-treated patients and 1.3% of control-treated patients. \n\nMost ALT elevations occurred with concomitant methotrexate use. No ALT elevations ≥ 3 x ULN \n\noccurred in the Phase 3 trial of adalimumab in patients with polyarticular juvenile idiopathic arthritis \n\nwho were 2 to < 4 years. \n\n \n\nIn controlled phase 3 trials of adalimumab in patients with Crohn’s disease and ulcerative colitis with \n\na control period ranging from 4 to 52 weeks. ALT elevations ≥ 3 x ULN occurred in 0.9% of \n\nadalimumab-treated patients and 0.9% of controlled-treated patients. \n\n \n\nIn the phase 3 trial of adalimumab in patients with paediatric Crohn’s disease which evaluated efficacy \n\nand safety of two body weight adjusted maintenance dose regimens following body weight adjusted \n\ninduction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 x ULN occurred in 2.6% (5/192) of \n\npatients of whom 4 were receiving concomitant immunosuppressants at baseline. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n21 \n\n \n\nIn controlled phase 3 trials of adalimumab in patients with plaque psoriasis with a control period \n\nduration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of adalimumab-\n\ntreated patients and 1.8% of control-treated patients. \n\n \n\nNo ALT elevations ≥ 3 X ULN occurred in the phase 3 trial of adalimumab in paediatric patients with \n\nplaque psoriasis. \n\n \n\nIn controlled trials of adalimumab (initial doses of 160 mg at week 0 and 80 mg at week 2, followed \n\nby 40 mg every week starting at week 4), in patients with hidradenitis suppurativa with a control \n\nperiod duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of \n\nadalimumab-treated patients and 0.6% of control-treated patients. \n\n \n\nIn controlled trials of adalimumab (initial doses of 80 mg at week 0 followed by 40 mg every other \n\nweek starting at week 1) in patients with uveitis up to 80 weeks with a median exposure of 166.5 days \n\nand 105.0 days in adalimumab-treated and control-treated patients, respectively, ALT elevations \n\n≥ 3 x ULN occurred in 2.4% of adalimumab-treated patients and 2.4% of control-treated patients. \n\n \n\nAcross all indications in clinical trials patients with raised ALT were asymptomatic and in most cases \n\nelevations were transient and resolved on continued treatment. However, there have also been post-\n\nmarketing reports of liver failure as well as less severe liver disorders that may precede liver failure, \n\nsuch as hepatitis including autoimmune hepatitis in patients receiving adalimumab. \n\n \n\nConcurrent treatment with azathioprine/6-mercaptopurine \n\n \n\nIn adult Crohn’s disease studies, higher incidences of malignant and serious infection-related adverse \n\nevents were seen with the combination of adalimumab and azathioprine/6-mercaptopurine compared \n\nwith adalimumab alone. \n\n \n\nReporting of suspected adverse reactions \n\n \n\nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \n\nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \n\nprofessionals are asked to report any suspected adverse reactions via the national reporting system \n\nlisted in Appendix V. \n\n \n\n4.9 Overdose \n\n \n\nNo dose-limiting toxicity was observed during clinical trials. The highest dose level evaluated has \n\nbeen multiple intravenous doses of 10 mg/kg, which is approximately 15 times the recommended \n\ndose. \n\n \n\n5. PHARMACOLOGICAL PROPERTIES \n\n \n\n5.1 Pharmacodynamic properties \n\n \n\nPharmacotherapeutic group: Immunosuppressants, Tumour Necrosis Factor alpha (TNFα) inhibitors. \n\nATC code: L04AB04 \n\n \n\nSOLYMBIC is a biosimilar medicinal product. Detailed information is available on the website of the \n\nEuropean Medicines Agency http://www.ema.europa.eu. \n\n \n\nMechanism of action \n\n \n\nAdalimumab binds specifically to TNF and neutralises the biological function of TNF by blocking its \n\ninteraction with the p55 and p75 cell surface TNF receptors. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\nhttp://www.ema.europa.eu/\n\n\n \n\n22 \n\nAdalimumab also modulates biological responses that are induced or regulated by TNF, including \n\nchanges in the levels of adhesion molecules responsible for leucocyte migration (ELAM-1, VCAM-1, \n\nand ICAM-1 with an IC50 of 0.1-0.2 nM). \n\n \n\nPharmacodynamic effects \n\n \n\nAfter treatment with adalimumab, a rapid decrease in levels of acute phase reactants of inflammation \n\n(C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) and serum cytokines (IL-6) was \n\nobserved, compared to baseline in patients with rheumatoid arthritis. Serum levels of matrix \n\nmetalloproteinases (MMP-1 and MMP-3) that produce tissue remodelling responsible for cartilage \n\ndestruction were also decreased after adalimumab administration. Patients treated with adalimumab \n\nusually experienced improvement in haematological signs of chronic inflammation. \n\n \n\nA rapid decrease in CRP levels was also observed in patients with polyarticular juvenile idiopathic \n\narthritis, Crohn's disease, ulcerative colitis and hidradenitis suppurativa after treatment with \n\nadalimumab. In patients with Crohn’s disease, a reduction of the number of cells expressing \n\ninflammatory markers in the colon including a significant reduction of expression of TNFα was seen. \n\nEndoscopic studies in intestinal mucosa have shown evidence of mucosal healing in adalimumab-\n\ntreated patients. \n\n \n\nClinical efficacy and safety \n\n \n\nRheumatoid arthritis \n\n \n\nAdalimumab was evaluated in over 3,000 patients in all rheumatoid arthritis clinical trials. The \n\nefficacy and safety of adalimumab were assessed in five randomised, double-blind and well-controlled \n\nstudies. Some patients were treated for up to 120 months duration. \n\n \n\nRA study I evaluated 271 patients with moderately to severely active rheumatoid arthritis who were \n\n≥ 18 years old, had failed therapy with at least one disease-modifying, anti-rheumatic drug and had \n\ninsufficient efficacy with methotrexate at doses of 12.5 to 25 mg (10 mg if methotrexate-intolerant) \n\nevery week and whose methotrexate dose remained constant at 10 to 25 mg every week. Doses of 20, \n\n40 or 80 mg of adalimumab or placebo were given every other week for 24 weeks. \n\n \n\nRA study II evaluated 544 patients with moderately to severely active rheumatoid arthritis who were \n\n≥ 18 years old and had failed therapy with at least one disease-modifying, anti-rheumatic drugs. Doses \n\nof 20 or 40 mg of adalimumab were given by subcutaneous injection every other week with placebo \n\non alternative weeks or every week for 26 weeks; placebo was given every week for the same \n\nduration. No other disease-modifying anti-rheumatic drugs were allowed. \n\n \n\nRA study III evaluated 619 patients with moderately to severely active rheumatoid arthritis who were \n\n≥ 18 years old, and who had an ineffective response to methotrexate at doses of 12.5 to 25 mg or have \n\nbeen intolerant to 10 mg of methotrexate every week. There were three groups in this study. The first \n\nreceived placebo injections every week for 52 weeks. The second received 20 mg of adalimumab \n\nevery week for 52 weeks. The third group received 40 mg of adalimumab every other week with \n\nplacebo injections on alternate weeks. Upon completion of the first 52 weeks, 457 patients enrolled in \n\nan open-label extension phase in which 40 mg of adalimumab/MTX was administered every other \n\nweek up to 10 years. \n\n \n\nRA study IV primarily assessed safety in 636 patients with moderately to severely active rheumatoid \n\narthritis who were ≥ 18 years old. Patients were permitted to be either disease-modifying, anti-\n\nrheumatic drug-naïve or to remain on their pre-existing rheumatologic therapy provided that therapy \n\nwas stable for a minimum of 28 days. These therapies include methotrexate, leflunomide, \n\nhydroxychloroquine, sulfasalazine and/or gold salts. Patients were randomised to 40 mg of \n\nadalimumab or placebo every other week for 24 weeks. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n23 \n\nRA study V evaluated 799 methotrexate-naïve, adult patients with moderate to severely active early \n\nrheumatoid arthritis (mean disease duration less than 9 months). This study evaluated the efficacy of \n\nadalimumab 40 mg every other week/methotrexate combination therapy, adalimumab 40 mg every \n\nother week monotherapy and methotrexate monotherapy in reducing the signs and symptoms and rate \n\nof progression of joint damage in rheumatoid arthritis for 104 weeks. Upon completion of the first 104 \n\nweeks, 497 patients enrolled in an open-label extension phase in which 40 mg of adalimumab was \n\nadministered every other week up to 10 years. \n\n \n\nThe primary end point in RA studies I, II and III and the secondary endpoint in RA study IV was the \n\npercent of patients who achieved an ACR 20 response at week 24 or 26. The primary endpoint in RA \n\nstudy V was the percent of patients who achieved an ACR 50 response at week 52. RA studies III and \n\nV had an additional primary endpoint at 52 weeks of retardation of disease progression (as detected by \n\nx-ray results). RA study III also had a primary endpoint of changes in quality of life. \n\n \n\nACR response \n\n \n\nThe percent of adalimumab-treated patients achieving ACR 20, 50 and 70 responses was consistent \n\nacross RA studies I, II and III. The results for the 40 mg every other week dose are summarised in \n\ntable 4. \n\n \n\nTable 4 ACR responses in placebo-controlled trials (percent of patients) \n\n \n\nResponse \n\n \n\nRA study Ia** RA study IIa** RA study IIIa** \nPlacebo/ \n\nMTXc \n\nn = 60 \n\nAdalimumabb\n\n/ MTXc \n\nn = 63 \n\nPlacebo \n\nn = 110 \nAdalimumabb \n\nn = 113 \n\nPlacebo/ \n\nMTXc \n\nn = 200 \n\nAdalimumabb\n\n/ MTXc \n\nn = 207 \n\nACR 20 \n\n6 months 13.3% 65.1% 19.1% 46.0% 29.5% 63.3% \n\n12 months NA NA NA NA 24.0% 58.9% \n\nACR 50 \n\n6 months 6.7% 52.4% 8.2% 22.1% 9.5% 39.1% \n\n12 months NA NA NA NA 9.5% 41.5% \n\nACR 70 \n\n6 months 3.3% 23.8% 1.8% 12.4% 2.5% 20.8% \n\n12 months NA NA NA NA 4.5% 23.2% \na RA study I at 24 weeks, RA study II at 26 weeks, and RA study III at 24 and 52 weeks \nb 40 mg adalimumab administered every other week \nc MTX = methotrexate \n\n** p < 0.01, adalimumab versus placebo \n\n \n\nIn RA studies I-IV, all individual components of the ACR response criteria (number of tender and \n\nswollen joints, physician and patient assessment of disease activity and pain, disability index (HAQ) \n\nscores and CRP (mg/dL) values) improved at 24 or 26 weeks compared to placebo. In RA study III, \n\nthese improvements were maintained throughout 52 weeks. \n\n \n\nIn the open-label extension for RA study III, most patients who were ACR responders maintained \n\nresponse when followed for up to 10 years. Of 207 patients who were randomised to adalimumab \n\n40 mg every other week, 114 patients continued on adalimumab 40 mg every other week for 5 years. \n\nAmong those, 86 patients (75.4%) had ACR 20 responses; 72 patients (63.2%) had ACR 50 responses; \n\nand 41 patients (36%) had ACR 70 responses. Of 207 patients, 81 patients continued on adalimumab \n\n40 mg every other week for 10 years. Among those, 64 patients (79.0%) had ACR 20 responses; 56 \n\npatients (69.1%) had ACR 50 responses; and 43 patients (53.1%) had ACR 70 responses. \n\n \n\nIn RA study IV, the ACR 20 response of patients treated with adalimumab plus standard of care was \n\nstatistically significantly better than patients treated with placebo plus standard of care (p < 0.001). \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n24 \n\nIn RA studies I-IV, adalimumab-treated patients achieved statistically significant ACR 20 and 50 \n\nresponses compared to placebo as early as one to two weeks after initiation of treatment. \n\n \n\nIn RA study V with early rheumatoid arthritis patients who were methotrexate naïve, combination \n\ntherapy with adalimumab and methotrexate led to faster and significantly greater ACR responses than \n\nmethotrexate monotherapy and adalimumab monotherapy at week 52 and responses were sustained at \n\nweek 104 (see table 5). \n\n \n\nTable 5 ACR responses in RA study V (percent of patients) \n\n \n\nResponse MTX \n\nn = 257 \n\nAdalimumab\n\nn = 274 \n\nAdalimumab \n\n/MTX \n\nn = 268 \n\np-valuea p-valueb p-valuec \n\nACR 20 \n\nWeek 52 62.6% 54.4% 72.8% 0.013 < 0.001 0.043 \n\nWeek 104 56.0% 49.3% 69.4% 0.002 < 0.001 0.140 \n\nACR 50 \n\nWeek 52 45.9% 41.2% 61.6% < 0.001 < 0.001 0.317 \n\nWeek 104 42.8% 36.9% 59.0% < 0.001 < 0.001 0.162 \n\nACR 70 \n\nWeek 52 27.2% 25.9% 45.5% < 0.001 < 0.001 0.656 \n\nWeek 104 28.4% 28.1% 46.6% < 0.001 < 0.001 0.864 \na p-value is from the pairwise comparison of methotrexate monotherapy and adalimumab/methotrexate \n\ncombination therapy using the Mann-Whitney U test \nb p-value is from the pairwise comparison of adalimumab monotherapy and adalimumab/methotrexate \n\ncombination therapy using the Mann-Whitney U test \nc p-value is from the pairwise comparison of adalimumab monotherapy and methotrexate monotherapy using \n\nthe Mann-Whitney U test \n\n \n\nIn the open-label extension for RA study V, ACR response rates were maintained when followed for \n\nup to 10 years. Of 542 patients who were randomised to adalimumab 40 mg every other week, 170 \n\npatients continued on adalimumab 40 mg every other week for 10 years. Among those, 154 patients \n\n(90.6%) had ACR 20 responses; 127 patients (74.7%) had ACR 50 responses; and 102 patients \n\n(60.0%) had ACR 70 responses. \n\n \n\nAt week 52, 42.9% of patients who received adalimumab/methotrexate combination therapy achieved \n\nclinical remission (DAS28 < 2.6) compared to 20.6% of patients receiving methotrexate monotherapy \n\nand 23.4% of patients receiving adalimumab monotherapy. Adalimumab/methotrexate combination \n\ntherapy was clinically and statistically superior to methotrexate (p < 0.001) and adalimumab \n\nmonotherapy (p < 0.001) in achieving a low disease state in patients with recently diagnosed moderate \n\nto severe rheumatoid arthritis. The response for the two monotherapy arms was similar (p = 0.447). \n\n \n\nRadiographic response \n\n \n\nIn RA study III, where adalimumab-treated patients had a mean duration of rheumatoid arthritis of \n\napproximately 11 years, structural joint damage was assessed radiographically and expressed as \n\nchange in modified Total Sharp Score (TSS) and its components, the erosion score and joint space \n\nnarrowing score. Adalimumab/methotrexate patients demonstrated significantly less radiographic \n\nprogression than patients receiving methotrexate alone at 6 and 12 months (see table 6). \n\n \n\nIn the open-label extension of RA study III, the reduction in rate of progression of structural damage is \n\nmaintained for 8 and 10 years in a subset of patients. At 8 years, 81 of 207 patients originally treated \n\nwith 40 mg adalimumab every other week were evaluated radiographically. Among those, 48 patients \n\nshowed no progression of structural damage defined by a change from baseline in the mTSS of 0.5 or \n\nless. At 10 years, 79 of 207 patients originally treated with 40 mg adalimumab every other week were \n\nevaluated radiographically. Among those, 40 patients showed no progression of structural damage \n\ndefined by a change from baseline in the mTSS of 0.5 or less. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n25 \n\n \n\nTable 6 Radiographic mean changes over 12 months in RA study III \n\n \n\n Placebo/ \n\nMTXa \n\nAdalimumab \n\n/MTX \n\n40 mg every other \n\nweek \n\nPlacebo/MTX- \n\nadalimumab /MTX \n\n(95% confidence \n\nintervalb) \n\np-value \n\nTotal Sharp Score 2.7 0.1 2.6 (1.4, 3.8) < 0.001c \n\nErosion score 1.6 0.0 1.6 (0.9, 2.2) < 0.001 \n\nJSNd score 1.0 0.1 0.9 (0.3, 1.4) 0.002 \na methotrexate \nb 95% confidence intervals for the differences in change scores between methotrexate and adalimumab \nc Based on rank analysis \nd Joint Space Narrowing \n\n \n\nIn RA study V, structural joint damage was assessed radiographically and expressed as change in \n\nmodified Total Sharp Score (see table 7). \n\n \n\nTable 7 Radiographic mean changes at week 52 in RA study V \n\n \n\n MTX \n\nn = 257 \n\n(95% \n\nconfidence \n\ninterval) \n\nAdalimumab \n\nn = 274 \n\n(95% \n\nconfidence \n\ninterval) \n\nAdalimumab \n\n/MTX \n\nn = 268 \n\n(95% \n\nconfidence \n\ninterval) \n\np-valuea p-valueb p-valuec \n\nTotal sharp \n\nscore \n\n5.7 (4.2-7.3) 3.0 (1.7-4.3) 1.3 (0.5-2.1) < 0.001 0.0020 < 0.001 \n\nErosion \n\nscore \n\n3.7 (2.7-4.7) 1.7 (1.0-2.4) 0.8 (0.4-1.2) < 0.001 0.0082 < 0.001 \n\nJSN score 2.0 (1.2-2.8) 1.3 (0.5-2.1) 0.5 (0-1.0) < 0.001 0.0037 0.151 \na p-value is from the pairwise comparison of methotrexate monotherapy and adalimumab/methotrexate \n\ncombination therapy using the Mann-Whitney U test \nb p-value is from the pairwise comparison of adalimumab monotherapy and adalimumab/methotrexate \n\ncombination therapy using the Mann-Whitney U test \nc p-value is from the pairwise comparison of adalimumab monotherapy and methotrexate monotherapy using \n\nthe Mann-Whitney U test \n \n\nFollowing 52 weeks and 104 weeks of treatment, the percentage of patients without progression \n\n(change from baseline in modified Total Sharp Score ≤ 0.5) was significantly higher with \n\nadalimumab/methotrexate combination therapy (63.8% and 61.2% respectively) compared to \n\nmethotrexate monotherapy (37.4% and 33.5% respectively, p < 0.001) and adalimumab monotherapy \n\n(50.7%, p < 0.002 and 44.5%, p < 0.001 respectively). \n\n \n\nIn the open-label extension of RA study V, the mean change from baseline at year 10 in the modified \n\nTotal Sharp Score was 10.8, 9.2 and 3.9 in patients originally randomised to methotrexate \n\nmonotherapy, adalimumab monotherapy and adalimumab/methotrexate combination therapy, \n\nrespectively. The corresponding proportions of patients with no radiographic progression were 31.3%, \n\n23.7% and 36.7% respectively. \n\n \n\nQuality of life and physical function \n\n \n\nHealth-related quality of life and physical function were assessed using the disability index of the \n\nHealth Assessment Questionnaire (HAQ) in the four original adequate and well-controlled trials, \n\nwhich was a pre-specified primary endpoint at week 52 in RA study III. All doses/schedules of \n\nadalimumab in all four studies showed statistically significantly greater improvement in the disability \n\nindex of the HAQ from baseline to month 6 compared to placebo and in RA study III the same was \n\nseen at week 52. Results from the Short Form Health Survey (SF 36) for all doses/schedules of \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n26 \n\nadalimumab in all four studies support these findings, with statistically significant physical component \n\nsummary (PCS) scores, as well as statistically significant pain and vitality domain scores for the \n\n40 mg every other week dose. A statistically significant decrease in fatigue as measured by functional \n\nassessment of chronic illness therapy (FACIT) scores was seen in all three studies in which it was \n\nassessed (RA studies I, III, IV). \n\n \n\nIn RA study III, most subjects who achieved improvement in physical function and continued \n\ntreatment maintained improvement through week 520 (120 months) of open-label treatment. \n\nImprovement in quality of life was measured up to week 156 (36 months) and improvement was \n\nmaintained through that time. \n\n \n\nIn RA study V, the improvement in the HAQ disability index and the physical component of the SF 36 \n\nshowed greater improvement (p < 0.001) for adalimumab/methotrexate combination therapy versus \n\nmethotrexate monotherapy and adalimumab monotherapy at week 52, which was maintained through \n\nweek 104. Among the 250 subjects who completed the open-label extension study, improvements in \n\nphysical function were maintained through 10 years of treatment. \n\n \n\nEnthesitis-related arthritis \n\n \n\nThe safety and efficacy of adalimumab were assessed in a multicentre, randomised, double-blind study \n\nin 46 paediatric patients (6 to 17 years old) with moderate enthesitis-related arthritis. Patients were \n\nrandomised to receive either 24 mg/m2 body surface area (BSA) of adalimumab up to a maximum of \n\n40 mg, or placebo every other week for 12 weeks. The double-blind period is followed by an open-\n\nlabel (OL) period during which patients received 24 mg/m2 BSA of adalimumab up to a maximum of \n\n40 mg every other week subcutaneously for up to an additional 192 weeks. The primary endpoint was \n\nthe percent change from baseline to week 12 in the number of active joints with arthritis (swelling not \n\ndue to deformity or joints with loss of motion plus pain and/or tenderness), which was achieved with \n\nmean percent decrease of -62.6% (median percent change -88.9%) in patients in the adalimumab \n\ngroup compared to -11.6% (median percent change -50.0%) in patients in the placebo group. \n\nImprovement in number of active joints with arthritis was maintained during the OL period through \n\nweek 156 for the 26 of 31 (84%) patients in the adalimumab group who remained in the study. \n\nAlthough not statistically significant, the majority of patients demonstrated clinical improvement in \n\nsecondary endpoints such as number of sites of enthesitis, tender joint count (TJC), swollen joint count \n\n(SJC), paediatric ACR 50 response, and paediatric ACR 70 response. \n\n \n\nAxial spondyloarthritis \n\n \n\nAnkylosing spondylitis (AS) \n\n \n\nAdalimumab 40 mg every other week was assessed in 393 patients in two randomised, 24 week \n\ndouble-blind, placebo-controlled studies in patients with active ankylosing spondylitis (mean baseline \n\nscore of disease activity [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)] was 6.3 in \n\nall groups) who have had an inadequate response to conventional therapy. Seventy-nine (20.1%) \n\npatients were treated concomitantly with disease-modifying anti-rheumatic drugs, and 37 (9.4%) \n\npatients with glucocorticoids. The blinded period was followed by an open-label period during which \n\npatients received adalimumab 40 mg every other week subcutaneously for up to an additional 28 \n\nweeks. Subjects (n = 215, 54.7%) who failed to achieve ASAS 20 at weeks 12, or 16 or 20 received \n\nearly escape open-label adalimumab 40 mg every other week subcutaneously and were subsequently \n\ntreated as non-responders in the double-blind statistical analyses. \n\n \n\nIn the larger AS study I with 315 patients, results showed statistically significant improvement of the \n\nsigns and symptoms of ankylosing spondylitis in patients treated with adalimumab compared to \n\nplacebo. Significant response was first observed at week 2 and maintained through 24 weeks (table 8). \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n27 \n\nTable 8 Efficacy responses in placebo-controlled AS study – study I reduction of signs and \n\nsymptoms \n\n \n\nResponse Placebo \n\nN = 107 \n\nAdalimumab \nN = 208 \n\nASASa 20 \n\nWeek 2 16% 42%*** \n\nWeek 12 21% 58%*** \n\nWeek 24 19% 51%*** \n\nASAS 50 \n\nWeek 2 3% 16%*** \n\nWeek 12 10% 38%*** \n\nWeek 24 11% 35%*** \n\nASAS 70 \n\nWeek 2 0% 7%** \n\nWeek 12 5% 23%*** \n\nWeek 24 8% 24%*** \n\nBASDAIb 50 \n\nWeek 2 4% 20%*** \n\nWeek 12 16% 45%*** \n\nWeek 24 15% 42%*** \n***, ** Statistically significant at p < 0.001, < 0.01 for all comparisons between adalimumab and placebo at \n\nweeks 2, 12 and 24 \na Assessments in Ankylosing Spondylitis \nb Bath Ankylosing Spondylitis Disease Activity Index \n\n \n\nAdalimumab-treated patients had significantly greater improvement at week 12 which was maintained \n\nthrough week 24 in both the SF36 and Ankylosing Spondylitis Quality of Life Questionnaire \n\n(ASQoL). \n\n \n\nSimilar trends (not all statistically significant) were seen in the smaller randomised, double-blind, \n\nplacebo controlled AS study II of 82 adult patients with active ankylosing spondylitis. \n\n \n\nAxial spondyloarthritis without radiographic evidence of AS \n\n \n\nAdalimumab 40 mg every other week was assessed in 185 patients in one randomised, 12 week \n\ndouble-blind, placebo-controlled study in patients with active non-radiographic axial spondyloarthritis \n\n(mean baseline score of disease activity [Bath Ankylosing Spondylitis Disease Activity Index \n\n(BASDAI)] was 6.4 for patients treated with adalimumab and 6.5 for those on placebo) who have had \n\nan inadequate response to or intolerance to ≥ 1 NSAIDs, or a contraindication for NSAIDs. \n\n \n\nThirty-three (18%) of patients were treated concomitantly with disease-modifying anti-rheumatic \n\ndrugs, and 146 (79%) patients with NSAIDs at baseline. The double-blind period was followed by an \n\nopen-label period during which patients receive adalimumab 40 mg every other week subcutaneously \n\nfor up to an additional 144 weeks. Week 12 results showed statistically significant improvement of the \n\nsigns and symptoms of active non-radiographic axial spondyloarthritis in patients treated with \n\nadalimumab compared to placebo (table 9). \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n28 \n\nTable 9 Efficacy response in placebo-controlled axial SpA study \n\n \n\nDouble-Blind Response at week \n\n12 \n\nPlacebo \n\nN = 94 \n\nAdalimumab \n\nN = 91 \n\nASASa 40 15% 36%*** \n\nASAS 20 31% 52%** \n\nASAS 5/6 6% 31%*** \n\nASAS partial remission 5% 16%* \n\nBASDAIb 50 15% 35%** \n\nASDASc,d,e -0.3 -1.0*** \n\nASDAS Inactive Disease 4% 24%*** \n\nhs-CRPd,f,g -0.3 -4.7*** \n\nSPARCCh MRI Sacroiliac Jointsd,i -0.6 -3.2** \n\nSPARCC MRI Spined,j -0.2 -1.8** \na Assessment of Spondyloarthritis International Society \nb Bath Ankylosing Spondylitis Disease Activity Index \nc Ankylosing Spondylitis Disease Activity Score \nd mean change from baseline \ne n = 91 placebo and n = 87 adalimumab \nf high sensitivity C-Reactive Protein (mg/L) \ng n = 73 placebo and n = 70 adalimumab \nh Spondyloarthritis Research Consortium of Canada \ni n = 84 placebo and adalimumab \nj n = 82 placebo and n = 85 adalimumab \n\n***, **, * Statistically significant at p < 0.001, < 0.01, and < 0.05, respectively, for all comparisons between \n\nadalimumab and placebo \n\n \n\nIn the open-label extension, improvement in the signs and symptoms was maintained with \n\nadalimumab therapy through week 156. \n\n \n\nInhibition of inflammation \n\n \n\nSignificant improvement of signs of inflammation as measured by hs-CRP and MRI of both Sacroiliac \n\nJoints and the Spine was maintained in adalimumab-treated patients through week 156 and week 104, \n\nrespectively. \n\n \n\nQuality of life and physical function \n\n \n\nHealth-related quality of life and physical function were assessed using the HAQ-S and the SF-36 \n\nquestionnaires. Adalimumab showed statistically significantly greater improvement in the HAQ-S \n\ntotal score and the SF-36 Physical Component Score (PCS) from baseline to week 12 compared to \n\nplacebo. Improvement in health-related quality of life and physical function was maintained during the \n\nopen-label extension through week 156. \n\n \n\nPsoriatic arthritis \n\n \n\nAdalimumab, 40 mg every other week, was studied in patients with moderately to severely active \n\npsoriatic arthritis in two placebo-controlled studies, PsA studies I and II. PsA study I with 24 week \n\nduration, treated 313 adult patients who had an inadequate response to non-steroidal anti-inflammatory \n\ndrug therapy and of these, approximately 50% were taking methotrexate. PsA study II with 12-week \n\nduration, treated 100 patients who had an inadequate response to DMARD therapy. Upon completion \n\nof both studies, 383 patients enrolled in an open-label extension study, in which 40 mg adalimumab \n\nwas administered every other week (eow). \n\n \n\nThere is insufficient evidence of the efficacy of adalimumab in patients with ankylosing spondylitis-\n\nlike psoriatic arthropathy due to the small number of patients studied. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n29 \n\nTable 10 ACR response in placebo-controlled psoriatic arthritis studies (percent of patients) \n\n \n\n PsA study I PsA Study II \n \n\nPsA study II \n\nResponse Placebo \n\nN = 162 \n\nAdalimumab \n\nN = 151 \n\nPlacebo \n\nN = 49 \n\nAdalimumab \n\nN = 51 \n\nACR 20 \n\nWeek 12 14% 58%*** 16% 39%* \n\nWeek 24 15% 57%*** N/A N/A \n\nACR 50 \n\nWeek 12 4% 36%*** 2% 25%*** \n\nWeek 24 6% 39%*** N/A N/A \n\nACR 70 \n\nWeek 12 1% 20%*** 0% 14%* \n\nWeek 24 1% 23%*** N/A N/A \n*** p < 0.001 for all comparisons between adalimumab and placebo \n\n* p < 0.05 for all comparisons between adalimumab and placebo \n\nN/A not applicable \n\n \n\nACR responses in PsA study I were similar with and without concomitant methotrexate therapy. ACR \n\nresponses were maintained in the open-label extension study for up to 136 weeks. \n\n \n\nRadiographic changes were assessed in the psoriatic arthritis studies. Radiographs of hands, wrists, \n\nand feet were obtained at baseline and week 24 during the double-blind period when patients were on \n\nadalimumab or placebo and at week 48 when all patients were on open-label adalimumab. A modified \n\nTotal Sharp Score (mTSS), which included distal interphalangeal joints (i.e. not identical to the TSS \n\nused for rheumatoid arthritis), was used. \n\n \n\nAdalimumab treatment reduced the rate of progression of peripheral joint damage compared with \n\nplacebo treatment as measured by change from baseline in mTSS (mean ± SD) 0.8 ± 2.5 in the placebo \n\ngroup (at week 24) compared with 0.0 ± 1.9; (p < 0.001) in the adalimumab group (at week 48). \n\n \n\nIn subjects treated with adalimumab with no radiographic progression from baseline to week 48 \n\n(n = 102), 84% continued to show no radiographic progression through 144 weeks of treatment. \n\nAdalimumab-treated patients demonstrated statistically significant improvement in physical function \n\nas assessed by HAQ and Short Form Health Survey (SF 36) compared to placebo at week 24. \n\nImproved physical function continued during the open-label extension up to week 136. \n\n \n\nPsoriasis \n\n \n\nThe safety and efficacy of adalimumab were studied in adult patients with chronic plaque psoriasis \n\n(≥ 10% BSA involvement and Psoriasis Area and Severity Index (PASI) ≥ 12 or ≥ 10) who were \n\ncandidates for systemic therapy or phototherapy in randomised, double-blind studies. 73% of patients \n\nenrolled in psoriasis studies I and II had received prior systemic therapy or phototherapy. The safety \n\nand efficacy of adalimumab were also studied in adult patients with moderate to severe chronic plaque \n\npsoriasis with concomitant hand and/or foot psoriasis who were candidates for systemic therapy in a \n\nrandomised double-blind study (psoriasis study III). \n\n \n\nPsoriasis study I (REVEAL) evaluated 1,212 patients within three treatment periods. In period A, \n\npatients received placebo or adalimumab at an initial dose of 80 mg followed by 40 mg every other \n\nweek starting one week after the initial dose. After 16 weeks of therapy, patients who achieved at least \n\na PASI 75 response (PASI score improvement of at least 75% relative to baseline), entered period B \n\nand received open-label 40 mg adalimumab every other week. Patients who maintained ≥ PASI 75 \n\nresponse at week 33 and were originally randomised to active therapy in period A, were re-randomised \n\nin period C to receive 40 mg adalimumab every other week or placebo for an additional 19 weeks. \n\nAcross all treatment groups, the mean baseline PASI score was 18.9 and the baseline Physician’s \n\nGlobal Assessment (PGA) score ranged from “moderate” (53% of subjects included) to “severe” \n\n(41%) to “very severe” (6%). \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n30 \n\n \n\nPsoriasis study II (CHAMPION) compared the efficacy and safety of adalimumab versus methotrexate \n\nand placebo in 271 patients. Patients received placebo, an initial dose of MTX 7.5 mg and thereafter \n\ndose increases up to week 12, with a maximum dose of 25 mg or an initial dose of 80 mg adalimumab \n\nfollowed by 40 mg every other week (starting one week after the initial dose) for 16 weeks. There are \n\nno data available comparing adalimumab and MTX beyond 16 weeks of therapy. Patients receiving \n\nMTX who achieved a ≥ PASI 50 response at week 8 and/or 12 did not receive further dose increases. \n\nAcross all treatment groups, the mean baseline PASI score was 19.7 and the baseline PGA score \n\nranged from “mild” (< 1%) to “moderate” (48%) to “severe” (46%) to “very severe” (6%). \n\n \n\nPatients participating in all phase 2 and phase 3 psoriasis studies were eligible to enrol into an open-\n\nlabel extension trial, where adalimumab was given for at least an additional 108 weeks. \n\n \n\nIn psoriasis studies I and II, a primary endpoint was the proportion of patients who achieved a PASI \n\n75 response from baseline at week 16 (see tables 11 and 12). \n\n \n\nTable 11 Ps study I (REVEAL) - efficacy results at 16 weeks \n\n \n\n Placebo \n\nN = 398 \n\nn (%) \n\nAdalimumab 40 mg eow \n\nN = 814 \n\nn (%) \n\n≥ PASI 75a 26 (6.5) 578 (70.9)b \n\nPASI 100 3 (0.8) 163 (20.0)b \n\nPGA: Clear/minimal 17 (4.3) 506 (62.2)b \na Percent of patients achieving PASI75 response was calculated as centre-adjusted rate \nb p < 0.001, adalimumab versus placebo \n\n \n\nTable 12 Ps study II (CHAMPION) efficacy results at 16 weeks \n\n \n\n Placebo \n\nN = 53 \n\nn (%) \n\nMTX \n\nN = 110 \n\nn (%) \n\nAdalimumab 40 mg eow \n\nN = 108 \n\nn (%) \n\n≥ PASI 75 10 (18.9) 39 (35.5) 86 (79.6) a, b \n\nPASI 100 1 (1.9) 8 (7.3) 18 (16.7) c, d \n\nPGA: Clear/minimal 6 (11.3) 33 (30.0) 79 (73.1) a, b \na p < 0.001 adalimumab versus placebo \nb p < 0.001 adalimumab versus methotrexate \nc p < 0.01 adalimumab versus placebo \nd p < 0.05 adalimumab versus methotrexate \n\n \n\nIn psoriasis study I, 28% of patients who were PASI 75 responders and were re-randomised to placebo \n\nat week 33 compared to 5% continuing on adalimumab, p < 0.001, experienced “loss of adequate \n\nresponse” (PASI score after week 33 and on or before week 52 that resulted in a < PASI 50 response \n\nrelative to baseline with a minimum of a 6-point increase in PASI score relative to week 33). Of the \n\npatients who lost adequate response after re-randomisation to placebo who then enrolled into the open-\n\nlabel extension trial, 38% (25/66) and 55% (36/66) regained PASI 75 response after 12 and 24 weeks \n\nof retreatment, respectively. \n\n \n\nA total of 233 PASI 75 responders at week 16 and week 33 received continuous adalimumab therapy \n\nfor 52 weeks in psoriasis study I, and continued adalimumab in the open-label extension trial. PASI 75 \n\nand PGA of clear or minimal response rates in these patients were 74.7% and 59.0%, respectively, \n\nafter an additional 108 weeks of open-label therapy (total of 160 weeks). In an analysis in which all \n\npatients who dropped out of the study for adverse events or lack of efficacy, or who dose-escalated, \n\nwere considered non-responders, PASI 75 and PGA of clear or minimal response rates in these \n\npatients were 69.6% and 55.7%, respectively, after an additional 108 weeks of open-label therapy \n\n(total of 160 weeks). \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n31 \n\nA total of 347 stable responders participated in a withdrawal and retreatment evaluation in an open-\n\nlabel extension study. During the withdrawal period, symptoms of psoriasis returned over time with a \n\nmedian time to relapse (decline to PGA “moderate” or worse) of approximately 5 months. None of \n\nthese patients experienced rebound during the withdrawal period. A total of 76.5% (218/285) of \n\npatients who entered the retreatment period had a response of PGA “clear” or “minimal” after 16 \n\nweeks of retreatment, irrespective of whether they relapsed during withdrawal (69.1%[123/178] and \n\n88.8% [95/107] for patients who relapsed and who did not relapse during the withdrawal period, \n\nrespectively). A similar safety profile was observed during retreatment as before withdrawal. \n\n \n\nSignificant improvements at week 16 from baseline compared to placebo (studies I and II) and MTX \n\n(study II) were demonstrated in the DLQI (Dermatology Life Quality Index). In study I, improvements \n\nin the physical and mental component summary scores of the SF-36 were also significant compared to \n\nplacebo. \n\n \n\nIn an open-label extension study, for patients who dose escalated from 40 mg every other week to \n\n40 mg weekly due to a PASI response below 50%, 26.4% (92/349) and 37.8% (132/349) of patients \n\nachieved PASI 75 response at week 12 and 24, respectively. \n\n \n\nPsoriasis study III (REACH) compared the efficacy and safety of adalimumab versus placebo in 72 \n\npatients with moderate to severe chronic plaque psoriasis and hand and/or foot psoriasis. Patients \n\nreceived an initial dose of 80 mg adalimumab followed by 40 mg every other week (starting one week \n\nafter the initial dose) or placebo for 16 weeks. At week 16, a statistically significantly greater \n\nproportion of patients who received adalimumab achieved PGA of 'clear' or 'almost clear' for the hands \n\nand/or feet compared to patients who received placebo (30.6% versus 4.3%, respectively [P = 0.014]). \n\n \n\nPsoriasis study IV compared efficacy and safety of adalimumab versus placebo in 217 adult patients \n\nwith moderate to severe nail psoriasis. Patients received an initial dose of 80 mg adalimumab followed \n\nby 40 mg every other week (starting one week after the initial dose) or placebo for 26 weeks followed \n\nby open-label adalimumab treatment for an additional 26 weeks. Nail psoriasis assessments included \n\nthe Modified Nail Psoriasis Severity Index (mNAPSI), the Physician’s Global Assessment of \n\nFingernail Psoriasis (PGA-F) and the Nail Psoriasis Severity Index (NAPSI) (see table 13). \n\nAdalimumab demonstrated a treatment benefit in nail psoriasis patients with different extents of skin \n\ninvolvement (BSA ≥ 10% (60% of patients) and BSA < 10% and ≥ 5% (40% of patients)). \n \n\nTable 13 Ps study IV efficacy results at 16, 26 and 52 weeks \n\n \n\nEndpoint Week 16 \n\nPlacebo-controlled \n\nWeek 26 \n\nPlacebo-controlled \n\nWeek 52 \n\nOpen-label \n\nPlacebo \n\nN = 108 \n\nAdalimumab\n\n40 mg eow \n\nN = 109 \n\nPlacebo \n\nN = 108 \n\nAdalimumab \n\n40 mg eow \n\nN = 109 \n\nAdalimumab \n\n40 mg eow \n\nN = 80 \n\n≥ mNAPSI 75 (%) 2.9 26.0a 3.4 46.6a 65.0 \n\nPGA-F clear/minimal and \n\n≥ 2-grade improvement \n\n(%) \n\n2.9 29.7a 6.9 48.9a 61.3 \n\nPercent change in total \n\nfingernail NAPSI (%) \n\n-7.8 -44.2 a -11.5 -56.2a -72.2 \n\na p < 0.001, Adalimumab versus placebo \n\n \n\nAdalimumab treated patients showed statistically significant improvements at week 26 compared with \n\nplacebo in the DLQI. \n\n \n\n \n\nPaediatric plaque psoriasis \n\n \n\nThe efficacy of adalimumab was assessed in a randomised, double-blind, controlled study of \n\n114 paediatric patients from 4 years of age with severe chronic plaque psoriasis (as defined by a PGA \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n32 \n\n≥ 4 or > 20% BSA involvement or > 10% BSA involvement with very thick lesions or PASI ≥ 20 or \n\n≥ 10 with clinically relevant facial, genital, or hand/foot involvement) who were inadequately \n\ncontrolled with topical therapy and heliotherapy or phototherapy. \n\n \n\nPatients received adalimumab 0.8 mg/kg every other week (up to 40 mg), 0.4 mg/kg every other week \n\n(up to 20 mg), or methotrexate 0.1–0.4 mg/kg weekly (up to 25 mg). At week 16, more patients \n\nrandomised to adalimumab 0.8 mg/kg had positive efficacy responses (e.g. PASI 75) than those \n\nrandomised to 0.4 mg/kg every other week or MTX. \n\n \n\nTable 14 Paediatric plaque psoriasis efficacy results at 16 weeks \n\n \n\n MTXa \n\nN = 37 \n\nAdalimumab 0.8 mg/kg eow \n\nN = 38 \n\nPASI 75b 12 (32.4%) 22 (57.9%) \n\nPGA: Clear/minimalc 15 (40.5%) 23 (60.5%) \na MTX = methotrexate \nb P = 0.027, adalimumab 0.8 mg/kg versus MTX \nc P = 0.083, adalimumab 0.8 mg/kg versus MTX \n\n \n\nPatients who achieved PASI 75 and PGA clear or minimal were withdrawn from treatment for up to \n\n36 weeks and monitored for loss of disease control (i.e. a worsening of PGA by at least 2 grades). \n\nPatients were then retreated with adalimumab 0.8 mg/kg every other week for an additional 16 weeks \n\nand response rates observed during retreatment were similar to the previous double-blind period: PASI \n\n75 response of 78.9% (15 of 19 subjects) and PGA clear or minimal of 52.6% (10 of 19 subjects). \n\n \n\nIn the open-label period of the study, PASI 75 and PGA clear or minimal responses were maintained \n\nfor up to an additional 52 weeks with no new safety findings. \n\n \n\nHidradenitis suppurativa \n\n \n\nThe safety and efficacy of adalimumab were assessed in randomised, double-blind, placebo-controlled \n\nstudies and an open-label extension study in adult patients with moderate to severe hidradenitis \n\nsuppurativa (HS) who were intolerant, had a contraindication or an inadequate response to at least a 3-\n\nmonth trial of systemic antibiotic therapy. The patients in HS-I and HS-II had Hurley Stage II or III \n\ndisease with at least 3 abscesses or inflammatory nodules. \n\n \n\nStudy HS-I (PIONEER I) evaluated 307 patients with 2 treatment periods. In Period A, patients \n\nreceived placebo or adalimumab at an initial dose of 160 mg at week 0, 80 mg at week 2, and 40 mg \n\nevery week starting at week 4 to week 11. Concomitant antibiotic use was not allowed during the \n\nstudy. After 12 weeks of therapy, patients who had received adalimumab in Period A were re-\n\nrandomised in Period B to 1 of 3 treatment groups (adalimumab 40 mg every week, adalimumab \n\n40 mg every other week, or placebo from week 12 to week 35). Patients who had been randomised to \n\nplacebo in Period A were assigned to receive adalimumab 40 mg every week in Period B. \n\n \n\nStudy HS-II (PIONEER II) evaluated 326 patients with 2 treatment periods. In Period A, patients \n\nreceived placebo or adalimumab at an initial dose of 160 mg at week 0 and 80 mg at week 2 and \n\n40 mg every week starting at week 4 to week 11. 19.3% of patients had continued baseline oral \n\nantibiotic therapy during the study. After 12 weeks of therapy, patients who had received adalimumab \n\nin Period A were re-randomised in Period B to 1 of 3 treatment groups (adalimumab 40 mg every \n\nweek, adalimumab 40 mg every other week, or placebo from week 12 to week 35). Patients who had \n\nbeen randomised to placebo in Period A were assigned to receive placebo in Period B. \n\n \n\nPatients participating in Studies HS-I and HS-II were eligible to enrol into an open-label extension \n\nstudy in which adalimumab 40 mg was administered every week. Mean exposure in all adalimumab \n\npopulation was 762 days. Throughout all 3 studies patients used topical antiseptic wash daily. \n\n \n\nClinical response \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n33 \n\n \n\nReduction of inflammatory lesions and prevention of worsening of abscesses and draining fistulas was \n\nassessed using Hidradenitis Suppurativa clinical response (HiSCR; at least a 50% reduction in total \n\nabscess and inflammatory nodule count with no increase in abscess count and no increase in draining \n\nfistula count relative to Baseline). Reduction in HS-related skin pain was assessed using a Numeric \n\nRating Scale in patients who entered the study with an initial baseline score of 3 or greater on a 11 \n\npoint scale. \n\n \n\nAt week 12, a significantly higher proportion of patients treated with adalimumab versus placebo \n\nachieved HiSCR. At week 12, a significantly higher proportion of patients in study HS-II experienced \n\na clinically relevant decrease in HS-related skin pain (see table 15). Patients treated with adalimumab \n\nhad significantly reduced risk of disease flare during the initial 12 weeks of treatment. \n\n \n\nTable 15 Efficacy results at 12 weeks, HS studies I and II \n\n \nHS study I HS study II \n\nPlacebo Adalimumab 40 mg \n\nweekly \n\nPlacebo Adalimumab 40 mg \n\nweekly \n\nHidradenitis \n\nSuppurativa Clinical \n\nResponse (HiSCR)a \n\nN = 154 \n\n40 (26.0%) \n\nN = 153 \n\n64 (41.8%) * \n\nN = 163 \n\n45 (27.6%) \n\nN = 163 \n\n96 (58.9%)*** \n\n≥30% Reduction in \n\nSkin Painb \n\nN = 109 \n\n27 (24.8%) \n\nN = 122 \n\n34 (27.9%) \n\nN = 111 \n\n23 (20.7%) \n\nN = 105 \n\n48 (45.7%)*** \n\n*P < 0.05, ***P < 0.001, adalimumab versus placebo \na Among all randomised patients \nb Among patients with baseline HS-related skin pain assessment ≥ 3, based on Numeric Rating Scale 0 – 10; 0 = \n\nno skin pain, 10 = skin pain as bad as you can imagine \n\n \n\nTreatment with adalimumab 40 mg every week significantly reduced the risk of worsening of \n\nabscesses and draining fistulas. Approximately twice the proportion of patients in the placebo group in \n\nthe first 12 weeks of Studies HS-I and HS-II, compared with those in the adalimumab group \n\nexperienced worsening of abscesses (23.0% versus 11.4%, respectively) and draining fistulas (30.0% \n\nversus 13.9%, respectively). \n\n \n\nGreater improvements at week 12 from baseline compared to placebo were demonstrated in skin-\n\nspecific health-related quality of life, as measured by the Dermatology Life Quality Index (DLQI; \n\nStudies HS-I and HS-II), patient global satisfaction with medication treatment as measured by the \n\nTreatment Satisfaction Questionnaire-medication (TSQM; Studies HS-I and HS-II), and physical \n\nhealth as measured by the physical component summary score of the SF-36 (study HS-I). \n\n \n\nIn patients with at least a partial response to adalimumab 40 mg weekly at week 12, the HiSCR rate at \n\nweek 36 was higher in patients who continued weekly adalimumab than in patients in whom dosing \n\nfrequency was reduced to every other week, or in whom treatment was withdrawn (see table 16). \n\n \n\nTable 16 Proportion of patientsa achieving HiSCRb at weeks 24 and 36 after treatment \n\nreassignment from weekly adalimumab at week 12 \n\n \nPlacebo (treatment \n\nwithdrawal) \n\nN = 73 \n\nAdalimumab 40 mg \n\nevery other week \n\nN = 70 \n\nAdalimumab 40 mg \n\nweekly \n\nN = 70 \n\nWeek 24 24 (32.9%) 36 (51.4%) 40 (57.1%) \n\nWeek 36 22 (30.1%) 28 (40.0%) 39 (55.7%) \n\na Patients with at least a partial response to adalimumab 40 mg weekly after 12 weeks of treatment \nb Patients meeting protocol-specified criteria for loss of response or no improvement were required to \n\ndiscontinue from the studies and were counted as non-responders \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n34 \n\n \n\nAmong patients who were at least partial responders at week 12, and who received continuous weekly \n\nadalimumab therapy, the HiSCR rate at week 48 was 68.3% and at week 96 was 65.1%. Longer term \n\ntreatment with adalimumab 40 mg weekly for 96 weeks identified no new safety findings. \n\n \n\nAmong patients whose adalimumab treatment was withdrawn at week 12 in Studies HS-I and HS-II, \n\nthe HiSCR rate 12 weeks after re-introduction of adalimumab 40 mg weekly returned to levels similar \n\nto that observed before withdrawal (56.0%). \n\n \n\nCrohn’s disease \n\n \n\nThe safety and efficacy of adalimumab were assessed in over 1,500 patients with moderately to \n\nseverely active Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥ 220 and ≤ 450) in \n\nrandomised, double-blind, placebo-controlled studies. Concomitant stable doses of aminosalicylates, \n\ncorticosteroids, and/or immunomodulatory agents were permitted and 80% of patients continued to \n\nreceive at least one of these medications. \n\n \n\nInduction of clinical remission (defined as CDAI < 150) was evaluated in two studies, CD study I \n\n(CLASSIC I) and CD study II (GAIN). In CD study I, 299 TNF-antagonist naïve patients were \n\nrandomised to one of four treatment groups; placebo at weeks 0 and 2, 160 mg adalimumab at week 0 \n\nand 80 mg at week 2, 80 mg at week 0 and 40 mg at week 2, and 40 mg at week 0 and 20 mg at week \n\n2. In CD study II, 325 patients who had lost response or were intolerant to infliximab were randomised \n\nto receive either 160 mg adalimumab at week 0 and 80 mg at week 2 or placebo at weeks 0 and 2. The \n\nprimary non-responders were excluded from the studies and therefore these patients were not further \n\nevaluated. \n\n \n\nMaintenance of clinical remission was evaluated in CD study III (CHARM). In CD study III, 854 \n\npatients received open-label 80 mg at week 0 and 40 mg at week 2. At week 4 patients were \n\nrandomised to 40 mg every other week, 40 mg every week, or placebo with a total study duration of \n\n56 weeks. Patients in clinical response (decrease in CDAI ≥ 70) at week 4 were stratified and analysed \n\nseparately from those not in clinical response at week 4. Corticosteroid taper was permitted after week \n\n8. \n\n \n\nCD study I and CD study II induction of remission and response rates are presented in table 17 \n\n \n\nTable 17 Induction of clinical remission and response (percent of patients) \n\n \n\n CD study I: infliximab naïve patients CD study II: infliximab \n\nexperienced patients \n\n Placebo \n\nN = 74 \n\nAdalimumab \n\n80/40 mg \n\nN = 75 \n\nAdalimumab \n\n160/80 mg \n\nN = 76 \n\nPlacebo \n\nN = 166 \n\nAdalimumab \n\n160/80 mg \n\nN = 159 \n\nWeek 4 \n\nClinical remission 12% 24% 36%* 7% 21%* \n\nClinical response \n\n(CR-100) \n\n24% 37% 49%** 25% 38%** \n\nAll p-values are pairwise comparisons of proportions for adalimumab versus placebo \n\n* p < 0.001 \n\n** p < 0.01 \n\n \n\nSimilar remission rates were observed for the 160/80 mg and 80/40 mg induction regimens by week 8 \n\nand adverse events were more frequently noted in the 160/80 mg group. \n\n \n\nIn CD study III, at week 4, 58% (499/854) of patients were in clinical response and were assessed in \n\nthe primary analysis. Of those in clinical response at week 4, 48% had been previously exposed to \n\nother TNF-antagonists. Maintenance of remission and response rates are presented in table 18. Clinical \n\nremission results remained relatively constant irrespective of previous TNF-antagonist exposure. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n35 \n\n \n\nDisease-related hospitalisations and surgeries were statistically significantly reduced with adalimumab \n\ncompared with placebo at week 56. \n\n \n\nTable 18 Maintenance of clinical remission and response (percent of patients) \n\n \n\n Placebo 40 mg adalimumab \n\nevery other week \n\n40 mg \n\nadalimumab every \n\nweek \n\nWeek 26 N = 170 N = 172 N = 157 \n\nClinical remission 17% 40%* 47%* \n\nClinical response (CR-100) 27% 52%* 52%* \n\nPatients in steroid-free \n\nremission for > = 90 \n\ndaysa \n\n3% (2/66) 19% (11/58)** 15% (11/74)** \n\nWeek 56 N = 170 N = 172 N = 157 \n\nClinical remission 12% 36%* 41%* \n\nClinical response (CR-100) 17% 41%* 48%* \n\nPatients in steroid-free \n\nremission for > = 90 \n\ndaysa \n\n5% (3/66) 29% (17/58)* 20% (15/74)** \n\n* p < 0.001 for adalimumab versus placebo pairwise comparisons of proportions \n\n** p < 0.02 for adalimumab versus placebo pairwise comparisons of proportions \na Of those receiving corticosteroids at baseline \n\n \n\nAmong patients who were not in response at week 4, 43% of adalimumab maintenance patients \n\nresponded by week 12 compared to 30% of placebo maintenance patients. These results suggest that \n\nsome patients who have not responded by week 4 benefit from continued maintenance therapy through \n\nweek 12. Therapy continued beyond 12 weeks did not result in significantly more responses (see \n\nsection 4.2). \n\n \n\n117/276 patients from CD study I and 272/777 patients from CD studies II and III were followed \n\nthrough at least 3 years of open-label adalimumab therapy. 88 and 189 patients, respectively, \n\ncontinued to be in clinical remission. Clinical response (CR-100) was maintained in 102 and \n\n233 patients, respectively. \n\n \n\nQuality of life \n\n \n\nIn CD study I and CD study II, statistically significant improvement in the disease-specific \n\ninflammatory bowel disease questionnaire (IBDQ) total score was achieved at week 4 in patients \n\nrandomised to adalimumab 80/40 mg and 160/80 mg compared to placebo and was seen at weeks 26 \n\nand 56 in CD study III as well among the adalimumab treatment groups compared to the placebo \n\ngroup. \n\n \n\nPaediatric Crohn’s disease \n\n \n\nAdalimumab was assessed in a multicentre, randomised, double-blind clinical trial designed to \n\nevaluate the efficacy and safety of induction and maintenance treatment with doses dependent on body \n\nweight (< 40 kg or ≥ 40 kg) in 192 paediatric subjects between the ages of 6 and 17 (inclusive) years, \n\nwith moderate to severe Crohn´s disease (CD) defined as Paediatric Crohn's Disease Activity Index \n\n(PCDAI) score > 30. Subjects had to have failed conventional therapy (including a corticosteroid \n\nand/or an immunomodulator) for CD. Subjects may also have previously lost response or been \n\nintolerant to infliximab. \n\n \n\nAll subjects received open-label induction therapy at a dose based on their baseline body weight: \n\n160 mg at week 0 and 80 mg at week 2 for subjects ≥ 40 kg, and 80 mg and 40 mg, respectively, for \n\nsubjects < 40 kg. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n36 \n\n \n\nAt week 4, subjects were randomised 1:1 based on their body weight at the time to either the low dose \n\nor standard dose maintenance regimens as shown in table 19. \n\n \n\nTable 19 Maintenance regimen \n\n \n\nPatient weight Low dose Standard dose \n\n< 40 kg 10 mg eow 20 mg eow \n\n≥ 40 kg 20 mg eow 40 mg eow \n\n \n\nEfficacy results \n\n \n\nThe primary endpoint of the study was clinical remission at week 26, defined as PCDAI score ≤ 10. \n\n \n\nClinical remission and clinical response (defined as reduction in PCDAI score of at least 15 points \n\nfrom baseline) rates are presented in table 20. Rates of discontinuation of corticosteroids or \n\nimmunomodulators are presented in table 21. \n\n \n\nTable 20 Paediatric CD study PCDAI clinical remission and response \n\n \n\n Standard dose \n\n40/20 mg eow N = 93 \n\nLow dose \n\n20/10 mg eow \n\nN = 95 \n\nP value* \n\nWeek 26 \n\nClinical remission 38.7% 28.4% 0.075 \n\nClinical response 59.1% 48.4% 0.073 \n\nWeek 52 \n\nClinical remission 33.3% 23.2% 0.100 \n\nClinical response 41.9% 28.4% 0.038 \n\n* p value for standard dose versus low dose comparison \n\n \n\nTable 21 Paediatric CD study discontinuation of corticosteroids or immunomodulators and \n\nfistula remission \n\n \n\n Standard dose \n\n40/20 mg eow \n\nLow dose \n\n20/10 mg eow \n\nP value1 \n\nDiscontinued corticosteroids N = 33 N = 38 \n\nWeek 26 84.8% 65.8% 0.066 \n\nWeek 52 69.7% 60.5% 0.420 \n\nDiscontinuation of \n\nImmunomodulators2 \n\nN = 60 N = 57 \n\nWeek 52 30.0% 29.8% 0.983 \n\nFistula remission3 N = 15 N = 21 \n\nWeek 26 46.7% 38.1% 0.608 \n\nWeek 52 40.0% 23.8% 0.303 \n1 p value for standard dose versus low dose comparison \n2 Immunosuppressant therapy could only be discontinued at or after week 26 at the investigator's discretion if the \n\nsubject met the clinical response criterion \n3 defined as a closure of all fistulas that were draining at baseline for at least 2 consecutive post-baseline visits \n\n \n\nStatistically significant increases (improvement) from baseline to week 26 and 52 in body mass index \n\nand height velocity were observed for both treatment groups. \n\n \n\nStatistically and clinically significant improvements from baseline were also observed in both \n\ntreatment groups for quality of life parameters (including IMPACT III). \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n37 \n\nOne hundred patients (n = 100) from the Paediatric CD Study continued in an open-label long-term \n\nextension study. After 5 years of adalimumab therapy, 74.0% (37/50) of the 50 patients remaining in \n\nthe study continued to be in clinical remission, and 92.0% (46/50) of patients continued to be in \n\nclinical response per PCDAI. \n\n \n\nUlcerative colitis \n\n \n\nThe safety and efficacy of multiple doses of adalimumab were assessed in adult patients with \n\nmoderately to severely active ulcerative colitis (Mayo score 6 to 12 with endoscopy subscore of 2 to 3) \n\nin randomised, double-blind, placebo-controlled studies. \n\n \n\nIn study UC-I, 390 TNF-antagonist naïve patients were randomised to receive either placebo at weeks \n\n0 and 2, 160 mg adalimumab at week 0 followed by 80 mg at week 2, or 80 mg adalimumab at week 0 \n\nfollowed by 40 mg at week 2. After week 2, patients in both adalimumab arms received 40 mg every \n\nother week. Clinical remission (defined as Mayo score ≤ 2 with no subscore > 1) was assessed at week \n\n8. \n\n \n\nIn study UC-II, 248 patients received 160 mg of adalimumab at week 0, 80 mg at week 2 and 40 mg \n\nevery other week thereafter, and 246 patients received placebo. Clinical results were assessed for \n\ninduction of remission at week 8 and for maintenance of remission at week 52. \n\n \n\nPatients induced with 160/80 mg adalimumab achieved clinical remission versus placebo at week 8 in \n\nstatistically significantly greater percentages in study UC-I (18% versus 9% respectively, p = 0.031) \n\nand study UC-II (17% versus 9% respectively, p = 0.019). In study UC-II, among those treated with \n\nadalimumab who were in remission at week 8, 21/41 (51%) were in remission at week 52. \n\n \n\nResults from the overall UC-II study population are shown in table 22. \n\n \n\nTable 22 Response, remission and mucosal healing in study UC-II (percent of patients) \n\n \n\n Placebo Adalimumab 40 mg \n\neow \n \n\nWeek 52 \n \n\nN = 246 N=248 \n \n\nN = 248 \n\nClinical response 18% 30%* \n\nClinical remission 9% 17%* \n\nMucosal healing 15% 25%* \n\nSteroid-free remission for ≥ 90 daysa 6% \n\n(N = 140) \n\n13%* \n\n(N = 150) \n\nWeek 8 and 52 \n\nSustained response 12% 24%** \n\nSustained remission 4% 8%* \n\nSustained mucosal healing 11% 19%* \n\nClinical remission is Mayo score ≤ 2 with no subscore > 1; \n\nClinical response is decrease from baseline in Mayo score ≥ 3 points and ≥ 30% plus a decrease in the rectal \n\nbleeding subscore [RBS] ≥ 1 or an absolute RBS of 0 or 1; \n\n* p < 0.05 for adalimumab versus placebo pairwise comparison of proportions \n\n** p < 0.001 for adalimumab versus placebo pairwise comparison of proportions \na Of those receiving corticosteroids at baseline \n\n \n\nOf those patients who had a response at week 8, 47% were in response, 29% were in remission, 41% \n\nhad mucosal healing, and 20% were in steroid-free remission for ≥ 90 days at week 52. \n\n \n\nApproximately 40% of patients in study UC-II had failed prior anti-TNF treatment with infliximab. \n\nThe efficacy of adalimumab in those patients was reduced compared to that in anti-TNF naïve \n\npatients. Among patients who had failed prior anti-TNF treatment, week 52 remission was achieved by \n\n3% on placebo and 10% on adalimumab. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n38 \n\nPatients from studies UC-I and UC-II had the option to roll over into an open-label long-term \n\nextension study (UC III). Following 3 years of adalimumab therapy, 75% (301/402) continued to be in \n\nclinical remission per partial Mayo score. \n\n \n\nHospitalisation rates \n\n \n\nDuring 52 weeks of studies UC-I and UC-II, lower rates of all-cause hospitalisations and UC-related \n\nhospitalisations were observed for the adalimumab-treated arm compared to the placebo arm. The \n\nnumber of all cause hospitalisations in the adalimumab treatment group was 0.18 per patient year \n\nversus 0.26 per patient year in the placebo group and the corresponding figures for UC-related \n\nhospitalisations were 0.12 per patient year versus 0.22 per patient year. \n\n \n\nQuality of life \n\n \n\nIn study UC-II, treatment with adalimumab resulted in improvements in the Inflammatory Bowel \n\nDisease Questionnaire (IBDQ) score. \n\n \n\nUveitis \n\n \n\nThe safety and efficacy of adalimumab were assessed in adult patients with non-infectious \n\nintermediate, posterior, and panuveitis, excluding patients with isolated anterior uveitis, in two \n\nrandomised, doublemasked, placebo-controlled studies (UV I and II). Patients received placebo or \n\nadalimumab at an initial dose of 80 mg followed by 40 mg every other week starting one week after \n\nthe initial dose. Concomitant stable doses of one non-biologic immunosuppressant were permitted. \n\n \n\nStudy UV I evaluated 217 patients with active uveitis despite treatment with corticosteroids (oral \n\nprednisone at a dose of 10 to 60 mg/day). All patients received a 2 week standardised dose of \n\nprednisone 60 mg/day at study entry followed by a mandatory taper schedule, with complete \n\ncorticosteroid discontinuation by week 15. \n\n \n\nStudy UV II evaluated 226 patients with inactive uveitis requiring chronic corticosteroid treatment \n\n(oral prednisone 10 to 35 mg/day) at baseline to control their disease. Patients subsequently underwent \n\na mandatory taper schedule, with complete corticosteroid discontinuation by week 19. \n\n \n\nThe primary efficacy endpoint in both studies was ‘time to treatment failure’. Treatment failure was \n\ndefined by a multi-component outcome based on inflammatory chorioretinal and/or inflammatory \n\nretinal vascular lesions, anterior chamber (AC) cell grade, vitreous haze (VH) grade and best corrected \n\nvisual acuity (BCVA). \n\n \n\nClinical response \n\n \n\nResults from both studies demonstrated statistically significant reduction of the risk of treatment \n\nfailure in patients treated with adalimumab versus patients receiving placebo (See table 23). Both \n\nstudies demonstrated an early and sustained effect of adalimumab on the treatment failure rate versus \n\nplacebo (see figure 1). \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n39 \n\nTable 23 Time to treatment failure in studies UV I and UV II \n\n \n\nAnalysis \n\n Treatment \n\n \n\nN Failure \n\nN (%) \n\n \n\nMedian \n\ntime to \n\nfailure \n\n(months) \n\n \n\nHRa CI 95% \n\nfor HRa \n\n \n\nP Value \nb\n\n \n\n \n\nTime to treatment failure at or after week 6 in study UV I \n\nPrimary analysis (ITT) \n\n \n\n Placebo 107 84 (78.5) 3.0 -- -- -- \n\n Adalimumab 110 60 (54.5) 5.6 0.50 0.36, \n\n0.70 \n\n< 0.001 \n\nTime to treatment failure at or after week 2 in study UV II \n\nPrimary analysis (ITT) \n\n \n\n Placebo 111 61 (55.0) 8.3 -- -- -- \n\n Adalimumab 115 45 (39.1) NEc 0.57 0.39, \n\n0.84 \n\n0.004 \n\n \nNote: Treatment failure at or after week 6 (study UV I), or at or after week 2 (study UV II), was counted as \n\nevent. Drop outs due to reasons other than treatment failure were censored at the time of dropping out. \na HR of adalimumab versus placebo from proportional hazards regression with treatment as factor. \nb 2-sided P value from log rank test. \nc NE = not estimable. Fewer than half of at-risk subjects had an event. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n40 \n\nFigure 1: Kaplan-Meier curves summarising time to treatment failure on or after week 6 (study \n\nUV I) or week 2 (study UV II) \n\n \n\nNote: P# = Placebo (number of events/number at risk); A# = Adalimumab (number of events/number at risk). \n\n \n\nIn study UV I statistically significant differences in favour of adalimumab versus placebo were \n\nobserved for each component of treatment failure. In study UV II, statistically significant differences \n\nwere observed for visual acuity only, but the other components were numerically in favour of \n\nadalimumab. \n\n \n\nOf the 417 subjects included in the uncontrolled long-term extension of Studies UV I and UV II, 46 \n\nsubjects were regarded ineligible (e.g. developed complications secondary to diabetic retinopathy, due \n\nto cataract surgery or vitrectomy) and were excluded from the primary analysis of efficacy. Of the 371 \n\nremaining patients, 276 evaluable patients reached 78 weeks of open-label adalimumab treatment. \n\nBased on the observed data approach, 222 (80.4%) were in quiescence (no active inflammatory \n\nlesions, AC cell grade ≤ 0.5+, VH grade ≤ 0.5+) with a concomitant steroid dose ≤ 7.5 mg per day, \n\nand 184 (66.7%) were in steroid-free quiescence. BCVA was either improved or maintained (< 5 \n\nletters deterioration) in 88.4% of the eyes at week 78. Among the patients who discontinued the study \n\nprior to week 78, 11% discontinued due to adverse events, and 5% due to insufficient response to \n\nadalimumab treatment. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n41 \n\nQuality of life \n\n \n\nPatient reported outcomes regarding vision-related functioning were measured in both clinical studies, \n\nusing the NEI VFQ-25. Adalimumab was numerically favoured for the majority of subscores with \n\nstatistically significant mean differences for general vision, ocular pain, near vision, mental health, and \n\ntotal score in study UV I, and for general vision and mental health in study UV II. vision related \n\neffects were not numerically in favour of adalimumab for colour vision in study UVI and for colour \n\nvision, peripheral vision and near vision in study UV II. \n\n \n\nImmunogenicity \n\n \n\nAnti-adalimumab antibodies may develop during adalimumab treatment. Formation of anti-\n\nadalimumab antibodies is associated with increased clearance and reduced efficacy of adalimumab. \n\nThere is no apparent correlation between the presence of anti-adalimumab antibodies and the \n\noccurrence of adverse events. \n\n \n\nPaediatric population \n\n \n\nThe European Medicines Agency has deferred the obligation to submit the results of the studies with \n\nadalimumab in one or more subsets of the paediatric population in ulcerative colitis and non-infectious \n\nuveitis, see section 4.2 for information on paediatric use. \n\n \n\n5.2 Pharmacokinetic properties \n\n \n\nAbsorption and distribution \n\n \n\nAfter subcutaneous administration of a single 40 mg dose, absorption and distribution of adalimumab \n\nwas slow, with peak serum concentrations being reached about 5 days after administration. The \n\naverage absolute bioavailability of adalimumab estimated from three studies following a single 40 mg \n\nsubcutaneous dose was 64%. After single intravenous doses ranging from 0.25 to 10 mg/kg, \n\nconcentrations were dose proportional. After doses of 0.5 mg/kg (~40 mg), clearances ranged from \n\n11 to 15 mL/hour, the distribution volume (Vss) ranged from 5 to 6 litres and the mean terminal phase \n\nhalf-life was approximately two weeks. Adalimumab concentrations in the synovial fluid from several \n\nrheumatoid arthritis patients ranged from 31-96% of those in serum. \n\n \n\nFollowing subcutaneous administration of 40 mg of adalimumab every other week in adult rheumatoid \n\narthritis (RA) patients the mean steady-state trough concentrations were approximately 5 μg/mL \n\n(without concomitant methotrexate) and 8 to 9 μg/mL (with concomitant methotrexate), respectively. \n\nThe serum adalimumab trough levels at steady-state increased roughly proportionally with dose \n\nfollowing 20, 40 and 80 mg subcutaneous dosing every other week and every week. \n\n \n\nFollowing the administration of 24 mg/m2 (up to a maximum of 40 mg) subcutaneously every other \n\nweek to patients with enthesitis-related arthritis who were 6 to 17 years, the mean trough steady-state \n\n(values measured at week 24) serum adalimumab concentrations were 8.8 ± 6.6 µg/mL for \n\nadalimumab without concomitant methotrexate and 11.8 ± 4.3 µg/mL with concomitant methotrexate. \n\n \n\nIn adult patients with psoriasis, the mean steady-state trough concentration was 5 μg/mL during \n\nadalimumab 40 mg every other week monotherapy treatment. \n\n \n\nFollowing the administration of 0.8 mg/kg (up to a maximum of 40 mg) subcutaneously every other \n\nweek to paediatric patients with chronic plaque psoriasis, the mean ± SD steady-state adalimumab \n\ntrough concentration was approximately 7.4 ± 5.8 μg/mL (79% CV). \n\n \n\nIn patients with hidradenitis suppurativa, a dose of 160 mg adalimumab on week 0 followed by 80 mg \n\non week 2 achieved serum adalimumab trough concentrations of approximately 7 to 8 μg/mL at week \n\n2 and week 4. The mean steady-state trough concentration at week 12 through week 36 were \n\napproximately 8 to 10 μg/mL during adalimumab 40 mg every week treatment. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n42 \n\n \n\nIn patients with Crohn’s disease, the loading dose of 80 mg adalimumab on week 0 followed by 40 mg \n\nadalimumab on week 2 achieves serum adalimumab trough concentrations of approximately \n\n5.5 μg/mL during the induction period. A loading dose of 160 mg adalimumab on week 0 followed by \n\n80 mg adalimumab on week 2 achieves serum adalimumab trough concentrations of approximately \n\n12 μg/mL during the induction period. Mean steady-state trough levels of approximately 7 μg/mL \n\nwere observed in Crohn’s disease patients who received a maintenance dose of 40 mg adalimumab \n\nevery other week. \n\n \n\nIn paediatric patients with moderate to severe CD, the open-label adalimumab induction dose was \n\n160/80 mg or 80/40 mg at weeks 0 and 2, respectively, dependent on a body weight cut-off of 40 kg. \n\nAt week 4, patients were randomised 1:1 to either the Standard Dose (40/20 mg eow) or Low Dose \n\n(20/10 mg eow) maintenance treatment groups based on their body weight. The mean (±SD) serum \n\nadalimumab trough concentrations achieved at week 4 were 15.7 ± 6.6 μg/mL for patients ≥ 40 kg \n\n(160/80 mg) and 10.6 ± 6.1 μg/mL for patients < 40 kg (80/40 mg). \n\n \n\nFor patients who stayed on their randomised therapy, the mean (±SD) adalimumab trough \n\nconcentrations at week 52 were 9.5 ± 5.6 μg/mL for the standard dose group and 3.5 ± 2.2 μg/mL for \n\nthe low dose group. The mean trough concentrations were maintained in patients who continued to \n\nreceive adalimumab treatment every other week for 52 weeks. For patients who dose escalated from \n\nevery other week to weekly regimen, the mean (±SD) serum concentrations of adalimumab at week 52 \n\nwere 15.3 ± 11.4 μg/mL (40/20 mg, weekly) and 6.7 ± 3.5 μg/mL (20/10 mg, weekly). \n\n \n\nIn patients with ulcerative colitis, a loading dose of 160 mg adalimumab on week 0 followed by 80 mg \n\nadalimumab on week 2 achieves serum adalimumab trough concentrations of approximately 12 μg/mL \n\nduring the induction period. Mean steady-state trough levels of approximately 8 μg/mL were observed \n\nin ulcerative colitis patients who received a maintenance dose of 40 mg adalimumab every other week. \n\n \n\nIn patients with uveitis, a loading dose of 80 mg adalimumab on week 0 followed by 40 mg \n\nadalimumab every other week starting at week 1, resulted in mean steady-state concentrations of \n\napproximately 8 to 10 μg/mL. \n\n \n\nElimination \n\n \n\nPopulation pharmacokinetic analyses with data from over 1,300 RA patients revealed a trend toward \n\nhigher apparent clearance of adalimumab with increasing body weight. After adjustment for weight \n\ndifferences, gender and age appeared to have a minimal effect on adalimumab clearance. The serum \n\nlevels of free adalimumab (not bound to anti-adalimumab antibodies, AAA) were observed to be \n\nlower in patients with measurable AAA. \n\n \n\nHepatic or renal impairment \n\n \n\nAdalimumab has not been studied in patients with hepatic or renal impairment. \n\n \n\n5.3 Preclinical safety data \n\n \n\nNon-clinical data reveal no special hazard for humans based on studies of single dose toxicity, \n\nrepeated dose toxicity, and genotoxicity. \n\n \n\nAn embryo-foetal developmental toxicity/perinatal developmental study has been performed in \n\nCynomolgus monkeys at 0, 30 and 100 mg/kg (9-17 monkeys/group) and has revealed no evidence of \n\nharm to the foetuses due to adalimumab. Neither carcinogenicity studies, nor a standard assessment of \n\nfertility and postnatal toxicity, were performed with adalimumab due to the lack of appropriate models \n\nfor an antibody with limited cross-reactivity to rodent TNF and to the development of neutralising \n\nantibodies in rodents. \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n43 \n\n6. PHARMACEUTICAL PARTICULARS \n\n \n\n6.1 List of excipients \n\n \n\nGlacial acetic acid \n\nSucrose \n\nPolysorbate 80 \n\nSodium hydroxide (for pH adjustment) \n\nWater for injections \n\n \n\n6.2 Incompatibilities \n\n \n\nIn the absence of compatibility studies, this medicinal product must not be mixed with other medicinal \n\nproducts. \n\n \n\n6.3 Shelf life \n\n \n\n2 years \n\n \n\n6.4 Special precautions for storage \n\n \n\nStore in a refrigerator (2°C – 8°C). \n\nDo not freeze. \n\nKeep SOLYMBIC in the outer carton in order to protect from light. \n\n \n\nThe pre-filled syringe or pre-filled pen may be stored at temperatures up to a maximum of 25°C for a \n\nperiod of up to 14 days. The pre-filled syringe or pre-filled pen must be protected from light, and \n\ndiscarded if not used within the 14-day period. \n\n \n\n6.5 Nature and contents of container \n\n \n\nSOLYMBIC 20 mg solution for injection in pre-filled syringe \n\n0.4 mL solution in pre-filled syringe (type I glass) with a plunger stopper (bromobutyl rubber) and a \n\nstainless steel needle with a needle shield (thermoplastic elastomer). The needle cover of the pre-filled \n\nsyringe is made from dry natural rubber (a derivative of latex) (see section 4.4). \n\n \n\nPacks size of one pre-filled syringe. \n\n \n\nSOLYMBIC 40 mg solution for injection in pre-filled syringe \n\n0.8 mL solution in pre-filled syringe (type I glass) with a plunger stopper (bromobutyl rubber) and a \n\nstainless steel needle with a needle shield (thermoplastic elastomer). The needle cover of the pre-filled \n\nsyringe is made from dry natural rubber (a derivative of latex) (see section 4.4). \n \n\nPacks sizes of one, two, four and six pre-filled syringes. \n\nNot all pack sizes may be marketed. \n\n \n\nSOLYMBIC 40 mg solution for injection in pre-filled pen \n\n0.8 mL solution for injection in pre-filled pen for patient use containing a pre-filled syringe (type I \n\nglass). The pen is a single use, disposable, handheld, mechanical injection device. The needle cover of \n\nthe pre-filled pen is made from dry natural rubber (a derivative of latex) (see section 4.4). \n\n \n\nPacks sizes of one, two, four and six pre-filled pens. \n\nNot all pack sizes may be marketed. \n\n \n\n6.6 Special precautions for disposal and other handling \n\n \n\nDetailed instructions for use are provided in the package leaflet. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n44 \n\n \n\nAny unused medicinal product or waste material should be disposed of in accordance with local \n\nrequirements. \n\n \n\n \n\n7. MARKETING AUTHORISATION HOLDER \n\n \n\nAmgen Europe B.V. \n\nMinervum 7061 \n\nNL-4817 ZK Breda \n\nThe Netherlands \n\n \n\n \n\n8. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nSOLYMBIC 20 mg solution for injection in pre-filled syringe \n\nEU/1/16/1163/001 – 1 pack \n\nSOLYMBIC 40 mg solution for injection in pre-filled syringe \n\nEU/1/16/1163/002 – 1 pack \n\nEU/1/16/1163/003 – 2 pack \n\nEU/1/16/1163/004 – 4 pack \n\nEU/1/16/1163/005 – 6 pack \n\nSOLYMBIC 40 mg solution for injection in pre-filled pen \n\nEU/1/16/1163/006 – 1 pack \n\nEU/1/16/1163/007 – 2 pack \n\nEU/1/16/1163/008 – 4 pack \n\nEU/1/16/1163/009 – 6 pack \n\n \n\n \n\n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n\n \n\nDate of first authorisation: 22 March 2017 \n\n \n\n \n\n10. DATE OF REVISION OF THE TEXT \n\n \n\n \n\n \n\nDetailed information on this medicinal product is available on the website of the European Medicines \n\nAgency http://www.ema.europa.eu \n\n M\ned\n\nici\nna\n\nl p\nrod\n\nuc\nt n\n\no l\non\n\nge\nr a\n\nuth\nori\n\nse\nd\n\nhttp://www.ema.europa.eu/\n\n\n \n\n45 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX II \n\n \n\nA. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND \n\nMANUFACTURERS RESPONSIBLE FOR BATCH RELEASE \n\n \n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n\n \n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n\n \n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n46 \n\nA. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND \n\nMANUFACTURERS RESPONSIBLE FOR BATCH RELEASE \n\n \n\nName and address of the manufacturer of the biological active substance \n\nAmgen Inc \n\nOne Amgen Center Drive \n\nThousand Oaks, California \n\n91320 \n\nUnited States \n\n \n\nName and address of the manufacturers responsible for batch release \n\nAmgen Europe B.V. \n\nMinervum 7061 \n\n4817 ZK Breda \n\nThe Netherlands \n\n \n\nAmgen Technology Ireland UC \n\nPottery Road \n\nDun Laoghaire, Co Dublin \n\nIreland \n\n \n\nAmgen NV \n\nTelecomlaan 5-7 \n\n1831 Diegem \n\nBelgium \n\n \n\nThe printed package leaflet of the medicinal product must state the name and address of the \n\nmanufacturer responsible for the release of the concerned batch. \n\n \n\n \n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n\n \n\nMedicinal product subject to restricted medical prescription (see Annex I: Summary of Product \n\nCharacteristics, section 4.2). \n\n \n\n \n\nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n\n \n\n• Periodic safety update reports \n \n\nThe requirements for submission of periodic safety update reports for this medicinal product are set \n\nout in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive \n\n2001/83/EC and any subsequent updates published on the European medicines web-portal. \n\n \n\n \n\nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n\n \n\n• Risk Management Plan (RMP) \n \n\nThe MAH shall perform the required pharmacovigilance activities and interventions detailed in the \n\nagreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent \n\nupdates of the RMP. \n\n \n\nAn updated RMP should be submitted: \n\n• At the request of the European Medicines Agency; \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n47 \n\n• Whenever the risk management system is modified, especially as the result of new information \nbeing received that may lead to a significant change to the benefit/risk profile or as the result of \n\nan important (pharmacovigilance or risk minimisation) milestone being reached. \n\n \n\n• Additional risk minimisation measures \n \n\nPrior to launch of Solymbic in each Member State the Marketing Authorisation Holder (MAH) must \n\nagree about the content and format of the educational programme, including communication media, \n\ndistribution modalities, and any other aspects of the programme, with the National Competent \n\nAuthority. \n\n \n\nThe MAH shall ensure that in each Member State where Solymbic is marketed, all healthcare \n\nprofessionals who are expected to prescribe Solymbic have are provided with the following \n\neducational package: \n\n• Physician educational material \n\n• Patient information pack \n \n\nThe physician educational material should contain: \n\n• The Summary of Product Characteristics \n\n• Guide for healthcare professionals \n\n• Patient alert card \n \n\nThe Guide for healthcare professionals shall contain the following key elements: \n\n• Relevant information on the safety concerns of serious infections, sepsis, tuberculosis and \nopportunistic infections; congestive heart failure; demyelinating disorders; malignancies to be \n\naddressed by the additional risk minimisation measures (e.g. seriousness, severity, frequency, \n\ntime to onset, reversibility of the AE as applicable). \n\n \n\nThe patient alert card shall contain the following key messages: \n\n• A warning message for HCPs treating the patient at any time, including in conditions of \nemergency, that the patient is using Solymbic. \n\n• That Solymbic treatment may increase the potential risks of serious infections, sepsis, \ntuberculosis and opportunistic infections; congestive heart failure; demyelinating disorders; \n\nmalignancies. \n\n• Signs or symptoms of the safety concern and when to seek attention from a HCP \n\n• Contact details of the prescriber \n \n\nThe patient information pack should contain: \n\n• Patient information leaflet \n Me\n\ndic\nina\n\nl p\nrod\n\nuc\nt n\n\no l\non\n\nge\nr a\n\nuth\nori\n\nse\nd\n\n\n\n \n\n48 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nANNEX III \n\n \n\nLABELLING AND PACKAGE LEAFLET \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n49 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nA. LABELLING \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n50 \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n\n \n\nCARTON PRE-FILLED SYRINGE \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nSOLYMBIC 20 mg solution for injection in pre-filled syringe \n\nadalimumab \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nEach pre-filled syringe contains 20 mg of adalimumab in 0.4 mL of solution. \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\nGlacial acetic acid, sucrose, polysorbate 80, sodium hydroxide and water for injection. \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\nSolution for injection. \n\n1 pre-filled syringe. \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nFor subcutaneous use. \n\nRead the package leaflet before use. \n\nSingle use only. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\nContains latex, read the package leaflet before use. \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n51 \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\nStore in a refrigerator. \n\nDo not freeze. \n\nDo not shake. \n\nStore in the original carton in order to protect from light. \n\n \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nAmgen Europe B.V. \n\nMinervum 7061, \n\nNL-4817 ZK Breda, \n\nThe Netherlands \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/16/1163/001 \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nSOLYMBIC 20 mg syringe \n\n \n\n \n\n17. UNIQUE IDENTIFIER – 2D BARCODE \n\n \n\n2D barcode carrying the unique identifier included. \n\n \n\n \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n\n \n\nPC \n\nSN \n\nNN \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n52 \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n\n \n\nLABEL PRE-FILLED SYRINGE \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n\n \n\nSOLYMBIC 20 mg injection \n\nadalimumab \n\nSC \n\n \n\n \n\n2. METHOD OF ADMINISTRATION \n\n \n\n \n\n3. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n4. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n\n \n\n0.4 mL \n\n \n\n \n\n6. OTHER \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n53 \n\n \n\nCARTON PRE-FILLED SYRINGE \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nSOLYMBIC 40 mg solution for injection in pre-filled syringe \n\nadalimumab \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nEach pre-filled syringe contains 40 mg of adalimumab in 0.8 mL of solution. \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\nGlacial acetic acid, sucrose, polysorbate 80, sodium hydroxide and water for injection. \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\nSolution for injection. \n\n1 pre-filled syringe. \n\n2 pre-filled syringes. \n\n4 pre-filled syringes. \n\n6 pre-filled syringes. \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nFor subcutaneous use. \n\nRead the package leaflet before use. \n\nSingle use only. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\nContains latex, read the package leaflet before use. \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n54 \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\nStore in a refrigerator. \n\nDo not freeze. \n\nDo not shake. \n\nStore in the original carton in order to protect from light. \n\n \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nAmgen Europe B.V. \n\nMinervum 7061, \n\nNL-4817 ZK Breda, \n\nThe Netherlands \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/16/1163/002 1 pack \n\nEU/1/16/1163/003 2 pack \n\nEU/1/16/1163/004 4 pack \n\nEU/1/16/1163/005 6 pack \n\n \n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nSOLYMBIC 40 mg syringe \n\n \n\n \n\n17. UNIQUE IDENTIFIER – 2D BARCODE \n\n \n\n2D barcode carrying the unique identifier included. \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n55 \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n\n \n\nPC \n\nSN \n\nNN \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n56 \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n\n \n\nLABEL PRE-FILLED SYRINGE \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n\n \n\nSOLYMBIC 40 mg injection \n\nadalimumab \n\nSC \n\n \n\n \n\n2. METHOD OF ADMINISTRATION \n\n \n\n \n\n3. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n4. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n\n \n\n0.8 mL \n\n \n\n \n\n6. OTHER \n\n \n\n \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n57 \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n\n \n\nCARTON PRE-FILLED PEN \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT \n\n \n\nSOLYMBIC 40 mg solution for injection in pre-filled pen \n\nadalimumab \n\n \n\n \n\n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n\n \n\nEach pre-filled pen contains 40 mg of adalimumab in 0.8 mL of solution. \n\n \n\n \n\n3. LIST OF EXCIPIENTS \n\n \n\nGlacial acetic acid, sucrose, polysorbate 80, sodium hydroxide and water for injection. \n\n \n\n \n\n4. PHARMACEUTICAL FORM AND CONTENTS \n\n \n\nSolution for injection. \n\n1 SureClick pre-filled pen. \n\n2 SureClick pre-filled pens. \n\n4 SureClick pre-filled pens. \n\n6 SureClick pre-filled pens. \n\n \n\n \n\n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n\n \n\nFor subcutaneous use. \n\nRead the package leaflet before use. \n\nSingle use only. \n\n \n\n \n\n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n\n \n\nKeep out of the sight and reach of children. \n\n \n\n \n\n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n\n \n\nContains latex, read the package leaflet before use. \n\n \n\n \n\n8. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n58 \n\n9. SPECIAL STORAGE CONDITIONS \n\n \n\nStore in a refrigerator. \n\nDo not freeze. \n\nDo not shake. \n\nStore in the original carton in order to protect from light. \n\n \n\n \n\n \n\n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \n\nAPPROPRIATE \n\n \n\n \n\n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n\n \n\nAmgen Europe B.V. \n\nMinervum 7061, \n\nNL-4817 ZK Breda, \n\nThe Netherlands \n\n \n\n \n\n12. MARKETING AUTHORISATION NUMBER(S) \n\n \n\nEU/1/16/1163/006 1 pack \n\nEU/1/16/1163/007 2 pack \n\nEU/1/16/1163/008 4 pack \n\nEU/1/16/1163/009 6 pack \n\n \n\n \n\n13. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n14. GENERAL CLASSIFICATION FOR SUPPLY \n\n \n\n \n\n15. INSTRUCTIONS ON USE \n\n \n\n \n\n16. INFORMATION IN BRAILLE \n\n \n\nSOLYMBIC 40 mg pen \n\n \n\n \n\n17. UNIQUE IDENTIFIER – 2D BARCODE \n\n \n\n2D barcode carrying the unique identifier included. \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n59 \n\n18. UNIQUE IDENTIFIER - HUMAN READABLE DATA \n\n \n\nPC \n\nSN \n\nNN \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n60 \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n\n \n\nLABEL PRE-FILLED PEN \n\n \n\n \n\n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n\n \n\nSOLYMBIC 40 mg injection \n\nadalimumab \n\nSC \n\n \n\n \n\n2. METHOD OF ADMINISTRATION \n\n \n\n \n\n3. EXPIRY DATE \n\n \n\nEXP \n\n \n\n \n\n4. BATCH NUMBER \n\n \n\nLot \n\n \n\n \n\n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n\n \n\n0.8 mL \n\n \n\n \n\n6. OTHER \n\n \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n61 \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\n \n\nB. PACKAGE LEAFLET \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n62 \n\nPackage leaflet: Information for the user \n\n \n\nSOLYMBIC 20 mg solution for injection in pre-filled syringe \n\nSOLYMBIC 40 mg solution for injection in pre-filled syringe \n\nadalimumab \n\n \n\nThis medicine is subject to additional monitoring. This will allow quick identification of new \n\nsafety information. You can help by reporting any side effects you may get. See the end of section 4 \n\nfor how to report side effects. \n\n \n\nRead all of this leaflet carefully before you start using this medicine because it contains \n\nimportant information for you. \n\n- Keep this leaflet. You may need to read it again. \n- Your doctor will also give you a Patient Alert Card, which contains important safety \n\ninformation that you need to be aware of before you are given SOLYMBIC and during \n\ntreatment with SOLYMBIC. Keep this Patient Alert Card with you. \n\n- If you have any further questions, ask your doctor or pharmacist. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n\n- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side \n\neffects not listed in this leaflet (see section 4). \n\n \n\nWhat is in this leaflet \n\n \n\n1. What SOLYMBIC is and what it is used for \n\n2. What you need to know before you use SOLYMBIC \n\n3. How to use SOLYMBIC \n\n4. Possible side effects \n\n5. How to store SOLYMBIC \n\n6. Contents of the pack and other information \n\n \n\n \n\n1. What SOLYMBIC is and what it is used for \n\n \n\nSOLYMBIC contains the active substance adalimumab, a selective immuno suppressive agent. \n\n \n\nSOLYMBIC is intended for treatment of rheumatoid arthritis, enthesitis-related arthritis in children 6 \n\nto 17 years, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of \n\nankylosing spondylitis, psoriatic arthritis, psoriasis, hidradenitis suppurativa, paediatric psoriasis \n\n(patients weighing either 23 to 28 kg or 47 kg and greater), Crohn’s disease in adults and children, \n\nulcerative colitis and non-infectious uveitis affecting the back of the eye. It is a medicine that \n\ndecreases the inflammation process of these diseases. The active ingredient, adalimumab, is a human \n\nmonoclonal antibody produced by cultured cells. Monoclonal antibodies are proteins that recognise \n\nand bind to other unique proteins. \n\n \n\nAdalimumab binds to a specific protein (tumour necrosis factor or TNFα), which is present at \n\nincreased levels in inflammatory diseases such as rheumatoid arthritis, enthesitis-related arthritis, \n\nankylosing spondylitis, axial spondyloarthritis without radiographic evidence of ankylosing \n\nspondylitis, psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis \n\nand non-infectious uveitis affecting the back of the eye. \n\n \n\nRheumatoid arthritis \n\n \n\nRheumatoid arthritis is an inflammatory disease of the joints. \n\n \n\nSOLYMBIC is used to treat rheumatoid arthritis in adults. If you have moderate to severe active \n\nrheumatoid arthritis, you may first be given other disease-modifying medicines, such as methotrexate. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n63 \n\nIf you do not respond well enough to these medicines, you will be given SOLYMBIC to treat your \n\nrheumatoid arthritis. \n\n \n\nSOLYMBIC can also be used to treat severe, active and progressive rheumatoid arthritis without \n\nprevious methotrexate treatment. \n\n \n\nSOLYMBIC slows down the damage to the cartilage and bone of the joints caused by the disease and \n\nto improve physical function. \n\n \n\nUsually, SOLYMBIC is used with methotrexate. If your doctor determines that methotrexate is \n\ninappropriate, SOLYMBIC can be given alone. \n\n \n\nEnthesitis-related arthritis \n\n \n\nEnthesitis-related arthritis is an inflammatory disease of the joints. \n\n \n\nSOLYMBIC is used to treat enthesitis-related arthritis in children and adolescents aged 6 to 17 years. \n\nYou may first be given other disease-modifying medicines, such as methotrexate. If you do not \n\nrespond well enough to these medicines, you will be given SOLYMBIC to treat your enthesitis-related \n\narthritis. \n\n \n\nAnkylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing \n\nspondylitis \n\n \n\nAnkylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing \n\nspondylitis, are inflammatory diseases of the spine. \n\n \n\nSOLYMBIC is used to treat ankylosing spondylitis and axial spondyloarthritis without radiographic \n\nevidence of ankylosing spondylitis in adults. If you have ankylosing spondylitis or axial \n\nspondyloarthritis without radiographic evidence of ankylosing spondylitis, you will first be given other \n\nmedicines. If you do not respond well enough to these medicines, you will be given SOLYMBIC to \n\nreduce the signs and symptoms of your disease. \n\n \n\nPsoriatic arthritis \n\n \n\nPsoriatic arthritis is an inflammation of the joints associated with psoriasis. \n\n \n\nSOLYMBIC is used to treat psoriatic arthritis in adults. SOLYMBIC slows down the damage to the \n\ncartilage and bone of the joints caused by the disease and to improve physical function. \n\n \n\nPlaque psoriasis in adults and children \n\n \n\nPlaque psoriasis is a skin condition that causes red, flaky, crusty patches of skin covered with silvery \n\nscales. Plaque psoriasis can also affect the nails, causing them to crumble, become thickened and lift \n\naway from the nail bed which can be painful. Psoriasis is believed to be caused by a problem with the \n\nbody’s immune system that leads to an increased production of skin cells. \n\n \n\nSOLYMBIC is used to treat moderate to severe plaque psoriasis in adults. SOLYMBIC is also used to \n\ntreat severe plaque psoriasis in children and adolescents weighing either 23 to 28 kg or 47 kg or \n\ngreater for whom topical therapy and phototherapies have either not worked very well or are not \n\nsuitable. \n\n \n\nHidradenitis suppurativa \n\n \n\nHidradenitis suppurativa (sometimes called acne inversa) is a chronic and often painful inflammatory \n\nskin disease. Symptoms may include tender nodules (lumps) and abscesses (boils) that may leak pus. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n64 \n\nIt most commonly affects specific areas of the skin, such as under the breasts, the armpits, inner \n\nthighs, groin and buttocks. Scarring may also occur in affected areas. \n\n \n\nSOLYMBIC is used to treat hidradenitis suppurativa in adults. SOLYMBIC can reduce the number of \n\nnodules and abscesses you have, and the pain that is often associated with the disease. \n\n \n\nCrohn’s disease in adults and children \n\n \n\nCrohn’s disease is an inflammatory disease of the digestive tract. \n\n \nSOLYMBIC is used to treat Crohn’s disease in adults and children aged 6 to 17 years. If you have \n\nCrohn’s disease you will first be given other medicines. If you do not respond well enough to these \n\nmedicines, you will be given SOLYMBIC to reduce the signs and symptoms of your Crohn’s disease. \n\n \n\nUlcerative colitis \n\n \n\nUlcerative colitis is an inflammatory disease of the bowel. \n\n \n\nSOLYMBIC is used to treat ulcerative colitis in adults. If you have ulcerative colitis you will first be \n\ngiven other medicines. If you do not respond well enough to these medicines, you will be given \n\nSOLYMBIC to reduce the signs and symptoms of your disease. \n\n \n\nNon-infectious uveitis affecting the back of the eye \n\n \n\nNon-infectious uveitis is an inflammatory disease affecting certain parts of the eye. SOLYMBIC is \n\nused to treat adults with non-infectious uveitis with inflammation affecting the back of the eye. This \n\ninflammation leads to a decrease of vision and/or the presence of floaters in the eye (black dots or \n\nwispy lines that move across the field of vision). SOLYMBIC works by reducing this inflammation. \n\n \n\n \n\n2. What you need to know before you use SOLYMBIC \n\n \n\nDo not use SOLYMBIC: \n\n \n\n- if you are allergic to adalimumab or any of the other ingredients of this medicine (listed in \n\nsection 6). \n\n- if you have a severe infection, including active tuberculosis (see “Warnings and precautions”). \n\nIt is important that you tell your doctor if you have symptoms of infections, e.g. fever, wounds, \n\nfeeling tired, dental problems. \n\n- if you have moderate or severe heart failure. It is important to tell your doctor if you have had or \n\nhave a serious heart condition (see “Warnings and precautions”). \n\n \n\nWarnings and precautions \n\n \n\nTalk to your doctor or pharmacist before using SOLYMBIC: \n\n \n\n- If you experience allergic reactions with symptoms such as chest tightness, wheezing, dizziness, \n\nswelling or rash do not inject more SOLYMBIC and contact your doctor immediately since, in \n\nrare cases, these reactions can be life threatening. \n \n\n- If you have an infection, including long-term or localised infection (for example, leg ulcer) \n\nconsult your doctor before starting SOLYMBIC. If you are unsure, please contact your doctor. \n\n \n\n- You might get infections more easily while you are receiving SOLYMBIC treatment. This risk \n\nmay increase if your lung function is impaired. These infections may be serious and include \n\ntuberculosis, infections caused by viruses, fungi, parasites or bacteria, or other opportunistic \n\ninfections and sepsis that may, in rare cases, be life-threatening. It is important to tell your \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n65 \n\ndoctor if you get symptoms such as fever, wounds, feeling tired or dental problems. Your doctor \n\nmay recommend temporary discontinuation of SOLYMBIC. \n\n \n\n- As cases of tuberculosis have been reported in patients treated with adalimumab, your doctor \n\nwill check you for signs and symptoms of tuberculosis before starting SOLYMBIC. This will \n\ninclude a thorough medical evaluation including your medical history and appropriate screening \n\ntests (for example chest x-ray and a tuberculin test). The conduct and results of these tests \n\nshould be recorded on your Patient Alert Card. It is very important that you tell your doctor if \n\nyou have ever had tuberculosis, or if you have been in close contact with someone who has had \n\ntuberculosis. Tuberculosis can develop during therapy even if you have received preventative \n\ntreatment for tuberculosis. If symptoms of tuberculosis (persistent cough, weight loss, \n\nlistlessness, mild fever), or any other infection appear during or after therapy, tell your doctor \n\nimmediately. \n\n \n\n- Advise your doctor if you reside or travel in regions where fungal infections such as \n\nhistoplasmosis coccidioidomycosis or blastomycosis are endemic. \n\n \n\n- Advise your doctor if you have a history of recurrent infections or other conditions that increase \n\nthe risk of infections. \n\n \n\n- Advise your doctor if you are a carrier of the hepatitis B virus (HBV), if you have active HBV \n\nor if you think you might be at risk of contracting HBV. Your doctor should test you for HBV. \n\nSOLYMBIC can cause reactivation of HBV in people who carry this virus. In some rare cases, \n\nespecially if you are taking other medicines that suppress the immune system, reactivation of \n\nHBV can be life-threatening. \n\n \n- If you are over 65 years you may be more susceptible to infections while taking SOLYMBIC. \n\nYou and your doctor should pay special attention to signs of infection while you are being \n\ntreated with SOLYMBIC. It is important to tell your doctor if you get symptoms of infections, \n\nsuch as fever, wounds, feeling tired or dental problems. \n\n \n\n- If you are about to undergo surgery or dental procedures please inform your doctor that you are \n\ntaking SOLYMBIC. Your doctor may recommend temporary discontinuation of SOLYMBIC. \n\n \n\n- If you have or develop demyelinating disease such as multiple sclerosis, your doctor will decide \n\nif you should receive or continue to receive SOLYMBIC. Tell your doctor immediately if you \n\nexperience symptoms like changes in your vision, weakness in your arms or legs or numbness \n\nor tingling in any part of your body. \n\n \n\n- Certain vaccines may cause infections and should not be given while receiving SOLYMBIC. \n\nPlease check with your doctor before you receive any vaccines. It is recommended that children, \n\nif possible, be brought up to date with all immunisations in agreement with current \n\nimmunisation guidelines prior to initiating SOLYMBIC therapy. If you received SOLYMBIC \n\nwhile you were pregnant, your baby may be at higher risk for getting such an infection for up to \n\napproximately five months after the last dose you received during pregnancy. It is important that \n\nyou tell your baby's doctors and other health care professionals about your SOLYMBIC use \n\nduring your pregnancy so they can decide when your baby should receive any vaccine. \n\n \n\n- If you have mild heart failure and you are being treated with SOLYMBIC, your heart failure \n\nstatus must be closely monitored by your doctor. It is important to tell your doctor if you have \n\nhad or have a serious heart condition. If you develop new or worsening symptoms of heart \n\nfailure (e.g. shortness of breath, or swelling of your feet), you must contact your doctor \n\nimmediately. \n\n \n\n- In some patients the body may fail to produce enough of the blood cells that help your body \n\nfight infections or help you to stop bleeding. If you develop a fever that does not go away, \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n66 \n\nbruise or bleed very easily or look very pale, call your doctor right away. Your doctor may \n\ndecide to stop treatment. \n\n \n\n- There have been very rare cases of certain kinds of cancer in children and adult patients taking \n\nadalimumab or other TNF blockers. People with more serious rheumatoid arthritis that have had \n\nthe disease for a long time may have a higher than average risk of getting lymphoma (a type of \n\ncancer that affects the lymph system), and leukaemia (a type of cancer that affects the blood and \n\nbone marrow). If you take SOLYMBIC the risk of getting lymphoma, leukaemia, or other \n\ncancers may increase. On rare occasions, a specific and severe type of lymphoma has been \n\nobserved in some patients taking adalimumab. Some of those patients were also treated with \n\nazathioprine or 6-mercaptopurine. Tell your doctor if you are taking azathioprine or \n\n6-mercaptopurine with SOLYMBIC. In addition, cases of non-melanoma skin cancer have been \n\nobserved in patients taking adalimumab. If new skin lesions appear during or after therapy or if \n\nexisting lesions change appearance, tell your doctor. \n\n \n\n- There have been cases of cancers other than lymphoma in patients with a specific type of lung \n\ndisease called Chronic Obstructive Pulmonary Disease (COPD) treated with another TNF \n\nblocker. If you have COPD, or are a heavy smoker, you should discuss with your doctor \n\nwhether treatment with a TNF blocker is appropriate for you. \n\n \n\nThe needle cover of the pre-filled syringe is made from dry natural rubber (a derivative of latex), \n\nwhich may cause allergic reactions. \n\n \n\nIn order to improve the traceability of this medicine, your doctor or pharmacist should record the \n\ntradename and the lot number of the product you have been given in your patient file. You may also \n\nwish to make a note of these details in case you are asked for this information in the future. \n\n \n\nChildren and adolescents \n\n \n- Vaccinations: if possible children should be up to date with all vaccinations before using \n\nSOLYMBIC. \n\n- Do not use the 20 mg or 40 mg pre-filled syringe if doses other than 20 mg or 40 mg are \n\nrecommended. \n\n \n\nOther medicines and SOLYMBIC \n\n \n\nTell your doctor or pharmacist if you are taking, have recently taken or might take any other \n\nmedicines. \n\n \n\nSOLYMBIC can be taken together with methotrexate or certain disease-modifying anti-rheumatic \n\nagents (sulfasalazine, hydroxychloroquine, leflunomide and injectable gold preparations), steroids or \n\npain medications including non-steroidal anti-inflammatory drugs (NSAIDs). \n\n \n\nYou should not take SOLYMBIC with medicines containing the active substance, anakinra or \n\nabatacept. If you have questions, please ask your doctor. \n\n \n\nPregnancy and breast-feeding \n\n \n\nThe effects of SOLYMBIC in pregnant women are not known and so the use of SOLYMBIC in \n\npregnant women is not recommended. You are advised to avoid becoming pregnant and must use \n\nadequate contraception while using SOLYMBIC and for at least 5 months after the last SOLYMBIC \n\ntreatment. If you become pregnant, you should consult your doctor. \n\n \n\nIt is not known whether SOLYMBIC passes into breast milk. \n\n \n\nIf you are a breast-feeding mother, you should stop breast-feeding during SOLYMBIC treatment and \n\nfor at least 5 months after the last SOLYMBIC treatment. If you received SOLYMBIC during your \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n67 \n\npregnancy, your baby may have a higher risk for getting an infection. It is important that you tell your \n\nbaby’s doctors and other health care professionals about your SOLYMBIC use during your pregnancy \n\nbefore the baby receives any vaccine (for more information see section on vaccination). \n\n \n\nIf you think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for \n\nadvice before taking this medicine. \n\n \n\nDriving and using machines \n\n \n\nSOLYMBIC may have a minor influence on your ability to drive, cycle or use machines. Room \n\nspinning sensation and vision disturbances may occur after taking SOLYMBIC. \n\n \n\nSOLYMBIC contains sodium \n\n \n\nThis medicine contains less than 1 mmol of sodium (23 mg) per 0.8 mL dose, i.e. essentially ‘sodium-\n\nfree’. \n\n \n\n \n\n3. How to use SOLYMBIC \n\n \n\nAlways use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor \n\nor pharmacist if you are not sure. \n\n \n\nAdults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or axial spondyloarthritis \n\nwithout radiographic evidence of ankylosing spondylitis \n\n \n\nSOLYMBIC is injected under the skin (subcutaneous use). The usual dose for adults with rheumatoid \n\narthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of ankylosing \nspondylitis, and for patients with psoriatic arthritis is 40 mg given every other week as a single dose. \n\n \n\nIn rheumatoid arthritis, methotrexate is continued while using SOLYMBIC. If your doctor determines \n\nthat methotrexate is inappropriate, SOLYMBIC can be given alone. \n\n \n\nIf you have rheumatoid arthritis and you do not receive methotrexate with your SOLYMBIC therapy, \n\nyour doctor may decide to give 40 mg every week. \n\n \n\nChildren with enthesitis-related arthritis \n\n \n\nThe recommended dose of SOLYMBIC for patients with enthesitis-related arthritis, aged 6 to 17 years \n\ndepends on the height and weight of the child. Your child’s doctor will tell you the correct dose to use. \n\n \n\nAdults with psoriasis \n\n \n\nThe usual dose for adults with psoriasis is an initial dose of 80 mg, followed by 40 mg given every \n\nother week starting one week after the initial dose. You should continue to inject SOLYMBIC for as \n\nlong as your doctor has told you. Depending on your response, your doctor may increase the dose \n\nfrequency to 40 mg every week. \n\n \n\nChildren or adolescents with plaque psoriasis \n\n \n\nThe recommended dose of SOLYMBIC for patients aged 4 to 17 years with plaque psoriasis depends \n\non the weight of your child. SOLYMBIC should only be used in patients weighing either 23 to 28 kg \n\nor 47 kg and greater. Your child’s doctor will tell you the correct dose to use. \n\n \n\nAdults with hidradenitis suppurativa \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n68 \n\nThe usual dose regimen for hidradenitis suppurativa is an initial dose of 160 mg (as four 40 mg \n\ninjections in one day or two 40 mg injections per day for two consecutive days), followed by an 80 mg \n\ndose (as two 40 mg injections on the same day) two weeks later. After two further weeks, continue \n\nwith a dose of 40 mg every week. It is recommended that you use an antiseptic wash daily on the \n\naffected areas. \n\n \n\nAdults with Crohn’s disease \n\n \n\nThe usual dose regimen for Crohn’s disease is 80 mg initially followed by 40 mg every other week \n\ntwo weeks later. If a faster response is required, your doctor may prescribe an initial dose of 160 mg \n\n(as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), \n\nfollowed by 80 mg two weeks later, and thereafter as 40 mg every other week. Depending on your \n\nresponse, your doctor may increase the dose frequency to 40 mg every week. \n\n \n\nChildren or adolescents with Crohn's disease \n\n \n\nChildren or adolescents weighing less than 40 kg: \n\n \n\nThe usual dose regimen is 40 mg initially followed by 20 mg two weeks later. If a faster response is \n\nrequired, your doctor may prescribe an initial dose of 80 mg (as two 40 mg injections in 1 day) \n\nfollowed by 40 mg two weeks later. \n\n \n\nThereafter, the usual dose is 20 mg every other week. Depending on your response, your doctor may \n\nincrease the dose frequency to 20 mg every week. \n\n \n\nChildren or adolescents weighing 40 kg or more: \n\n \n\nThe usual dose regimen is 80 mg initially followed by 40 mg two weeks later. If a faster response is \n\nrequired, your doctor may prescribe an initial dose of 160 mg (as four 40 mg injections in 1 day or as \n\ntwo 40 mg injections per day for 2 consecutive days) followed by 80 mg two weeks later. \n\n \n\nThereafter, the usual dose is 40 mg every other week. Depending on your response, your doctor may \n\nincrease the dose frequency to 40 mg every week. \n\n \n\nAdults with ulcerative colitis \n\n \n\nThe usual SOLYMBIC dose for adults with ulcerative colitis is 160 mg initially (dose can be \n\nadministered as four 40 mg injections in one day or as two 40 mg injections per day for two \n\nconsecutive days) followed by 80 mg two weeks later, then 40 mg every other week. Depending on \n\nyour response, your doctor may increase the dose to 40 mg every week. \n\n \n\nAdults with non-infectious uveitis \n\n \n\nThe usual dose for adults with non-infectious uveitis is an initial dose of 80 mg, followed by 40 mg \n\ngiven every other week starting one week after the initial dose. You should continue to inject \n\nSOLYMBIC for as long as your doctor has told you. \n\n \n\nIn non-infectious uveitis, corticosteroids or other medicines that influence the immune system may be \n\ncontinued while using SOLYMBIC. SOLYMBIC can also be given alone. \n \n\nMethod and route of administration \n\n \n\nSOLYMBIC is administered by injection under the skin (subcutaneous injection). \n\n \n\nIf you use more SOLYMBIC than you should \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n69 \n\nIf you accidentally inject SOLYMBIC more frequently than told to by your doctor or pharmacist, you \n\nshould call your doctor or pharmacist and tell him/her that you have taken more. Always take the outer \n\ncarton of this medicine with you, even if it is empty. \n\n \n\nIf you forget to use SOLYMBIC \n\n \n\nIf you forget to give yourself an injection, you should inject it as soon as you remember. Then take \n\nyour next dose as you would have on your originally scheduled day, had you not forgotten a dose. \n\n \n\nIf you stop using SOLYMBIC \n\n \n\nThe decision to stop using SOLYMBIC should be discussed with your doctor. Your symptoms may \n\nreturn upon discontinuation. \n\n \n\nIf you have any further questions on the use of this medicine, ask your doctor or pharmacist. \n\n \n\n \n\n4. Possible side effects \n\n \n\nLike all medicines, this medicine can cause side effects, although not everybody gets them. Most side \n\neffects are mild to moderate. However, some may be serious and require treatment. Side effects may \n\noccur at least up to 4 months after the last SOLYMBIC injection. \n\n \n\nTell your doctor immediately if you notice any of the following: \n\n• severe rash, hives or other signs of allergic reaction; \n\n• swollen face, hands, feet; \n\n• trouble breathing, swallowing; \n\n• shortness of breath with exertion or upon lying down or swelling of the feet. \n \n\nTell your doctor as soon as possible if you notice any of the following: \n\n• signs of infection such as fever, feeling sick, wounds, dental problems, burning on urination; \n\n• feeling weak or tired; \n\n• coughing; \n\n• tingling; \n\n• numbness; \n\n• double vision; \n\n• arm or leg weakness; \n\n• a bump or open sore that doesn't heal; \n\n• signs and symptoms suggestive of blood disorders such as persistent fever, bruising, bleeding, \n\npaleness. \n\n \n\nThe symptoms described above can be signs of the below listed side effects, which have been \n\nobserved with adalimumab: \n\n \n\nVery common side effects (may affect more than 1 in 10 people): \n\n• injection site reactions (including pain, swelling, redness or itching); \n\n• respiratory tract infections (including cold, runny nose, sinus infection, pneumonia); \n\n• headache; \n\n• abdominal pain; \n\n• nausea and vomiting; \n\n• rash; \n\n• musculoskeletal pain. \n \n\nCommon side effects (may affect up to 1 in 10 people): \n\n• serious infections (including blood poisoning and influenza); \n\n• skin infections (including cellulitis and shingles); \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n70 \n\n• ear infections; \n\n• oral infections (including tooth infections and cold sores); \n\n• reproductive tract infections; \n\n• urinary tract infection; \n\n• fungal infections; \n\n• joint infections; \n\n• benign tumours; \n\n• skin cancer; \n\n• allergic reactions (including seasonal allergy); \n\n• dehydration; \n\n• mood swings (including depression); \n\n• anxiety; \n\n• difficulty sleeping; \n\n• sensation disorders such as tingling, prickling or numbness; \n\n• migraine; \n\n• nerve root compression (including low back pain and leg pain); \n\n• vision disturbances; \n\n• eye inflammation; \n\n• inflammation of the eye lid and eye swelling; \n\n• vertigo; \n\n• sensation of heart beating rapidly; \n\n• high blood pressure; \n\n• flushing; \n\n• haematoma; \n\n• cough; \n\n• asthma; \n\n• shortness of breath; \n\n• gastrointestinal bleeding; \n\n• dyspepsia (indigestion, bloating, heart burn); \n\n• acid reflux disease; \n\n• sicca syndrome (including dry eyes and dry mouth); \n\n• itching; \n\n• itchy rash; \n\n• bruising; \n\n• inflammation of the skin (such as eczema); \n\n• breaking of finger nails and toe nails; \n\n• increased sweating; \n\n• hair loss; \n\n• new onset or worsening of psoriasis; \n\n• muscle spasms; \n\n• blood in urine; \n\n• kidney problems; \n\n• chest pain; \n\n• oedema; \n\n• fever; \n\n• reduction in blood platelets which increases risk of bleeding or bruising; \n\n• impaired healing. \n\n \n\nUncommon side effects (may affect up to 1 in 100 people): \n\n• opportunistic infections (which include tuberculosis and other infections that occur when \n\nresistance to disease is lowered); \n\n• neurological infections (including viral meningitis); \n\n• eye infections; \n\n• bacterial infections; \n\n• diverticulitis (inflammation and infection of the large intestine); \n\n• cancer; \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n71 \n\n• cancer that affects the lymph system; \n\n• melanoma; \n\n• immune disorders that could affect the lungs, skin and lymph nodes (most commonly presenting \n\nas sarcoidosis); \n\n• vasculitis (inflammation of blood vessels); \n\n• tremor; \n\n• neuropathy; \n\n• stroke; \n\n• double vision; \n\n• hearing loss, buzzing; \n\n• sensation of heart beating irregularly such as skipped beats; \n\n• heart problems that can cause shortness of breath or ankle swelling; \n\n• heart attack; \n\n• a sac in the wall of a major artery, inflammation and clot of a vein, blockage of a blood vessel; \n\n• lung diseases causing shortness of breath (including inflammation); \n\n• pulmonary embolism (blockage in an artery of the lung); \n\n• pleural effusion (abnormal collection of fluid in the pleural space); \n\n• inflammation of the pancreas which causes severe pain in the abdomen and back; \n\n• difficulty in swallowing; \n\n• facial oedema; \n\n• gallbladder inflammation, gallbladder stones; \n\n• fatty liver; \n\n• night sweats; \n\n• scar; \n\n• abnormal muscle breakdown; \n\n• systemic lupus erythematosus (including inflammation of skin, heart, lung, joints and other \n\norgan systems); \n\n• sleep interruptions; \n\n• impotence; \n\n• inflammations. \n \n\nRare side effects (may affect up to 1 in 1,000 people): \n\n• leukaemia (cancer affecting the blood and bone marrow); \n\n• severe allergic reaction with shock; \n\n• multiple sclerosis; \n\n• nerve disorders (such as eye nerve inflammation and Guillain-Barré syndrome that may cause \n\nmuscle weakness, abnormal sensations, tingling in the arms and upper body); \n\n• heart stops pumping; \n\n• pulmonary fibrosis (scarring of the lung); \n\n• intestinal perforation; \n\n• hepatitis; \n• reactivation of hepatitis B; \n\n• autoimmune hepatitis (inflammation of the liver caused by the body's own immune system); \n\n• cutaneous vasculitis (inflammation of blood vessels in the skin); \n\n• Stevens-Johnson syndrome (early symptoms include malaise, fever, headache and rash); \n\n• facial oedema associated with allergic reactions; \n\n• erythema multiforme (inflammatory skin rash); \n\n• lupus-like syndrome. \n \n\nNot known (frequency cannot be estimated from available data): \n\n• hepatosplenic T-cell lymphoma (a rare blood cancer that is often fatal); \n\n• Merkel cell carcinoma (a type of skin cancer); \n\n• liver failure; \n\n• worsening of a condition called dermatomyositis (seen as a skin rash accompanying muscle \n\nweakness). \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n72 \n\nSome side effects observed with adalimumab may not have symptoms and may only be discovered \n\nthrough blood tests. These include: \n\n \n\nVery common side effects (may affect more than 1 in 10 people): \n\n• low blood measurements for white blood cells; \n\n• low blood measurements for red blood cells; \n\n• increased lipids in the blood; \n\n• elevated liver enzymes. \n \n\nCommon side effects (may affect up to 1 in 10 people): \n\n• high blood measurements for white blood cells; \n\n• low blood measurements for platelets; \n\n• increased uric acid in the blood; \n\n• abnormal blood measurements for sodium; \n\n• low blood measurements for calcium; \n\n• low blood measurements for phosphate; \n\n• high blood sugar; \n\n• high blood measurements for lactate dehydrogenase; \n\n• autoantibodies present in the blood. \n \n\nRare side effects (may affect up to 1 in 1,000 people): \n\n• low blood measurements for white blood cells, red blood cells and platelet count. \n \n\nNot known (frequency cannot be estimated from available data): \n\n• liver failure. \n\n \nReporting of side effects \n\n \n\nIf you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects \n\nnot listed in this leaflet. You can also report side effects directly via the national reporting system \n\nlisted in Appendix V. By reporting side effects you can help provide more information on the safety of \n\nthis medicine. \n\n \n\n \n\n5. How to store SOLYMBIC \n\n \n\nKeep this medicine out of the sight and reach of children. \n\n \n\nDo not use this medicine after the expiry date which is stated on the label and carton after EXP. The \n\nexpiry date refers to the last day of that month. \n\n \n\nStore in a refrigerator (2C – 8C). Do not freeze. \n\n \n\nStore in the original carton in order to protect from light. \n\n \n\nA single SOLYMBIC pre-filled syringe may be stored at temperatures up to a maximum of 25°C for a \n\nperiod of up to 14 days. The pre-filled syringe must be protected from light, and discarded if not used \n\nwithin the 14-day period. \n\n \n\nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \n\nthrow away medicines you no longer use. These measures will help protect the environment. \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n \n\n73 \n\n6. Contents of the pack and other information \n\n \n\nWhat SOLYMBIC contains \n\n- The active substance is adalimumab. Each pre-filled syringe contains 20 mg of adalimumab in \n0.4 mL of solution or 40 mg of adalimumab in 0.8 mL of solution. \n\n- The other ingredients are glacial acetic acid, sucrose, polysorbate 80, sodium hydroxide and \nwater for injection. \n\n \n\nWhat SOLYMBIC looks like and contents of the pack \n\n \n\nSOLYMBIC is a clear and colourless to slightly yellow solution. \n\n \n\nEach pack contains 1 single-use 20 mg pre-filled syringe (with yellow plunger rod). \n\nEach pack contains 1, 2, 4 or 6 single-use 40 mg pre-filled syringes (with blue plunger rod). \n\n \n\nMarketing Authorisation Holder and Manufacturer \n\nAmgen Europe B.V. \n\nMinervum 7061 \n\nNL-4817 ZK Breda \n\nThe Netherlands \n\n \n\nMarketing Authorisation Holder \n\nAmgen Europe B.V. \n\nMinervum 7061 \n\nNL-4817 ZK Breda \n\nThe Netherlands \n\n \n\nManufacturer \n\nAmgen Technology Ireland UC \n\nPottery Road \n\nDun Laoghaire \n\nCo Dublin \n\nIreland \n\n \n\nManufacturer \n\nAmgen NV \n\nTelecomlaan 5-7 \n\n1831 Diegem \n\nBelgium \n\n \n\nFor any information about this medicine, please contact the local representative of the Marketing \n\nAuthorisation Holder: \n\n \n\nBelgië/Belgique/Belgien \n\ns.a. Amgen n.v. \n\nTel/Tél: +32 (0)2 7752711 \n\n \n\nLietuva \n\nAmgen Switzerland AG Vilniaus filialas \n\nTel: +370 5 219 7474 \n\n \n\nБългария \n\nАмджен България ЕООД \n\nТел.: +359 (0)2 424 7440 \n\n \n\nLuxembourg/Luxemburg \n\ns.a. Amgen \n\nBelgique/Belgien \n\nTel/Tél: +32 (0)2 7752711 \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n74 \n\nČeská republika \n\nAmgen s.r.o. \n\nTel: +420 221 773 500 \n\n \n\nMagyarország \n\nAmgen Kft. \n\nTel.: +36 1 35 44 700 \n\n \n\nDanmark \n\nAmgen, filial af Amgen AB, Sverige \n\nTlf: +45 39617500 \n\n \n\nMalta \n\nAmgen B.V. \n\nThe Netherlands \n\nTel: +31 (0)76 5732500 \n\n \n\nDeutschland \n\nAMGEN GmbH \n\nTel.: +49 89 1490960 \n\n \n\nNederland \n\nAmgen B.V. \n\nTel: +31 (0)76 5732500 \n\n \n\nEesti \n\nAmgen Switzerland AG Vilniaus filialas \n\nTel: +372 586 09553 \n\n \n\nNorge \n\nAmgen AB \n\nTel: +47 23308000 \n\n \n\nΕλλάδα \n\nAmgen Ελλάς Φαρμακευτικά Ε.Π.Ε. \n\nΤηλ.: +30 210 3447000 \n\n \n\nÖsterreich \n\nAmgen GmbH \n\nTel: +43 (0)1 50 217 \n\n \n\nEspaña \n\nAmgen S.A. \n\nTel: +34 93 600 18 60 \n \n\nPolska \n\nAmgen Biotechnologia Sp. z o.o. \n\nTel.: +48 22 581 3000 \n\n \n\nFrance \n\nAmgen S.A.S. \n\nTél: +33 (0)9 69 363 363 \n\n \n\nPortugal \n\nAmgen Biofarmacêutica, Lda. \n\nTel: +351 21 4220550 \n\n \n\nHrvatska \n\nAmgen d.o.o. \n\nTel: +385 (0)1 562 57 20 \n\n \n\nRomânia \n\nAmgen România SRL \n\nTel: +4021 527 3000 \n\n \n\nIreland \n\nAmgen Limited \n\nUnited Kingdom \n\nTel: +44 (0)1223 420305 \n \n\nSlovenija \n\nAMGEN zdravila d.o.o. \n\nTel: +386 (0)1 585 1767 \n\n \n\nÍsland \n\nVistor hf. \n\nSími: +354 535 7000 \n\n \n\nSlovenská republika \n\nAmgen Slovakia s.r.o. \n\nTel: +421 2 321 114 49 \n\n \n\n \n\nItalia \n\nAmgen S.r.l. \n\nTel: +39 02 6241121 \n\n \n\nSuomi/Finland \n\nAmgen AB, sivuliike Suomessa/Amgen AB, filial \n\ni Finland \n\nPuh/Tel: +358 (0)9 54900500 \n\n \n\nKύπρος \n\nC.A. Papaellinas Ltd \n\nΤηλ.: +357 22741 741 \n\n \n\nSverige \n\nAmgen AB \n\nTel: +46 (0)8 6951100 \n\n \n\nLatvija \n\nAmgen Switzerland AG Rīgas filiāle \n\nTel: +371 257 25888 \n\n \n\nUnited Kingdom \n\nAmgen Limited \n\nTel: +44 (0)1223 420305 \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n75 \n\nThis leaflet was last revised in \n\n \n\nOther sources of information \n\n \n\nDetailed information on this medicine is available on the European Medicines Agency web site: \n\nhttp://www.ema.europa.eu. \n\n \n\n--------------------------------------------------------------------------------------------------------------------------- \n\n \n\nInstructions for use: \n\nSOLYMBIC single use pre-filled syringe \n\nFor subcutaneous use \n\n \n\nGuide to parts \n\n \n\nBefore use After use \n\nPlunger rod \n\nFinger flange \n\nLabel and \n\nexpiration date \n\nSyringe barrel \n\nMedicine \n\nNeedle \n\ncap on \n \n\n \n\n \n\nUsed plunger rod \n\nFinger flange \n\nLabel and \n\nexpiration date \n\nUsed syringe barrel \n\nUsed needle \n\nNeedle cap off \n \n\nImportant: Needle is inside \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\nhttp://www.ema.europa.eu/\n\n\n \n\n76 \n\nImportant \n\nBefore you use a SOLYMBIC pre-filled syringe, read this important information: \n\n \n\nUsing your SOLYMBIC pre-filled syringe \n\n● It is important that you do not try to give the injection unless you or your caregiver has \n\nreceived training. \n\n● Do not use a SOLYMBIC pre-filled syringe if it has been dropped on a hard surface. Part of \n\nthe SOLYMBIC pre-filled syringe may be broken even if you cannot see the break. Use a new \n\nSOLYMBIC pre-filled syringe. \n\n● The needle cover of the SOLYMBIC pre-filled syringe is made from dry natural rubber, which \n\ncontains latex. Tell your healthcare provider if you are allergic to latex. \n\n \n\nStep 1: Prepare \n \n\nA. Remove the number of SOLYMBIC pre-filled syringes you need from the package. \n\n \n\nGrab the syringe \n\nbarrel to remove \n\nthe syringe from \n\nthe tray. \n\n \n\n \n\n \n\nPlace your finger or thumb on \n\nedge of tray to secure it while \n\nyou remove the syringe. \n\nGrab Here \n\nPut the original package with any unused syringes back in the refrigerator. \n\n \n\nFor safety reasons: \n\n● Do not grasp the plunger rod. \n\n● Do not grasp the needle cap. \n\n● Do not remove the needle cap until you are ready to inject. \n\n● Do not remove the finger flange. This is part of the syringe. \n\nFor a more comfortable injection, leave the syringe at room temperature for 15 to 30 minutes before \n\ninjecting. \n\n● Do not put the syringe back in the refrigerator once it has reached room temperature. \n\n● Do not try to warm the syringe by using a heat source such as hot water or microwave. \n\n● Do not leave the syringe in direct sunlight. \n\n● Do not shake the syringe. \n\nImportant: Always hold the pre-filled syringe by the syringe barrel. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n77 \n\nB. Inspect the SOLYMBIC pre-filled syringe. \n\n Syringe barrel \n\nLabel expiration \n\ndate Plunger rod \n\n \nNeedle cap on Medicine Finger flange \n\n \n\nAlways hold the syringe by the syringe barrel. \n\n \n\nMake sure the medicine in the syringe is clear and colourless to slightly yellow. \n\n● Do not use the syringe if: \n\n - The medicine is cloudy or discoloured or contains flakes, or particles. \n- Any part appears cracked or broken. \n- The needle cap is missing or not securely attached. \n- The expiration date printed on the label has passed. \n\nIn all cases, use a new syringe. \n\n \n\nC. Gather all materials needed for your injection(s). \n\nWash your hands thoroughly with soap and water. \n\nOn a clean, well-lit work surface, place a new, pre-filled syringe. \n\n \n\nYou will also need these additional items, as they are not included in the carton: \n\n● Alcohol wipes \n\n● Cotton ball or gauze pad \n\n● Plaster \n\n● Sharps disposal container \n\n \n\n \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n78 \n\nD. Prepare and clean your injection site(s). \n\n \nBelly \n\n \n\nThigh \n\n \n\nYou can use: \n\n● Your thigh \n\n● Belly, except for a 2 inch (5 centimetres) area around your belly button \n\n \n\nClean your injection site with an alcohol wipe. Let your skin dry. \n\n● Do not touch this area again before injecting. \n\n● If you want to use the same injection site, make sure it is not the same spot on the injection \n\nsite you used for a previous injection. \n\n - Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting \ninto areas with scars or stretch marks. \n\n● If you have psoriasis, you should avoid injecting directly into raised, thick, red, or scaly skin \n\npatch or lesion. \n\n \n\nStep 2: Get ready \n \n\nE. Pull the needle cap straight out and away from your body when you are ready to inject. \n\n \n\nIt is normal to see a drop of liquid at the end of the needle. \n\n● Do not twist or bend the needle cap. \n\n● Do not put the needle cap back onto the syringe. \n\n● Do not remove the needle cap from the syringe until you are ready to inject. \n\nImportant: Throw the needle cap into the sharps disposal container provided. \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n79 \n\nF. Pinch your injection site to create a firm surface. \n\n \n\nPinch the skin firmly between your thumb and fingers, creating an area about 2 inch (5 centimetres) \n\nwide. \n\nImportant: Keep the skin pinched while injecting. \n\n \n\nStep 3: Inject \n \n\nG. Hold the pinch. With the needle cap off, insert the syringe into your skin at 45 to 90 degrees. \n\n \n\nDo not place your finger on the plunger rod while inserting the needle. \n\n \n\nH. Using slow and constant pressure, push the plunger rod all the way down until it stops moving. \n\n \n\n \n\nI. When done, release your thumb, and gently lift the syringe off of your skin. \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n80 \n\nStep 4: Finish \n \n\nJ. Discard the used syringe and the needle cap. \n\n \n\n● Do not reuse the used syringe. \n\n● Do not use any medicine that is left in the used syringe. \n\n● Put the used SOLYMBIC syringe in a sharps disposal container immediately after use. Do not \n\nthrow away (dispose of) the syringe in your household waste. \n\n● Talk with your doctor or pharmacist about proper disposal. There may be local guidelines for \n\ndisposal. \n\n● Do not recycle the syringe or sharps disposal container or throw them into the household \n\nwaste. \n\nImportant: Always keep the sharps disposal container out of the sight and reach of children. \n\n \n\nK. Examine the injection site. \n\nIf there is blood, press a cotton ball or gauze pad on your injection site. Do not rub the injection site. \n\nApply a plaster if needed. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n81 \n\nPackage leaflet: Information for the user \n\n \n\nSOLYMBIC 40 mg solution for injection in a pre-filled pen \n\nadalimumab \n\n \n\nThis medicine is subject to additional monitoring. This will allow quick identification of new safety \n\ninformation. You can help by reporting any side effects you may get. See the end of section 4 for how \n\nto report side effects. \n\n \n\nRead all of this leaflet carefully before you start using this medicine because it contains \n\nimportant information for you. \n\n- Keep this leaflet. You may need to read it again. \n- Your doctor will also give you a Patient Alert Card, which contains important safety \n\ninformation that you need to be aware of before you are given SOLYMBIC and during \n\ntreatment with SOLYMBIC. Keep this Patient Alert Card with you. \n\n- If you have any further questions, ask your doctor or pharmacist. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n\n- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side \n\neffects not listed in this leaflet (see section 4). \n\n \n\nWhat is in this leaflet \n\n \n\n1. What SOLYMBIC is and what it is used for \n\n2. What you need to know before you use SOLYMBIC \n\n3. How to use SOLYMBIC \n\n4. Possible side effects \n\n5. How to store SOLYMBIC \n\n6. Contents of the pack and other information \n\n \n\n \n\n1. What SOLYMBIC is and what it is used for \n\n \n\nSOLYMBIC contains the active substance adalimumab, a selective immuno suppressive agent. \n\n \n\nSOLYMBIC is intended for treatment of rheumatoid arthritis, enthesitis-related arthritis in children 6 \n\nto 17 years, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of \n\nankylosing spondylitis, psoriatic arthritis, psoriasis, hidradenitis suppurativa, paediatric psoriasis \n\n(patients weighing either 23 to 28 kg or 47 kg and greater), Crohn’s disease in adults and children, \n\nulcerative colitis and non-infectious uveitis affecting the back of the eye. It is a medicine that \n\ndecreases the inflammation process of these diseases. The active ingredient, adalimumab, is a human \n\nmonoclonal antibody produced by cultured cells. Monoclonal antibodies are proteins that recognise \n\nand bind to other unique proteins. \n\n \n\nAdalimumab binds to a specific protein (tumour necrosis factor or TNFα), which is present at \n\nincreased levels in inflammatory diseases such as rheumatoid arthritis, enthesitis-related arthritis, \n\nankylosing spondylitis, axial spondyloarthritis without radiographic evidence of ankylosing \n\nspondylitis, psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis \n\nand non-infectious uveitis affecting the back of the eye. \n\n \n\nRheumatoid arthritis \n\n \n\nRheumatoid arthritis is an inflammatory disease of the joints. \n\n \n\nSOLYMBIC is used to treat rheumatoid arthritis in adults. If you have moderate to severe active \n\nrheumatoid arthritis, you may first be given other disease-modifying medicines, such as methotrexate. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n82 \n\nIf you do not respond well enough to these medicines, you will be given SOLYMBIC to treat your \n\nrheumatoid arthritis. \n\n \n\nSOLYMBIC can also be used to treat severe, active and progressive rheumatoid arthritis without \n\nprevious methotrexate treatment. \n\n \n\nSOLYMBIC slows down the damage to the cartilage and bone of the joints caused by the disease and \n\nto improve physical function. \n\n \n\nUsually, SOLYMBIC is used with methotrexate. If your doctor determines that methotrexate is \n\ninappropriate, SOLYMBIC can be given alone. \n\n \n\nEnthesitis-related arthritis \n\n \n\nEnthesitis-related arthritis is an inflammatory disease of the joints. \n\n \n\nSOLYMBIC is used to treat enthesitis-related arthritis in children and adolescents aged 6 to 17 years. \n\nYou may first be given other disease-modifying medicines, such as methotrexate. If you do not \n\nrespond well enough to these medicines, you will be given SOLYMBIC to treat your enthesitis-related \n\narthritis. \n\n \n\nAnkylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing \n\nspondylitis \n\n \n\nAnkylosing spondylitis and axial spondyloarthritis without radiographic evidence of ankylosing \n\nspondylitis, are inflammatory diseases of the spine. \n\n \n\nSOLYMBIC is used to treat ankylosing spondylitis and axial spondyloarthritis without radiographic \n\nevidence of ankylosing spondylitis in adults. If you have ankylosing spondylitis or axial \n\nspondyloarthritis without radiographic evidence of ankylosing spondylitis, you will first be given other \n\nmedicines. If you do not respond well enough to these medicines, you will be given SOLYMBIC to \n\nreduce the signs and symptoms of your disease. \n\n \n\nPsoriatic arthritis \n\n \n\nPsoriatic arthritis is an inflammation of the joints associated with psoriasis. \n\n \n\nSOLYMBIC is used to treat psoriatic arthritis in adults. SOLYMBIC slows down the damage to the \n\ncartilage and bone of the joints caused by the disease and to improve physical function. \n\n \n\nPlaque psoriasis in adults and children \n\n \n\nPlaque psoriasis is a skin condition that causes red, flaky, crusty patches of skin covered with silvery \n\nscales. Plaque psoriasis can also affect the nails, causing them to crumble, become thickened and lift \n\naway from the nail bed which can be painful. Psoriasis is believed to be caused by a problem with the \n\nbody’s immune system that leads to an increased production of skin cells. \n\n \n\nSOLYMBIC is used to treat moderate to severe plaque psoriasis in adults. SOLYMBIC is also used to \n\ntreat severe plaque psoriasis in children and adolescents weighing either 23 to 28 kg or 47 kg or \n\ngreater for whom topical therapy and phototherapies have either not worked very well or are not \n\nsuitable. \n\n \n\nHidradenitis suppurativa \n\n \n\nHidradenitis suppurativa (sometimes called acne inversa) is a chronic and often painful inflammatory \n\nskin disease. Symptoms may include tender nodules (lumps) and abscesses (boils) that may leak pus. \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n83 \n\nIt most commonly affects specific areas of the skin, such as under the breasts, the armpits, inner \n\nthighs, groin and buttocks. Scarring may also occur in affected areas. \n\n \n\nSOLYMBIC is used to treat hidradenitis suppurativa in adults. SOLYMBIC can reduce the number of \n\nnodules and abscesses you have, and the pain that is often associated with the disease. \n\n \n\nCrohn’s disease in adults and children \n\n \n\nCrohn’s disease is an inflammatory disease of the digestive tract. \n\n \nSOLYMBIC is used to treat Crohn’s disease in adults and children aged 6 to 17 years. If you have \n\nCrohn’s disease you will first be given other medicines. If you do not respond well enough to these \n\nmedicines, you will be given SOLYMBIC to reduce the signs and symptoms of your Crohn’s disease. \n\n \n\nUlcerative colitis \n\n \n\nUlcerative colitis is an inflammatory disease of the bowel. \n\n \n\nSOLYMBIC is used to treat ulcerative colitis in adults. If you have ulcerative colitis you will first be \n\ngiven other medicines. If you do not respond well enough to these medicines, you will be given \n\nSOLYMBIC to reduce the signs and symptoms of your disease. \n\n \n\nNon-infectious uveitis affecting the back of the eye \n\n \n\nNon-infectious uveitis is an inflammatory disease affecting certain parts of the eye. SOLYMBIC is \n\nused to treat adults with non-infectious uveitis with inflammation affecting the back of the eye. This \n\ninflammation leads to a decrease of vision and/or the presence of floaters in the eye (black dots or \n\nwispy lines that move across the field of vision). SOLYMBIC works by reducing this inflammation. \n\n \n\n \n\n2. What you need to know before you use SOLYMBIC \n\n \n\nDo not use SOLYMBIC: \n\n \n\n- if you are allergic to adalimumab or any of the other ingredients of this medicine (listed in \n\nsection 6). \n\n- if you have a severe infection, including active tuberculosis (see “Warnings and precautions”). \n\nIt is important that you tell your doctor if you have symptoms of infections, e.g. fever, wounds, \n\nfeeling tired, dental problems. \n\n- if you have moderate or severe heart failure. It is important to tell your doctor if you have had or \n\nhave a serious heart condition (see “Warnings and precautions”). \n\n \n\nWarnings and precautions \n\n \n\nTalk to your doctor or pharmacist before using SOLYMBIC: \n\n \n\n- If you experience allergic reactions with symptoms such as chest tightness, wheezing, dizziness, \n\nswelling or rash do not inject more SOLYMBIC and contact your doctor immediately since, in \n\nrare cases, these reactions can be life threatening. \n \n\n- If you have an infection, including long-term or localised infection (for example, leg ulcer) \n\nconsult your doctor before starting SOLYMBIC. If you are unsure, please contact your doctor. \n\n \n\n- You might get infections more easily while you are receiving SOLYMBIC treatment. This risk \n\nmay increase if your lung function is impaired. These infections may be serious and include \n\ntuberculosis, infections caused by viruses, fungi, parasites or bacteria, or other opportunistic \n\ninfections and sepsis that may, in rare cases, be life-threatening. It is important to tell your \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n84 \n\ndoctor if you get symptoms such as fever, wounds, feeling tired or dental problems. Your doctor \n\nmay recommend temporary discontinuation of SOLYMBIC. \n\n \n\n- As cases of tuberculosis have been reported in patients treated with adalimumab, your doctor \n\nwill check you for signs and symptoms of tuberculosis before starting SOLYMBIC. This will \n\ninclude a thorough medical evaluation including your medical history and appropriate screening \n\ntests (for example chest x-ray and a tuberculin test). The conduct and results of these tests \n\nshould be recorded on your Patient Alert Card. It is very important that you tell your doctor if \n\nyou have ever had tuberculosis, or if you have been in close contact with someone who has had \n\ntuberculosis. Tuberculosis can develop during therapy even if you have received preventative \n\ntreatment for tuberculosis. If symptoms of tuberculosis (persistent cough, weight loss, \n\nlistlessness, mild fever), or any other infection appear during or after therapy, tell your doctor \n\nimmediately. \n\n \n\n- Advise your doctor if you reside or travel in regions where fungal infections such as \n\nhistoplasmosis coccidioidomycosis or blastomycosis are endemic. \n\n \n\n- Advise your doctor if you have a history of recurrent infections or other conditions that increase \n\nthe risk of infections. \n\n \n\n- Advise your doctor if you are a carrier of the hepatitis B virus (HBV), if you have active HBV \n\nor if you think you might be at risk of contracting HBV. Your doctor should test you for HBV. \n\nSOLYMBIC can cause reactivation of HBV in people who carry this virus. In some rare cases, \n\nespecially if you are taking other medicines that suppress the immune system, reactivation of \n\nHBV can be life-threatening. \n\n \n- If you are over 65 years you may be more susceptible to infections while taking SOLYMBIC. \n\nYou and your doctor should pay special attention to signs of infection while you are being \n\ntreated with SOLYMBIC. It is important to tell your doctor if you get symptoms of infections, \n\nsuch as fever, wounds, feeling tired or dental problems. \n\n \n\n- If you are about to undergo surgery or dental procedures please inform your doctor that you are \n\ntaking SOLYMBIC. Your doctor may recommend temporary discontinuation of SOLYMBIC. \n\n \n\n- If you have or develop demyelinating disease such as multiple sclerosis, your doctor will decide \n\nif you should receive or continue to receive SOLYMBIC. Tell your doctor immediately if you \n\nexperience symptoms like changes in your vision, weakness in your arms or legs or numbness \n\nor tingling in any part of your body. \n\n \n\n- Certain vaccines may cause infections and should not be given while receiving SOLYMBIC. \n\nPlease check with your doctor before you receive any vaccines. It is recommended that children, \n\nif possible, be brought up to date with all immunisations in agreement with current \n\nimmunisation guidelines prior to initiating SOLYMBIC therapy. If you received SOLYMBIC \n\nwhile you were pregnant, your baby may be at higher risk for getting such an infection for up to \n\napproximately five months after the last dose you received during pregnancy. It is important that \n\nyou tell your baby's doctors and other health care professionals about your SOLYMBIC use \n\nduring your pregnancy so they can decide when your baby should receive any vaccine. \n\n \n\n- If you have mild heart failure and you are being treated with SOLYMBIC, your heart failure \n\nstatus must be closely monitored by your doctor. It is important to tell your doctor if you have \n\nhad or have a serious heart condition. If you develop new or worsening symptoms of heart \n\nfailure (e.g. shortness of breath, or swelling of your feet), you must contact your doctor \n\nimmediately. \n\n \n\n- In some patients the body may fail to produce enough of the blood cells that help your body \n\nfight infections or help you to stop bleeding. If you develop a fever that does not go away, \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n85 \n\nbruise or bleed very easily or look very pale, call your doctor right away. Your doctor may \n\ndecide to stop treatment. \n\n \n\n- There have been very rare cases of certain kinds of cancer in children and adult patients taking \n\nadalimumab or other TNF blockers. People with more serious rheumatoid arthritis that have had \n\nthe disease for a long time may have a higher than average risk of getting lymphoma (a type of \n\ncancer that affects the lymph system), and leukaemia (a type of cancer that affects the blood and \n\nbone marrow). If you take SOLYMBIC the risk of getting lymphoma, leukaemia, or other \n\ncancers may increase. On rare occasions, a specific and severe type of lymphoma has been \n\nobserved in some patients taking adalimumab. Some of those patients were also treated with \n\nazathioprine or 6-mercaptopurine. Tell your doctor if you are taking azathioprine or 6-\n\nmercaptopurine with SOLYMBIC. In addition, cases of non-melanoma skin cancer have been \n\nobserved in patients taking adalimumab. If new skin lesions appear during or after therapy or if \n\nexisting lesions change appearance, tell your doctor. \n\n \n\n- There have been cases of cancers other than lymphoma in patients with a specific type of lung \n\ndisease called Chronic Obstructive Pulmonary Disease (COPD) treated with another TNF \n\nblocker. If you have COPD, or are a heavy smoker, you should discuss with your doctor \n\nwhether treatment with a TNF blocker is appropriate for you. \n\n \n\nThe needle cover of the pre-filled pen is made from dry natural rubber (a derivative of latex), which \n\nmay cause allergic reactions. \n\n \n\nIn order to improve the traceability of this medicine, your doctor or pharmacist should record the \n\ntradename and the lot number of the product you have been given in your patient file. You may also \n\nwish to make a note of these details in case you are asked for this information in the future. \n\n \n\nChildren and adolescents \n\n \n- Vaccinations: if possible children should be up to date with all vaccinations before using \n\nSOLYMBIC. \n\n \n\n- Do not use the 40 mg pre-filled pen if doses other than 40 mg are recommended. \n\n \n\nOther medicines and SOLYMBIC \n\n \n\nTell your doctor or pharmacist if you are taking, have recently taken or might take any other \n\nmedicines. \n\n \n\nSOLYMBIC can be taken together with methotrexate or certain disease-modifying anti-rheumatic \n\nagents (sulfasalazine, hydroxychloroquine, leflunomide and injectable gold preparations), steroids or \n\npain medications including non-steroidal anti-inflammatory drugs (NSAIDs). \n\n \n\nYou should not take SOLYMBIC with medicines containing the active substance, anakinra or \n\nabatacept. If you have questions, please ask your doctor. \n\n \n\nPregnancy and breast-feeding \n\n \n\nThe effects of SOLYMBIC in pregnant women are not known and so the use of SOLYMBIC in \n\npregnant women is not recommended. You are advised to avoid becoming pregnant and must use \n\nadequate contraception while using SOLYMBIC and for at least 5 months after the last SOLYMBIC \n\ntreatment. If you become pregnant, you should consult your doctor. \n\n \n\nIt is not known whether SOLYMBIC passes into breast milk. \n\n \n\nIf you are a breast-feeding mother, you should stop breast-feeding during SOLYMBIC treatment and \n\nfor at least 5 months after the last SOLYMBIC treatment. If you received SOLYMBIC during your \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n86 \n\npregnancy, your baby may have a higher risk for getting an infection. It is important that you tell your \n\nbaby’s doctors and other health care professionals about your SOLYMBIC use during your pregnancy \n\nbefore the baby receives any vaccine (for more information see section on vaccination). \n\n \n\nIf you think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for \n\nadvice before taking this medicine. \n\n \n\nDriving and using machines \n\n \n\nSOLYMBIC may have a minor influence on your ability to drive, cycle or use machines. Room \n\nspinning sensation and vision disturbances may occur after taking SOLYMBIC. \n\n \n\nSOLYMBIC contains sodium \n\n \n\nThis medicine contains less than 1 mmol of sodium (23 mg) per 0.8 mL dose, i.e. essentially ‘sodium-\n\nfree’. \n\n \n\n \n\n3. How to use SOLYMBIC \n\n \n\nAlways use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor \n\nor pharmacist if you are not sure. \n\n \n\nAdults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or axial spondyloarthritis \n\nwithout radiographic evidence of ankylosing spondylitis \n\n \n\nSOLYMBIC is injected under the skin (subcutaneous use). The usual dose for adults with rheumatoid \n\narthritis, ankylosing spondylitis, axial spondyloarthritis without radiographic evidence of ankylosing \nspondylitis, and for patients with psoriatic arthritis is 40 mg given every other week as a single dose. \n\n \n\nIn rheumatoid arthritis, methotrexate is continued while using SOLYMBIC. If your doctor determines \n\nthat methotrexate is inappropriate, SOLYMBIC can be given alone. \n\n \n\nIf you have rheumatoid arthritis and you do not receive methotrexate with your SOLYMBIC therapy, \n\nyour doctor may decide to give 40 mg every week. \n\n \n\nChildren with enthesitis-related arthritis \n\n \n\nThe recommended dose of SOLYMBIC for patients with enthesitis-related arthritis, aged 6 to 17 years \n\ndepends on the height and weight of the child. Your child’s doctor will tell you the correct dose to use. \n\n \n\nAdults with psoriasis \n\n \n\nThe usual dose for adults with psoriasis is an initial dose of 80 mg, followed by 40 mg given every \n\nother week starting one week after the initial dose. You should continue to inject SOLYMBIC for as \n\nlong as your doctor has told you. Depending on your response, your doctor may increase the dose \n\nfrequency to 40 mg every week. \n\n \n\nChildren or adolescents with plaque psoriasis \n\n \n\nThe recommended dose of SOLYMBIC for patients aged 4 to 17 years with plaque psoriasis depends \n\non the weight of your child. SOLYMBIC should only be used in patients weighing either 23 to 28 kg \n\nor 47 kg and greater. Your child’s doctor will tell you the correct dose to use. \n\n \n\nAdults with hidradenitis suppurativa \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n87 \n\nThe usual dose regimen for hidradenitis suppurativa is an initial dose of 160 mg (as four 40 mg \n\ninjections in one day or two 40 mg injections per day for two consecutive days), followed by an 80 mg \n\ndose (as two 40 mg injections on the same day) two weeks later. After two further weeks, continue \n\nwith a dose of 40 mg every week. It is recommended that you use an antiseptic wash daily on the \n\naffected areas. \n\n \n\nAdults with Crohn’s disease \n\n \n\nThe usual dose regimen for Crohn’s disease is 80 mg initially followed by 40 mg every other week \n\ntwo weeks later. If a faster response is required, your doctor may prescribe an initial dose of 160 mg \n\n(as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), \n\nfollowed by 80 mg two weeks later, and thereafter as 40 mg every other week. Depending on your \n\nresponse, your doctor may increase the dose frequency to 40 mg every week. \n\n \n\nChildren or adolescents with Crohn's disease \n\n \n\nChildren or adolescents weighing less than 40 kg: \n\n \n\nThe usual dose regimen is 40 mg initially followed by 20 mg two weeks later. If a faster response is \n\nrequired, your doctor may prescribe an initial dose of 80 mg (as two 40 mg injections in 1 day) \n\nfollowed by 40 mg two weeks later. \n\n \n\nThereafter, the usual dose is 20 mg every other week. Depending on your response, your doctor may \n\nincrease the dose frequency to 20 mg every week. \n\n \n\nDo not use the 40 mg pre-filled pen for the 20 mg dose in children or adolescent weighing less than \n\n40 kg with Crohn’s disease. The 20 mg solution for injection in pre-filled syringe can be used for the \n\n20 mg dose. \n\n \n\nChildren or adolescents weighing 40 kg or more: \n\n \n\nThe usual dose regimen is 80 mg initially followed by 40 mg two weeks later. If a faster response is \n\nrequired, your doctor may prescribe an initial dose of 160 mg (as four 40 mg injections in 1 day or as \n\ntwo 40 mg injections per day for 2 consecutive days) followed by 80 mg two weeks later. \n\n \n\nThereafter, the usual dose is 40 mg every other week. Depending on your response, your doctor may \n\nincrease the dose frequency to 40 mg every week. \n\n \n\nAdults with ulcerative colitis \n\n \n\nThe usual SOLYMBIC dose for adults with ulcerative colitis is 160 mg initially (dose can be \n\nadministered as four 40 mg injections in one day or as two 40 mg injections per day for two \n\nconsecutive days) followed by 80 mg two weeks later, then 40 mg every other week. Depending on \n\nyour response, your doctor may increase the dose to 40 mg every week. \n\n \n\nAdults with non-infectious uveitis \n\n \n\nThe usual dose for adults with non-infectious uveitis is an initial dose of 80 mg, followed by 40 mg \n\ngiven every other week starting one week after the initial dose. You should continue to inject \n\nSOLYMBIC for as long as your doctor has told you. \n\n \n\nIn non-infectious uveitis, corticosteroids or other medicines that influence the immune system may be \n\ncontinued while using SOLYMBIC. SOLYMBIC can also be given alone. \n \n\nMethod and route of administration \n\n \n\nSOLYMBIC is administered by injection under the skin (subcutaneous injection). \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n88 \n\n \n\nIf you use more SOLYMBIC than you should \n\n \n\nIf you accidentally inject SOLYMBIC more frequently than told to by your doctor or pharmacist, you \n\nshould call your doctor or pharmacist and tell him/her that you have taken more. Always take the outer \n\ncarton of this medicine with you, even if it is empty. \n\n \n\nIf you forget to use SOLYMBIC \n\n \n\nIf you forget to give yourself an injection, you should inject it as soon as you remember. Then take \n\nyour next dose as you would have on your originally scheduled day, had you not forgotten a dose. \n\n \n\nIf you stop using SOLYMBIC \n\n \n\nThe decision to stop using SOLYMBIC should be discussed with your doctor. Your symptoms may \n\nreturn upon discontinuation. \n\n \n\nIf you have any further questions on the use of this medicine, ask your doctor or pharmacist. \n\n \n\n \n\n4. Possible side effects \n\n \n\nLike all medicines, this medicine can cause side effects, although not everybody gets them. Most side \n\neffects are mild to moderate. However, some may be serious and require treatment. Side effects may \n\noccur at least up to 4 months after the last SOLYMBIC injection. \n\n \n\nTell your doctor immediately if you notice any of the following: \n\n• severe rash, hives or other signs of allergic reaction; \n\n• swollen face, hands, feet; \n\n• trouble breathing, swallowing; \n\n• shortness of breath with exertion or upon lying down or swelling of the feet. \n \n\nTell your doctor as soon as possible if you notice any of the following: \n\n• signs of infection such as fever, feeling sick, wounds, dental problems, burning on urination; \n\n• feeling weak or tired; \n\n• coughing; \n\n• tingling; \n\n• numbness; \n\n• double vision; \n\n• arm or leg weakness; \n\n• a bump or open sore that doesn't heal; \n\n• signs and symptoms suggestive of blood disorders such as persistent fever, bruising, bleeding, \n\npaleness. \n\n \n\nThe symptoms described above can be signs of the below listed side effects, which have been \n\nobserved with adalimumab: \n\n \n\nVery common side effects (may affect more than 1 in 10 people): \n\n• injection site reactions (including pain, swelling, redness or itching); \n\n• respiratory tract infections (including cold, runny nose, sinus infection, pneumonia); \n\n• headache; \n\n• abdominal pain; \n\n• nausea and vomiting; \n\n• rash; \n\n• musculoskeletal pain. \n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n89 \n\nCommon side effects (may affect up to 1 in 10 people): \n\n• serious infections (including blood poisoning and influenza); \n\n• skin infections (including cellulitis and shingles); \n\n• ear infections; \n\n• oral infections (including tooth infections and cold sores); \n\n• reproductive tract infections; \n\n• urinary tract infection; \n\n• fungal infections; \n\n• joint infections; \n\n• benign tumours; \n\n• skin cancer; \n\n• allergic reactions (including seasonal allergy); \n\n• dehydration; \n\n• mood swings (including depression); \n\n• anxiety; \n\n• difficulty sleeping; \n\n• sensation disorders such as tingling, prickling or numbness; \n\n• migraine; \n\n• nerve root compression (including low back pain and leg pain); \n\n• vision disturbances; \n\n• eye inflammation; \n\n• inflammation of the eye lid and eye swelling; \n\n• vertigo; \n\n• sensation of heart beating rapidly; \n\n• high blood pressure; \n\n• flushing; \n\n• haematoma; \n\n• cough; \n\n• asthma; \n\n• shortness of breath; \n\n• gastrointestinal bleeding; \n\n• dyspepsia (indigestion, bloating, heart burn); \n\n• acid reflux disease; \n\n• sicca syndrome (including dry eyes and dry mouth); \n\n• itching; \n\n• itchy rash; \n\n• bruising; \n\n• inflammation of the skin (such as eczema); \n\n• breaking of finger nails and toe nails; \n\n• increased sweating; \n\n• hair loss; \n\n• new onset or worsening of psoriasis; \n\n• muscle spasms; \n\n• blood in urine; \n\n• kidney problems; \n\n• chest pain; \n\n• oedema; \n\n• fever; \n\n• reduction in blood platelets which increases risk of bleeding or bruising; \n\n• impaired healing. \n\n \n\nUncommon side effects (may affect up to 1 in 100 people): \n\n• opportunistic infections (which include tuberculosis and other infections that occur when \n\nresistance to disease is lowered); \n\n• neurological infections (including viral meningitis); \n\n• eye infections; \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n90 \n\n• bacterial infections; \n\n• diverticulitis (inflammation and infection of the large intestine); \n\n• cancer; \n\n• cancer that affects the lymph system; \n\n• melanoma; \n\n• immune disorders that could affect the lungs, skin and lymph nodes (most commonly presenting \n\nas sarcoidosis); \n\n• vasculitis (inflammation of blood vessels); \n\n• tremor; \n\n• neuropathy; \n\n• stroke; \n\n• double vision; \n\n• hearing loss, buzzing; \n\n• sensation of heart beating irregularly such as skipped beats; \n\n• heart problems that can cause shortness of breath or ankle swelling; \n\n• heart attack; \n\n• a sac in the wall of a major artery, inflammation and clot of a vein, blockage of a blood vessel; \n\n• lung diseases causing shortness of breath (including inflammation); \n\n• pulmonary embolism (blockage in an artery of the lung); \n\n• pleural effusion (abnormal collection of fluid in the pleural space); \n\n• inflammation of the pancreas which causes severe pain in the abdomen and back; \n\n• difficulty in swallowing; \n\n• facial oedema; \n\n• gallbladder inflammation, gallbladder stones; \n\n• fatty liver; \n\n• night sweats; \n\n• scar; \n\n• abnormal muscle breakdown; \n\n• systemic lupus erythematosus (including inflammation of skin, heart, lung, joints and other \n\norgan systems); \n\n• sleep interruptions; \n\n• impotence; \n\n• inflammations. \n \n\nRare side effects (may affect up to 1 in 1,000 people): \n\n• leukaemia (cancer affecting the blood and bone marrow); \n\n• severe allergic reaction with shock; \n\n• multiple sclerosis; \n\n• nerve disorders (such as eye nerve inflammation and Guillain-Barré syndrome that may cause \n\nmuscle weakness, abnormal sensations, tingling in the arms and upper body); \n\n• heart stops pumping; \n\n• pulmonary fibrosis (scarring of the lung); \n\n• intestinal perforation; \n\n• hepatitis; \n• reactivation of hepatitis B; \n\n• autoimmune hepatitis (inflammation of the liver caused by the body's own immune system); \n\n• cutaneous vasculitis (inflammation of blood vessels in the skin); \n\n• Stevens-Johnson syndrome (early symptoms include malaise, fever, headache and rash); \n\n• facial oedema associated with allergic reactions; \n\n• erythema multiforme (inflammatory skin rash); \n\n• lupus-like syndrome. \n \n\nNot known (frequency cannot be estimated from available data): \n\n• hepatosplenic T-cell lymphoma (a rare blood cancer that is often fatal); \n\n• Merkel cell carcinoma (a type of skin cancer); \n\n• liver failure; \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n91 \n\n• worsening of a condition called dermatomyositis (seen as a skin rash accompanying muscle \n\nweakness). \n\n \n\nSome side effects observed with adalimumab may not have symptoms and may only be discovered \n\nthrough blood tests. These include: \n\n \n\nVery common side effects (may affect more than 1 in 10 people): \n\n• low blood measurements for white blood cells; \n\n• low blood measurements for red blood cells; \n\n• increased lipids in the blood; \n\n• elevated liver enzymes. \n \n\nCommon side effects (may affect up to 1 in 10 people): \n\n• high blood measurements for white blood cells; \n\n• low blood measurements for platelets; \n\n• increased uric acid in the blood; \n\n• abnormal blood measurements for sodium; \n\n• low blood measurements for calcium; \n\n• low blood measurements for phosphate; \n\n• high blood sugar; \n\n• high blood measurements for lactate dehydrogenase; \n\n• autoantibodies present in the blood. \n \n\nRare side effects (may affect up to 1 in 1,000 people): \n\n• low blood measurements for white blood cells, red blood cells and platelet count. \n \n\nNot known (frequency cannot be estimated from available data): \n\n• liver failure. \n\n \nReporting of side effects \n\n \n\nIf you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects \n\nnot listed in this leaflet. You can also report side effects directly via the national reporting system \nlisted in Appendix V. By reporting side effects you can help provide more information on the safety of \n\nthis medicine. \n\n \n\n \n\n5. How to store SOLYMBIC \n\n \n\nKeep this medicine out of the sight and reach of children. \n\n \n\nDo not use this medicine after the expiry date which is stated on the label and carton after EXP. The \n\nexpiry date refers to the last day of that month. \n\n \n\nStore in a refrigerator (2C – 8C). Do not freeze. \n\n \n\nStore in the original carton in order to protect from light. \n\n \n\nA single SOLYMBIC pre-filled pen may be stored at temperatures up to a maximum of 25°C for a \n\nperiod of up to 14 days. The pre-filled pen must be protected from light, and discarded if not used \n\nwithin the 14-day period. \n\n \n\nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \n\nthrow away medicines you no longer use. These measures will help protect the environment. \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n \n\n92 \n\n6. Contents of the pack and other information \n\n \n\nWhat SOLYMBIC contains \n\n- The active substance is adalimumab. Each pre-filled pen contains 40 mg of adalimumab in \n0.8 mL of solution. \n\n- The other ingredients are glacial acetic acid, sucrose, polysorbate 80, sodium hydroxide and \nwater for injection. \n\n \n\nWhat SOLYMBIC looks like and contents of the pack \n\n \n\nSOLYMBIC is a clear and colourless to slightly yellow solution. \n\n \n\nEach pack contains 1, 2, 4, or 6 single use SureClick pre-filled pens. \n\n \n\nMarketing Authorisation Holder and Manufacturer \n\nAmgen Europe B.V. \n\nMinervum 7061 \n\nNL-4817 ZK Breda \n\nThe Netherlands \n\n \n\nMarketing Authorisation Holder \n\nAmgen Europe B.V. \n\nMinervum 7061 \n\nNL-4817 ZK Breda \n\nThe Netherlands \n\n \n\nManufacturer \n\nAmgen Technology Ireland UC \n\nPottery Road \n\nDun Laoghaire \n\nCo Dublin \n\nIreland \n\n \n\nManufacturer \n\nAmgen NV \n\nTelecomlaan 5-7 \n\n1831 Diegem \n\nBelgium \n\nFor any information about this medicine, please contact the local representative of the Marketing \n\nAuthorisation Holder: \n\n \n\nBelgië/Belgique/Belgien \n\ns.a. Amgen n.v. \n\nTel/Tél: +32 (0)2 7752711 \n\n \n\nLietuva \n\nAmgen Switzerland AG Vilniaus filialas \n\nTel: +370 5 219 7474 \n\n \n\nБългария \n\nАмджен България ЕООД \n\nТел.: +359 (0)2 424 7440 \n\n \n\nLuxembourg/Luxemburg \n\ns.a. Amgen \n\nBelgique/Belgien \n\nTel/Tél: +32 (0)2 7752711 \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n93 \n\nČeská republika \n\nAmgen s.r.o. \n\nTel: +420 221 773 500 \n\n \n\nMagyarország \n\nAmgen Kft. \n\nTel.: +36 1 35 44 700 \n\n \n\nDanmark \n\nAmgen, filial af Amgen AB, Sverige \n\nTlf: +45 39617500 \n\n \n\nMalta \n\nAmgen B.V. \n\nThe Netherlands \n\nTel: +31 (0)76 5732500 \n\n \n\nDeutschland \n\nAMGEN GmbH \n\nTel.: +49 89 1490960 \n\n \n\nNederland \n\nAmgen B.V. \n\nTel: +31 (0)76 5732500 \n\n \n\nEesti \n\nAmgen Switzerland AG Vilniaus filialas \n\nTel: +372 586 09553 \n\n \n\nNorge \n\nAmgen AB \n\nTel: +47 23308000 \n\n \n\nΕλλάδα \n\nAmgen Ελλάς Φαρμακευτικά Ε.Π.Ε. \n\nΤηλ.: +30 210 3447000 \n\n \n\nÖsterreich \n\nAmgen GmbH \n\nTel: +43 (0)1 50 217 \n\n \n\nEspaña \n\nAmgen S.A. \n\nTel: +34 93 600 18 60 \n \n\nPolska \n\nAmgen Biotechnologia Sp. z o.o. \n\nTel.: +48 22 581 3000 \n\n \n\nFrance \n\nAmgen S.A.S. \n\nTél: +33 (0)9 69 363 363 \n\n \n\nPortugal \n\nAmgen Biofarmacêutica, Lda. \n\nTel: +351 21 4220550 \n\n \n\nHrvatska \n\nAmgen d.o.o. \n\nTel: +385 (0)1 562 57 20 \n\n \n\nRomânia \n\nAmgen România SRL \n\nTel: +4021 527 3000 \n\n \n\nIreland \n\nAmgen Limited \n\nUnited Kingdom \n\nTel: +44 (0)1223 420305 \n \n\nSlovenija \n\nAMGEN zdravila d.o.o. \n\nTel: +386 (0)1 585 1767 \n\n \n\nÍsland \n\nVistor hf. \n\nSími: +354 535 7000 \n\n \n\nSlovenská republika \n\nAmgen Slovakia s.r.o. \n\nTel: +421 2 321 114 49 \n\n \n\nItalia \n\nAmgen S.r.l. \n\nTel: +39 02 6241121 \n\n \n\nSuomi/Finland \n\nAmgen AB, sivuliike Suomessa/Amgen AB, filial \n\ni Finland \n\nPuh/Tel: +358 (0)9 54900500 \n\n \n\nKύπρος \n\nC.A. Papaellinas Ltd \n\nΤηλ.: +357 22741 741 \n\n \n\nSverige \n\nAmgen AB \n\nTel: +46 (0)8 6951100 \n\n \n\nLatvija \n\nAmgen Switzerland AG Rīgas filiāle \n\nTel: +371 257 25888 \n\n \n\nUnited Kingdom \n\nAmgen Limited \n\nTel: +44 (0)1223 420305 \n\n \n\n \n\nThis leaflet was last revised in \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n94 \n\n \n\nOther sources of information \n\n \n\nDetailed information on this medicine is available on the European Medicines Agency web site: \n\nhttp://www.ema.europa.eu. \n\n \n\n--------------------------------------------------------------------------------------------------------------------------- \n \n\nInstructions for use: \n\nSOLYMBIC single use SureClick pre-filled pen \n\nFor subcutaneous use \n\n \n\nGuide to parts \n\n \n\nBefore use After use \n\nBlue start button \n\nExpiration date \n\nWindow \n\nMedicine \n\nYellow cap on \n \n\n \n\nExpiration date \n\nYellow window \n\n(injection complete) \n\nYellow safety guard \n\nYellow cap off \n \n\nImportant: Needle is inside \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\nhttp://www.ema.europa.eu/\n\n\n \n\n95 \n\nImportant \n\nBefore you use a SOLYMBIC pre-filled pen, read this important information: \n\n \n\nUsing your SOLYMBIC pre-filled pen \n\n● It is important that you do not try to give the injection unless you or your caregiver has \n\nreceived training. \n\n● Do not use a SOLYMBIC pre-filled pen if it has been dropped on a hard surface. Part of the \n\nSOLYMBIC pre-filled pen may be broken even if you cannot see the break. Use a new \n\nSOLYMBIC pre-filled pen. \n\n● The needle cover of the SOLYMBIC pre-filled pen is made from dry natural rubber, which \n\ncontains latex. Tell your healthcare provider if you are allergic to latex. \n\n \n\nStep 1: Prepare \n \n\nA. Remove one SOLYMBIC pre-filled pen from the package. \n\nCarefully lift the pre-filled pen straight up out of the box. \n\n \n\nPut the original package with any unused pre-filled pens back in the refrigerator. \n\n \n\nFor a more comfortable injection, leave the pre-filled pen at room temperature for 15 to 30 minutes \n\nbefore injecting. \n\n \n\n● Do not put the pre-filled pen back in the refrigerator once it has reached room temperature. \n\n● Do not try to warm the pre-filled pen by using a heat source such as hot water or microwave. \n\n● Do not shake the pre-filled pen. \n\n● Do not remove the yellow cap from the pre-filled pen yet. \n\n \n\nB. Inspect the SOLYMBIC pre-filled pen. \n\n \nYellow cap on Window Medicine \n\n \n\nMake sure the medicine in the window is clear and colourless to slightly yellow. \n\n \n\n● Do not use the pre-filled pen if: \n\n - The medicine is cloudy or discoloured, or contains flakes or particles. \n- Any part appears cracked or broken. \n- The pre-filled pen has been dropped on a hard surface. \n- The yellow cap is missing or not securely attached. \n- The expiration date printed on the label has passed. \n\nIn all cases, use a new pre-filled pen. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n96 \n\nC. Gather all materials needed for your injection. \n\nWash your hands thoroughly with soap and water. \n\nOn a clean, well-lit work surface, place a new, pre-filled pen. \n\n \n\nYou will also need these additional items, as they are not included in the carton: \n\n● Alcohol wipes \n\n● Cotton ball or gauze pad \n\n● Plaster \n\n● Sharps disposal container \n\n \n\n \n \n\nD. Prepare and clean your injection site. \n\n \nBelly \n\nThigh \n\n \n\nYou can use: \n\n● Your thigh \n\n● Belly, except for a 2-inch (5 centimetre) area right around your belly button \n\n \n\nClean your injection site with an alcohol wipe. Let your skin dry. \n\n● Do not touch this area again before injecting. \n\n● If you want to use the same injection site, make sure it is not the same spot on the injection \n\nsite you used for a previous injection. \n\n - Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting \ninto areas with scars or stretch marks. \n\n● If you have psoriasis, you should avoid injecting directly into raised, thick, red, or scaly skin \n\npatch or lesion. \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n97 \n\nStep 2: Get ready \n\n \n\nE. Pull the yellow cap straight off when you are ready to inject. \n\n \n\nIt is normal to see a drop of liquid at the end of the needle or yellow safety guard. \n\n● Do not twist or bend the yellow cap. \n\n● Do not put the yellow cap back onto the pre-filled pen. \n\n● Do not remove the yellow cap from the pre-filled pen until you are ready to inject. \n\n \n\nF. Stretch or pinch your injection site to create a firm surface. \n\nStretch method \n\n \n\nStretch the skin firmly by moving your thumb and fingers in opposite directions, creating an area \n\nabout 2 inches (5 centimetres) wide. \n\nOR \n\nPinch method \n\n \n\nPinch the skin firmly between your thumb and fingers, creating an area about 2 inches (5 \n\ncentimetres) wide. \n\nImportant: Keep the skin stretched or pinched while injecting. \n\n \n\nStep 3: Inject \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n98 \n\n \n\nG. Hold the stretch or pinch. With the yellow cap off, place the pre-filled pen on your skin at \n\n90 degrees. \n\n \n\nImportant: Do not touch the blue start button yet. \n\n \n\nH. Firmly push the pre-filled pen down onto the skin until it stops moving. \n\n \n\n \n\n \n\n \n\nImportant: You must push all the way down but do not touch the blue start button until you are \n\nready to inject. \n\n \n\nI. When you are ready to inject, press the blue start button. \n\n \n\n \n\n“Click” \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n99 \n\nJ. Keep pushing down on your skin. Your injection could take about 10 seconds. \n\n \n\n~10s \n\n \n\n \n\nThe window turns yellow \n\nWhen the injection is done \n\n Note: After you remove the pre-filled pen from your \n\nskin, the needle will be automatically covered. \n\nImportant: When you remove the pre-filled pen, if the window has not turned yellow, or if it looks \n\nlike the medicine is still injecting, this means you have not received a full dose. Call your doctor \n\nimmediately. \n \n\n \n\n“Click” \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\n \n\n100 \n\nStep 4: Finish \n\n \n\nK. Discard the used pre-filled pen and the yellow cap. \n\n \n\n● Put the used pre-filled pen in a sharps disposal container immediately after use. Do not throw \n\naway (dispose of) the pre-filled pen in your household waste. \n\n● Talk with your doctor or pharmacist about proper disposal. There may be local guidelines for \n\ndisposal. \n\n● Do not reuse the pre-filled pen. \n\n● Do not recycle the pre-filled pen or sharps disposal container or throw them into the household \n\nwaste. \n\nImportant: Always keep the sharps disposal container out of the sight and reach of children. \n\n \n\nL. Examine the injection site. \n\nIf there is blood, press a cotton ball or gauze pad on your injection site. Do not rub the injection site. \n\nApply a plaster if needed. \n\n \n\n \n\n \n\nMe\ndic\n\nina\nl p\n\nrod\nuc\n\nt n\no l\n\non\nge\n\nr a\nuth\n\nori\nse\n\nd\n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. PACKAGE LEAFLET"},"Section_1":{"kind":"string","value":"{'Title': '1. what solymbic is and what it is used for', 'Section_Content': None, 'Entity_Recognition': [{'Text': 'solymbic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'solymbic', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 8}, {'Text': 'the active substance adalimumab', 'Type': 'TREATMENT', 'BeginOffset': 18, 'EndOffset': 49}, {'Text': 'a selective immuno suppressive agent', 'Type': 'TREATMENT', 'BeginOffset': 51, 'EndOffset': 87}, {'Text': 'solymbic', 'Type': 'TREATMENT', 'BeginOffset': 89, 'EndOffset': 97}, {'Id': 18, 'BeginOffset': 127, 'EndOffset': 147, 'Score': 0.9380980730056763, 'Text': 'rheumatoid arthritis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9627466797828674}]}, {'Id': 19, 'BeginOffset': 149, 'EndOffset': 177, 'Score': 0.6041703224182129, 'Text': 'enthesitis-related arthritis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9603227972984314}]}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 190, 'EndOffset': 191}, {'Text': '17', 'Type': 'NUMBER', 'BeginOffset': 195, 'EndOffset': 197}, {'Id': 20, 'BeginOffset': 205, 'EndOffset': 227, 'Score': 0.9579342007637024, 'Text': 'ankylosing spondylitis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9813807606697083}]}, {'Id': 21, 'BeginOffset': 229, 'EndOffset': 252, 'Score': 0.9722833633422852, 'Text': 'axial spondyloarthritis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9623560905456543}]}, {'Id': 22, 'BeginOffset': 286, 'EndOffset': 308, 'Score': 0.9856428503990173, 'Text': 'ankylosing spondylitis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9699355363845825}, {'Name': 'NEGATION', 'Score': 0.705845057964325}]}, {'Id': 23, 'BeginOffset': 310, 'EndOffset': 329, 'Score': 0.963595986366272, 'Text': 'psoriatic arthritis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9602843523025513}, {'Name': 'NEGATION', 'Score': 0.4848903715610504}]}, {'Id': 24, 'BeginOffset': 331, 'EndOffset': 340, 'Score': 0.9961013793945312, 'Text': 'psoriasis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9569918513298035}, {'Name': 'NEGATION', 'Score': 0.5252208709716797}]}, {'Id': 25, 'BeginOffset': 342, 'EndOffset': 366, 'Score': 0.9803966283798218, 'Text': 'hidradenitis suppurativa', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9599429368972778}, {'Name': 'NEGATION', 'Score': 0.4710710346698761}]}, {'Id': 26, 'BeginOffset': 368, 'EndOffset': 388, 'Score': 0.9330391883850098, 'Text': 'paediatric psoriasis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9622490406036377}]}, {'Text': '23', 'Type': 'NUMBER', 'BeginOffset': 415, 'EndOffset': 417}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 421, 'EndOffset': 423}, {'Text': '47', 'Type': 'NUMBER', 'BeginOffset': 430, 'EndOffset': 432}, {'Id': 27, 'BeginOffset': 450, 'EndOffset': 465, 'Score': 0.9336391687393188, 'Text': \"crohn's disease\", 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9537943601608276}]}, {'Id': 28, 'BeginOffset': 490, 'EndOffset': 508, 'Score': 0.8924723267555237, 'Text': 'ulcerative colitis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9698238968849182}]}, {'Id': 29, 'BeginOffset': 513, 'EndOffset': 535, 'Score': 0.8975576758384705, 'Text': 'non-infectious uveitis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9762471914291382}], 'Attributes': [{'Type': 'DIRECTION', 'Score': 0.417165070772171, 'RelationshipScore': 0.9942386150360107, 'RelationshipType': 'DIRECTION', 'Id': 0, 'BeginOffset': 550, 'EndOffset': 554, 'Text': 'back', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9844076633453369, 'RelationshipScore': 0.9918621778488159, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 1, 'BeginOffset': 562, 'EndOffset': 565, 'Text': 'eye', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 1, 'BeginOffset': 562, 'EndOffset': 565, 'Score': 0.9844076633453369, 'Text': 'eye', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Text': 'a medicine', 'Type': 'TREATMENT', 'BeginOffset': 573, 'EndOffset': 583}, {'Text': 'the inflammation process', 'Type': 'PROBLEM', 'BeginOffset': 599, 'EndOffset': 623}, {'Text': 'these diseases', 'Type': 'PROBLEM', 'BeginOffset': 627, 'EndOffset': 641}, {'Id': 10, 'BeginOffset': 666, 'EndOffset': 676, 'Score': 0.9122301936149597, 'Text': 'adalimumab', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'a human monoclonal antibody', 'Type': 'TEST', 'BeginOffset': 681, 'EndOffset': 708}, {'Id': 54, 'BeginOffset': 721, 'EndOffset': 729, 'Score': 0.3543238341808319, 'Text': 'cultured', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Id': 55, 'BeginOffset': 737, 'EndOffset': 758, 'Score': 0.7602129578590393, 'Text': 'monoclonal antibodies', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': 'adalimumab binds', 'Type': 'PROBLEM', 'BeginOffset': 822, 'EndOffset': 838}, {'Text': 'a specific protein (tumour necrosis factor', 'Type': 'PROBLEM', 'BeginOffset': 842, 'EndOffset': 884}, {'Text': 'inflammatory diseases', 'Type': 'PROBLEM', 'BeginOffset': 935, 'EndOffset': 956}, {'Id': 31, 'BeginOffset': 965, 'EndOffset': 985, 'Score': 0.903721809387207, 'Text': 'rheumatoid arthritis', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.952246367931366}]}, {'Id': 32, 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\"warnings and precautions\"). warnings and precautions talk to your doctor or pharmacist before using solymbic: - if you experience allergic reactions with symptoms such as chest tightness, wheezing, dizziness, swelling or rash do not inject more solymbic and contact your doctor immediately since, in rare cases, these reactions can be life threatening. - if you have an infection, including long-term or localised infection (for example, leg ulcer) consult your doctor before starting solymbic. if you are unsure, please contact your doctor. - you might get infections more easily while you are receiving solymbic treatment. this risk may increase if your lung function is impaired. these infections may be serious and include tuberculosis, infections caused by viruses, fungi, parasites or bacteria, or other opportunistic infections and sepsis that may, in rare cases, be life-threatening. it is important to tell your 65 doctor if you get symptoms such as fever, wounds, feeling tired or dental problems. your doctor may recommend temporary discontinuation of solymbic. - as cases of tuberculosis have been reported in patients treated with adalimumab, your doctor will check you for signs and symptoms of tuberculosis before starting solymbic. this will include a thorough medical evaluation including your medical history and appropriate screening tests (for example chest x-ray and a tuberculin test). the conduct and results of these tests should be recorded on your patient alert card. it is very important that you tell your doctor if you have ever had tuberculosis, or if you have been in close contact with someone who has had tuberculosis. tuberculosis can develop during therapy even if you have received preventative treatment for tuberculosis. if symptoms of tuberculosis (persistent cough, weight loss, listlessness, mild fever), or any other infection appear during or after therapy, tell your doctor immediately. - advise your doctor if you reside or travel in regions where fungal infections such as histoplasmosis coccidioidomycosis or blastomycosis are endemic. - advise your doctor if you have a history of recurrent infections or other conditions that increase the risk of infections. - advise your doctor if you are a carrier of the hepatitis b virus (hbv), if you have active hbv or if you think you might be at risk of contracting hbv. your doctor should test you for hbv. solymbic can cause reactivation of hbv in people who carry this virus. in some rare cases, especially if you are taking other medicines that suppress the immune system, reactivation of hbv can be life-threatening. - if you are over 65 years you may be more susceptible to infections while taking solymbic. you and your doctor should pay special attention to signs of infection while you are being treated with solymbic. it is important to tell your doctor if you get symptoms of infections, such as fever, wounds, feeling tired or dental problems. - if you are about to undergo surgery or dental procedures please inform your doctor that you are taking solymbic. your doctor may recommend temporary discontinuation of solymbic. - if you have or develop demyelinating disease such as multiple sclerosis, your doctor will decide if you should receive or continue to receive solymbic. tell your doctor immediately if you experience symptoms like changes in your vision, weakness in your arms or legs or numbness or tingling in any part of your body. - certain vaccines may cause infections and should not be given while receiving solymbic. please check with your doctor before you receive any vaccines. it is recommended that children, if possible, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating solymbic therapy. if you received solymbic while you were pregnant, your baby may be at higher risk for getting such an infection for up to approximately five months after the last dose you received during pregnancy. it is important that you tell your baby\\'s doctors and other health care professionals about your solymbic use during your pregnancy so they can decide when your baby should receive any vaccine. - if you have mild heart failure and you are being treated with solymbic, your heart failure status must be closely monitored by your doctor. it is important to tell your doctor if you have had or have a serious heart condition. if you develop new or worsening symptoms of heart failure (e.g. shortness of breath, or swelling of your feet), you must contact your doctor immediately. - in some patients the body may fail to produce enough of the blood cells that help your body fight infections or help you to stop bleeding. if you develop a fever that does not go away, 66 bruise or bleed very easily or look very pale, call your doctor right away. your doctor may decide to stop treatment. - there have been very rare cases of certain kinds of cancer in children and adult patients taking adalimumab or other tnf blockers. people with more serious rheumatoid arthritis that have had the disease for a long time may have a higher than average risk of getting lymphoma (a type of cancer that affects the lymph system), and leukaemia (a type of cancer that affects the blood and bone marrow). if you take solymbic the risk of getting lymphoma, leukaemia, or other cancers may increase. on rare occasions, a specific and severe type of lymphoma has been observed in some patients taking adalimumab. some of those patients were also treated with azathioprine or 6-mercaptopurine. tell your doctor if you are taking azathioprine or 6-mercaptopurine with solymbic. in addition, cases of non-melanoma skin cancer have been observed in patients taking adalimumab. if new skin lesions appear during or after therapy or if existing lesions change appearance, tell your doctor. - there have been cases of cancers other than lymphoma in patients with a specific type of lung disease called chronic obstructive pulmonary disease (copd) treated with another tnf blocker. if you have copd, or are a heavy smoker, you should discuss with your doctor whether treatment with a tnf blocker is appropriate for you. the needle cover of the pre-filled syringe is made from dry natural rubber (a derivative of latex), which may cause allergic reactions. in order to improve the traceability of this medicine, your doctor or pharmacist should record the tradename and the lot number of the product you have been given in your patient file. you may also wish to make a note of these details in case you are asked for this information in the future. children and adolescents - vaccinations: if possible children should be up to date with all vaccinations before using solymbic. - do not use the 20 mg or 40 mg pre-filled syringe if doses other than 20 mg or 40 mg are recommended. other medicines and solymbic tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. solymbic can be taken together with methotrexate or certain disease-modifying anti-rheumatic agents (sulfasalazine, hydroxychloroquine, leflunomide and injectable gold preparations), steroids or pain medications including non-steroidal anti-inflammatory drugs (nsaids). you should not take solymbic with medicines containing the active substance, anakinra or abatacept. if you have questions, please ask your doctor. pregnancy and breast-feeding the effects of solymbic in pregnant women are not known and so the use of solymbic in pregnant women is not recommended. you are advised to avoid becoming pregnant and must use adequate contraception while using solymbic and for at least 5 months after the last solymbic treatment. if you become pregnant, you should consult your doctor. it is not known whether solymbic passes into breast milk. if you are a breast-feeding mother, you should stop breast-feeding during solymbic treatment and for at least 5 months after the last solymbic treatment. if you received solymbic during your 67 pregnancy, your baby may have a higher risk for getting an infection. it is important that you tell your baby\\'s doctors and other health care professionals about your solymbic use during your pregnancy before the baby receives any vaccine (for more information see section on vaccination). if you think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. driving and using machines solymbic may have a minor influence on your ability to drive, cycle or use machines. room spinning sensation and vision disturbances may occur after taking solymbic. solymbic contains sodium this medicine contains less than 1 mmol of sodium (23 mg) per 0.8 ml dose, i.e. essentially \\'sodium- free\\'.', 'Entity_Recognition': [{'Text': 'solymbic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 34, 'EndOffset': 42}, {'Id': 6, 'BeginOffset': 46, 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every other week as a single dose. in rheumatoid arthritis, methotrexate is continued while using solymbic. if your doctor determines that methotrexate is inappropriate, solymbic can be given alone. if you have rheumatoid arthritis and you do not receive methotrexate with your solymbic therapy, your doctor may decide to give 40 mg every week. children with enthesitis-related arthritis the recommended dose of solymbic for patients with enthesitis-related arthritis, aged 6 to 17 years depends on the height and weight of the child. your child's doctor will tell you the correct dose to use. adults with psoriasis the usual dose for adults with psoriasis is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. you should continue to inject solymbic for as long as your doctor has told you. depending on your response, your doctor may increase the dose frequency to 40 mg every week. children or adolescents with plaque psoriasis the recommended dose of solymbic for patients aged 4 to 17 years with plaque psoriasis depends on the weight of your child. solymbic should only be used in patients weighing either 23 to 28 kg or 47 kg and greater. your child's doctor will tell you the correct dose to use. adults with hidradenitis suppurativa 68 the usual dose regimen for hidradenitis suppurativa is an initial dose of 160 mg (as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), followed by an 80 mg dose (as two 40 mg injections on the same day) two weeks later. after two further weeks, continue with a dose of 40 mg every week. it is recommended that you use an antiseptic wash daily on the affected areas. adults with crohn's disease the usual dose regimen for crohn's disease is 80 mg initially followed by 40 mg every other week two weeks later. if a faster response is required, your doctor may prescribe an initial dose of 160 mg (as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), followed by 80 mg two weeks later, and thereafter as 40 mg every other week. depending on your response, your doctor may increase the dose frequency to 40 mg every week. children or adolescents with crohn's disease children or adolescents weighing less than 40 kg: the usual dose regimen is 40 mg initially followed by 20 mg two weeks later. if a faster response is required, your doctor may prescribe an initial dose of 80 mg (as two 40 mg injections in 1 day) followed by 40 mg two weeks later. thereafter, the usual dose is 20 mg every other week. depending on your response, your doctor may increase the dose frequency to 20 mg every week. children or adolescents weighing 40 kg or more: the usual dose regimen is 80 mg initially followed by 40 mg two weeks later. if a faster response is required, your doctor may prescribe an initial dose of 160 mg (as four 40 mg injections in 1 day or as two 40 mg injections per day for 2 consecutive days) followed by 80 mg two weeks later. thereafter, the usual dose is 40 mg every other week. depending on your response, your doctor may increase the dose frequency to 40 mg every week. adults with ulcerative colitis the usual solymbic dose for adults with ulcerative colitis is 160 mg initially (dose can be administered as four 40 mg injections in one day or as two 40 mg injections per day for two consecutive days) followed by 80 mg two weeks later, then 40 mg every other week. depending on your response, your doctor may increase the dose to 40 mg every week. adults with non-infectious uveitis the usual dose for adults with non-infectious uveitis is an initial dose of 80 mg, followed by 40 mg given every other week starting one week after the initial dose. you should continue to inject solymbic for as long as your doctor has told you. in non-infectious uveitis, corticosteroids or other medicines that influence the immune system may be continued while using solymbic. solymbic can also be given alone. method and route of administration solymbic is administered by injection under the skin (subcutaneous injection). if you use more solymbic than you should 69 if you accidentally inject solymbic more frequently than told to by your doctor or pharmacist, you should call your doctor or pharmacist and tell him/her that you have taken more. always take the outer carton of this medicine with you, even if it is empty. if you forget to use solymbic if you forget to give yourself an injection, you should inject it as soon as you remember. then take your next dose as you would have on your originally scheduled day, had you not forgotten a dose. if you stop using solymbic the decision to stop using solymbic should be discussed with your doctor. your symptoms may return upon discontinuation. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.\", 'Entity_Recognition': [{'Text': 'solymbic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 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bruising, bleeding, paleness. the symptoms described above can be signs of the below listed side effects, which have been observed with adalimumab: very common side effects (may affect more than 1 in 10 people): injection site reactions (including pain, swelling, redness or itching); respiratory tract infections (including cold, runny nose, sinus infection, pneumonia); headache; abdominal pain; nausea and vomiting; rash; musculoskeletal pain. common side effects (may affect up to 1 in 10 people): serious infections (including blood poisoning and influenza); skin infections (including cellulitis and shingles); 70 ear infections; oral infections (including tooth infections and cold sores); reproductive tract infections; urinary tract infection; fungal infections; joint infections; benign tumours; skin cancer; allergic reactions (including seasonal allergy); dehydration; mood swings (including depression); anxiety; difficulty sleeping; sensation disorders such as tingling, prickling or numbness; migraine; nerve root compression (including low back pain and leg pain); vision disturbances; eye inflammation; inflammation of the eye lid and eye swelling; vertigo; sensation of heart beating rapidly; high blood pressure; flushing; haematoma; cough; asthma; shortness of breath; gastrointestinal bleeding; dyspepsia (indigestion, bloating, heart burn); acid reflux disease; sicca syndrome (including dry eyes and dry mouth); itching; itchy rash; bruising; inflammation of the skin (such as eczema); breaking of finger nails and toe nails; increased sweating; hair loss; new onset or worsening of psoriasis; muscle spasms; blood in urine; kidney problems; chest pain; oedema; fever; reduction in blood platelets which increases risk of bleeding or bruising; impaired healing. uncommon side effects (may affect up to 1 in 100 people): opportunistic infections (which include tuberculosis and other infections that occur when resistance to disease is lowered); neurological infections (including viral meningitis); eye infections; bacterial infections; diverticulitis (inflammation and infection of the large intestine); cancer; 71 cancer that affects the lymph system; melanoma; immune disorders that could affect the lungs, skin and lymph nodes (most commonly presenting as sarcoidosis); vasculitis (inflammation of blood vessels); tremor; neuropathy; stroke; double vision; hearing loss, buzzing; sensation of heart beating irregularly such as skipped beats; heart problems that can cause shortness of breath or ankle swelling; heart attack; a sac in the wall of a major artery, inflammation and clot of a vein, blockage of a blood vessel; lung diseases causing shortness of breath (including inflammation); pulmonary embolism (blockage in an artery of the lung); pleural effusion (abnormal collection of fluid in the pleural space); inflammation of the pancreas which causes severe pain in the abdomen and back; difficulty in swallowing; facial oedema; gallbladder inflammation, gallbladder stones; fatty liver; night sweats; scar; abnormal muscle breakdown; systemic lupus erythematosus (including inflammation of skin, heart, lung, joints and other organ systems); sleep interruptions; impotence; inflammations. rare side effects (may affect up to 1 in 1,000 people): leukaemia (cancer affecting the blood and bone marrow); severe allergic reaction with shock; multiple sclerosis; nerve disorders (such as eye nerve inflammation and guillain-barré syndrome that may cause muscle weakness, abnormal sensations, tingling in the arms and upper body); heart stops pumping; pulmonary fibrosis (scarring of the lung); intestinal perforation; hepatitis; reactivation of hepatitis b; autoimmune hepatitis (inflammation of the liver caused by the body's own immune system); cutaneous vasculitis (inflammation of blood vessels in the skin); stevens-johnson syndrome (early symptoms include malaise, fever, headache and rash); facial oedema associated with allergic reactions; erythema multiforme (inflammatory skin rash); lupus-like syndrome. not known (frequency cannot be estimated from available data): hepatosplenic t-cell lymphoma (a rare blood cancer that is often fatal); merkel cell carcinoma (a type of skin cancer); liver failure; worsening of a condition called dermatomyositis (seen as a skin rash accompanying muscle weakness). some side effects observed with adalimumab may not have symptoms and may only be discovered through blood tests. these include: very common side effects (may affect more than 1 in 10 people): low blood measurements for white blood cells; low blood measurements for red blood cells; increased lipids in the blood; elevated liver enzymes. common side effects (may affect up to 1 in 10 people): high blood measurements for white blood cells; low blood measurements for platelets; increased uric acid in the blood; abnormal blood measurements for sodium; low blood measurements for calcium; low blood measurements for phosphate; high blood sugar; high blood measurements for lactate dehydrogenase; autoantibodies present in the blood. rare side effects (may affect up to 1 in 1,000 people): low blood measurements for white blood cells, red blood cells and platelet count. not known (frequency cannot be estimated from available data): liver failure. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.\", 'Entity_Recognition': [{'Text': 'solymbic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 23, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 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within the 14-day period. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': [{'Text': 'solymbic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'a single solymbic pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 320, 'EndOffset': 356}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 406, 'EndOffset': 408}, {'Text': '14', 'Type': 'NUMBER', 'BeginOffset': 431, 'EndOffset': 433}, {'Text': 'the pre-filled syringe', 'Type': 'TREATMENT', 'BeginOffset': 440, 'EndOffset': 462}, {'Text': '14', 'Type': 'NUMBER', 'BeginOffset': 530, 'EndOffset': 532}]}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': 'what solymbic contains - the active substance is adalimumab. 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NAME OF THE MEDICINAL PRODUCT \n \nClopidogrel Teva Pharma 75 mg film-coated tablets \n \n \n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \nEach film-coated tablet contains 75 mg of clopidogrel (as hydrochloride). \n \nExcipient with known effect: \nEach film-coated tablet contains 13 mg of hydrogenated castor oil. \n \nFor the full list of excipients, see section 6.1. \n \n \n3. PHARMACEUTICAL FORM \n \nFilm-coated tablet. \nPink, round and slightly convex film-coated tablets. \n \n \n4. CLINICAL PARTICULARS \n \n4.1 Therapeutic indications \n \nPrevention of atherothrombotic events \n \nClopidogrel is indicated in: \n Adult patients suffering from myocardial infarction (from a few days until less than 35 days), \n\nischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial \ndisease. \n\n \n Adult patients suffering from acute coronary syndrome: \n\n- Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave \nmyocardial infarction), including patients undergoing a stent placement following \npercutaneous coronary intervention, in combination with acetylsalicylic acid (ASA). \n\n- ST segment elevation acute myocardial infarction, in combination with ASA in medically \ntreated patients eligible for thrombolytic therapy. \n\n \nPrevention of atherothrombotic and thromboembolic events in atrial fibrillation \nIn adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not \nsuitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, \nclopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and \nthromboembolic events, including stroke. \n \nFor further information please refer to section 5.1. \n \n4.2 Posology and method of administration \n \nPosology \n Adults and elderly \n \n\nClopidogrel should be given as a single daily dose of 75 mg. \n \nIn patients suffering from acute coronary syndrome: \n\n2 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave \nmyocardial infarction): clopidogrel treatment should be initiated with a single 300-mg \nloading dose and then continued at 75 mg once a day (with acetylsalicylic acid (ASA) \n75 mg-325 mg daily). Since higher doses of ASA were associated with higher bleeding \nrisk it is recommended that the dose of ASA should not be higher than 100 mg. The \noptimal duration of treatment has not been formally established. Clinical trial data \nsupport use up to 12 months, and the maximum benefit was seen at 3 months (see \nsection 5.1). \n\n- ST segment elevation acute myocardial infarction: clopidogrel should be given as a \nsingle daily dose of 75 mg initiated with a 300-mg loading dose in combination with \nASA and with or without thrombolytics. For patients over 75 years of age clopidogrel \nshould be initiated without a loading dose. Combined therapy should be started as early \nas possible after symptoms start and continued for at least four weeks. The benefit of the \ncombination of clopidogrel with ASA beyond four weeks has not been studied in this \nsetting (see section 5.1). \n \n\nIn patients with atrial fibrillation, clopidogrel should be given as a single daily dose of 75 mg. ASA \n(75-100 mg daily) should be initiated and continued in combination with clopidogrel (see section 5.1). \n \nIf a dose is missed: \n\n Within less than 12 hours after regular scheduled time: patients should take the dose \nimmediately and then take the next dose at the regular scheduled time. \n\n For more than 12 hours: patients should take the next dose at the regular scheduled time and \nshould not double the dose. \n\n \n Paediatric population \n\nClopidogrel should not be used in children because of efficacy concerns (see section 5.1). \n \n Renal impairment \n\nTherapeutic experience is limited in patients with renal impairment (see section 4.4). \n \n\n Hepatic impairment \nTherapeutic experience is limited in patients with moderate hepatic disease who may have \nbleeding diatheses (see section 4.4). \n\n \nMethod of administration \nFor oral use \nIt may be given with or without food. \n \n4.3 Contraindications \n \n Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. \n Severe hepatic impairment. \n Active pathological bleeding such as peptic ulcer or intracranial haemorrhage. \n \n4.4 Special warnings and precautions for use \n \nBleeding and haematological disorders \nDue to the risk of bleeding and haematological adverse reactions, blood cell count determination \nand/or other appropriate testing should be promptly considered whenever clinical symptoms \nsuggestive of bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet \nagents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding \nfrom trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, \nheparin, glycoprotein IIb/IIIa inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) including \nCox-2 inhibitors, or selective serotonin reuptake inhibitors (SSRIs), or other medicinal products \nassociated with bleeding risk such as pentoxifylline (see section 4.5). Patients should be followed \n\n3 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\ncarefully for any signs of bleeding including occult bleeding, especially during the first weeks of \ntreatment and/or after invasive cardiac procedures or surgery. The concomitant administration of \nclopidogrel with oral anticoagulants is not recommended since it may increase the intensity of \nbleedings (see section 4.5). \n \nIf a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable, \nclopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and \ndentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal \nproduct is taken. Clopidogrel prolongs bleeding time and should be used with caution in patients who \nhave lesions with a propensity to bleed (particularly gastrointestinal and intraocular). \n \nPatients should be told that it might take longer than usual to stop bleeding when they take clopidogrel \n(alone or in combination with ASA), and that they should report any unusual bleeding (site or \nduration) to their physician. \n \nThrombotic Thrombocytopenic Purpura (TTP) \nThrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of \nclopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and \nmicroangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction \nor fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis. \n \nAcquired haemophilia \nAcquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated \nactivated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired \nhaemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should \nbe managed and treated by specialists, and clopidogrel should be discontinued. \n \n \nRecent ischaemic stroke \nIn view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute \nischaemic stroke. \n \nCytochrome P450 2C19 (CYP2C19) \nPharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended \ndoses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. \nTests are available to identify a patient's CYP2C19 genotype. \n \nSince clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal \nproducts that inhibit the activity of this enzyme would be expected to result in reduced drug levels of \nthe active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a \nprecaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see \nsection 4.5 for a list of CYP2C19 inhibitors, see also section 5.2). \n \nCYP2C8 substrates \nCaution is required in patients treated concomitantly with clopidogrel and CYP2C8 substrate \nmedicinal products (see section 4.5). \n \nCross-reactions among thienopyridines \nPatients should be evaluated for history of hypersensitivity to thienopyridines (such as clopidogrel, \nticlopidine, prasugrel) since cross-reactivity among thienopyridines has been reported (see section 4.8). \nThienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or \nhaematological cross-reactions such as thrombocytopaenia and neutropaenia. Patients who had \ndeveloped a previous monitored allergic reaction and/or haematological reaction to one thienopyridine \nmay have an increased risk of developing the same or another reaction to another thienopyridine. \nMonitoring for signs of hypersensitivity in patients with a known allergy to thienopyridines is advised. \n \nRenal impairment \n\n4 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\nTherapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore \nclopidogrel should be used with caution in these patients (see section 4.2). \n \nHepatic impairment \nExperience is limited in patients with moderate hepatic disease who may have bleeding diatheses. \nClopidogrel should therefore be used with caution in this population (see section 4.2). \n \nExcipients \nThis medicinal product contains hydrogenated castor oil which may cause stomach upset and \ndiarrhoea. \n \n4.5 Interaction with other medicinal products and other forms of interaction \n \nMedicinal products associated with bleeding risk: There is an increased risk of bleeding due to the \npotential additive effect. The concomitant administration of medicinal products associated with \nbleeding risk should be undertaken with caution (see section 4.4). \n \nOral anticoagulants: the concomitant administration of clopidogrel with oral anticoagulants is not \nrecommended since it may increase the intensity of bleedings (see section 4.4). Although the \nadministration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin or \nInternational Normalised Ratio (INR) in patients receiving long-term warfarin therapy, \ncoadministration of clopidogrel with warfarin increases the risk of bleeding because of independent \neffects on hemostasis. \n \nGlycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who receive \nconcomitant glycoprotein IIb/IIIa inhibitors (see section 4.4). \n \nAcetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADP-induced \nplatelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet \naggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not \nsignificantly increase the prolongation of bleeding time induced by clopidogrel intake. A \npharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to \nincreased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see \nsection 4.4). However, clopidogrel and ASA have been administered together for up to one year (see \nsection 5.1). \n \nHeparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification \nof the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no \neffect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic \ninteraction between clopidogrel and heparin is possible, leading to increased risk of bleeding. \nTherefore, concomitant use should be undertaken with caution (see section 4.4). \n \nThrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or non-fibrin \nspecific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. \nThe incidence of clinically significant bleeding was similar to that observed when thrombolytic agents \nand heparin are co-administered with ASA (see section 4.8). \n \nNSAIDs: in a clinical study conducted in healthy volunteers, the concomitant administration of \nclopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of \ninteraction studies with other NSAIDs it is presently unclear whether there is an increased risk of \ngastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and \nclopidogrel should be co-administered with caution (see section 4.4). \n \nSSRIs: since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant \nadministration of SSRIs with clopidogrel should be undertaken with caution. \n \n\n5 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\nOther concomitant therapy: Since clopidogrel is metabolised to its active metabolite partly by \nCYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to \nresult in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this \ninteraction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors \nshould be discouraged (see sections 4.4 and 5.2). \n \nMedicinal products that are strong or moderate CYP2C19 inhibitors include, for example, omeprazole \nand esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, \ncarbamazepine, and efavirenz. \n \nProton Pump Inhibitors (PPI): \nOmeprazole 80 mg once daily administered either at the same time as clopidogrel or with 12 hours \nbetween the administrations of the two drugs decreased the exposure of the active metabolite by 45% \n(loading dose) and 40% (maintenance dose). The decrease was associated with a 39% (loading dose) \nand 21% (maintenance dose) reduction of inhibition of platelet aggregation. Esomeprazole is expected \nto give a similar interaction with clopidogrel. \n \nInconsistent data on the clinical implications of this pharmacokinetic (PK)/pharmacodynamic (PD) \ninteraction in terms of major cardiovascular events have been reported from both observational and \nclinical studies. As a precaution, concomitant use of omeprazole or esomeprazole should be \ndiscouraged (see section 4.4). \n \nLess pronounced reductions of metabolite exposure has been observed with pantoprazole or \nlansoprazole. \nThe plasma concentrations of the active metabolite was 20% reduced (loading dose) and 14% reduced \n(maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was \nassociated with a reduction of the mean inhibition of platelet aggregation by 15% and 11%, \nrespectively. These results indicate that clopidogrel can be administered with pantoprazole. \n \nThere is no evidence that other medicinal products that reduce stomach acid such as H2 blockers or \nantacids interfere with antiplatelet activity of clopidogrel. \n \nOther medicinal products: A number of other clinical studies have been conducted with clopidogrel \nand other concomitant medicinal products to investigate the potential for pharmacodynamic and \npharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed \nwhen clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. \nFurthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the \ncoadministration of phenobarbital or oestrogen. \n \nThe pharmacokinetics of digoxin or theophylline were not modified by the co-administration of \nclopidogrel. Antacids did not modify the extent of clopidogrel absorption. \n \nData from the CAPRIE study indicate that phenytoin and tolbutamide which are metabolised by \nCYP2C9 can be safely co-administered with clopidogrel. \n \nCYP2C8 substrate medicinal products: Clopidogrel has been shown to increase repaglinide exposure \nin healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to \ninhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased \nplasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by \nCYP2C8 metabolism (e.g., repaglinide, paclitaxel) should be undertaken with caution (see section 4.4). \n \nApart from the specific medicinal product interaction information described above, interaction studies \nwith clopidogrel and some medicinal products commonly administered in patients with \natherothrombotic disease have not been performed. However, patients entered into clinical trials with \nclopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers, \nACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents \n\n6 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n(including insulin), antiepileptic agents, and GPIIb/IIIa antagonists without evidence of clinically \nsignificant adverse interactions. \n \n4.6 Fertility, pregnancy and lactation \n \nPregnancy \nAs no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not to \nuse clopidogrel during pregnancy as a precautionary measure. \n \nAnimal studies do not indicate direct or indirect harmful effects with respect to pregnancy, \nembryonal/foetal development, parturition or postnatal development (see section 5.3). \n \nBreast-feeding \nIt is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown \nexcretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not be \ncontinued during treatment with Clopidogrel Teva Pharma. \n \nFertility \nClopidogrel was not shown to alter fertility in animal studies. \n \n4.7 Effects on ability to drive and use machines \n \nClopidogrel has no or negligible influence on the ability to drive and use machines. \n \n4.8 Undesirable effects \n \nSummary of the safety profile \n \nClopidogrel has been evaluated for safety in more than 44,000 patients, who have participated in \nclinical studies, including over 12,000 patients treated for 1 year or more. Overall, clopidogrel \n75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. The \nclinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY, COMMIT and \nACTIVE-A studies are discussed below. In addition to clinical studies experience, adverse reactions \nhave been spontaneously reported. \n \nBleeding is the most common reaction reported both in clinical studies as well as in post-marketing \nexperience where it was mostly reported during the first month of treatment. \n \nIn CAPRIE, in patients treated with either clopidogrel or ASA, the overall incidence of any bleeding \nwas 9.3%. The incidence of severe cases was similar for clopidogrel and ASA. \n \nIn CURE, there was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronary \nbypass graft surgery in patients who stopped therapy more than five days prior to surgery. In patients \nwho remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for \nclopidogrel plus ASA, and 6.3% for placebo plus ASA. \n \nIn CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group vs. the \nplacebo plus ASA group. The incidence of major bleeding was similar between groups. This was \nconsistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or \nheparin therapy. \n \nIn COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and similar \nin both groups. \n \nIn ACTIVE-A, the rate of major bleeding was greater in the clopidogrel + ASA group than in the \nplacebo + ASA group (6.7% versus 4.3%). Major bleeding was mostly of extracranial origin in both \ngroups (5.3% in the clopidogrel + ASA group; 3.5% in the placebo +ASA group), mainly from the \n\n7 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\ngastrointestinal tract (3.5% vs. 1.8%). There was an excess of intracranial bleeding in the clopidogrel \n+ ASA treatment group compared to the placebo + ASA group (1.4% versus 0.8%, respectively). \nThere was no statistically significant difference in the rates of fatal bleeding (1.1% in the clopidogrel + \nASA group and 0.7% in the placebo +ASA group) and haemorrhagic stroke (0.8% and 0.6%, \nrespectively) between groups. \n \nTabulated list of adverse reactions \n \nAdverse reactions that occurred either during clinical studies or that were spontaneously reported are \npresented in the table below. Their frequency is defined using the following conventions: common ( \n1/100 to <1/10); uncommon ( 1/1,000 to < 1/100); rare (1/10,000 to <1/1,000); very rare \n(<1/10,000), not known (cannot be estimated from the available data). Within each system organ class, \nadverse reactions are presented in order of decreasing seriousness. \n\n8 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n \nSystem Organ \n\nClass \nCommon Uncommon Rare Very rare, not \n\nknown* \nBlood and the \nlymphatic system \ndisorders \n\n Thrombocytopenia, \nleucopenia, \neosinophilia \n\nNeutropenia, \nincluding \nsevere \nneutropenia \n\nThrombotic \nthrombocytopenic \npurpura (TTP) (see \nsection 4.4), aplastic \nanaemia, \npancytopenia, \nagranulocytosis, \nsevere \nthrombocytopenia, \nacquired haemophilia \nA, granulocytopenia, \nanaemia \n\nImmune system \ndisorders \n\n Serum sickness, \nanaphylactoid \nreactions, \ncross-reactive drug \nhypersensitivity \namong \nthienopyridines (such \nas ticlopidine, \nprasugrel) (see \nsection 4.4)* \n\nPsychiatric \ndisorders \n\n Hallucinations, \nconfusion \n\nNervous system \ndisorders \n\n Intracranial \nbleeding (some \ncases were reported \nwith fatal outcome), \nheadache, \nparaesthesia, \ndizziness \n\n Taste disturbances \n\nEye disorders Eye bleeding \n(conjunctival, \nocular, retinal) \n\n \n\nEar and labyrinth \ndisorders \n\n Vertigo \n\nVascular disorders Haematoma Serious haemorrhage, \nhaemorrhage of \noperative wound, \nvasculitis, \nhypotension \n\nRespiratory, \nthoracic and \nmediastinal \ndisorders \n\nEpistaxis Respiratory tract \nbleeding \n(haemoptysis, \npulmonary \nhaemorrhage), \nbronchospasm, \ninterstitial \npneumonitis, \neosinophilic \npneumonia \n \n \n \n\n9 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\nSystem Organ \nClass \n\nCommon Uncommon Rare Very rare, not \nknown* \n\nGastrointestinal \ndisorders \n\nGastrointestinal \nhaemorrhage, \ndiarrhoea, \nabdominal \npain, dyspepsia \n\nGastric ulcer and \nduodenal ulcer, \ngastritis, vomiting, \nnausea, \nconstipation, \nflatulence \n\nRetroperitoneal \nhaemorrhage \n\nGastrointestinal and \nretroperitoneal \nhaemorrhage with \nfatal outcome, \npancreatitis, colitis \n(including ulcerative \nor lymphocytic \ncolitis), stomatitis \n\nHepato-biliary \ndisorders \n\n Acute liver failure, \nhepatitis, abnormal \nliver function test \n\nSkin and \nsubcutaneous \ntissue disorders \n\nBruising Rash, pruritus, skin \nbleeding (purpura) \n\n Bullous dermatitis \n(toxic epidermal \nnecrolysis, Stevens \nJohnson Syndrome, \nerythema multiforme, \nacute generalised \nexanthematous \npustulosis (AGEP)), \nangioedema, \ndrug-induced \nhypersensitivity \nsyndrome, drug rash \nwith eosinophilia and \nsystemic symptoms \n(DRESS), rash \nerythematous or \nexfoliative, urticaria, \neczema, lichen planus \n\nReproductive \nsystems and breast \ndisorders \n\n Gynaecomastia \n\nMusculoskeletal, \nconnective tissue \nand bone disorders \n\n Musculo-skeletal \nbleeding \n(haemarthrosis), \narthritis, arthralgia, \nmyalgia \n\nRenal and urinary \ndisorders \n\n Haematuria Glomerulonephritis, \nblood creatinine \nincreased \n\nGeneral disorders \nand administration \nsite conditions \n\nBleeding at \npuncture site \n\n Fever \n\nInvestigations Bleeding time \nprolonged, \nneutrophil count \ndecreased, platelet \ncount decreased \n\n \n\n* Information related to clopidogrel with frequency “not known”. \n \nReporting of suspected adverse reactions \nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \n\n10 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V. \n \n4.9 Overdose \n \nOverdose following clopidogrel administration may lead to prolonged bleeding time and subsequent \nbleeding complications. Appropriate therapy should be considered if bleedings are observed. \nNo antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of \nprolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel. \n \n \n5. PHARMACOLOGICAL PROPERTIES \n \n5.1 Pharmacodynamic properties \n \nPharmacotherapeutic group: Antithrombotic agents, platelet aggregation inhibitors excl. heparin, ATC \nCode: B01AC-04. \n \nMechanism of action \n \nClopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel \nmust be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet \naggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine \ndiphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the \nglycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible \nbinding, platelets exposed are affected for the remainder of their lifespan (approximately 7-10 days) \nand recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet \naggregation induced by agonists other than ADP is also inhibited by blocking the amplification of \nplatelet activation by released ADP. \n \nBecause the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or \nsubject to inhibition by other medicinal products, not all patients will have adequate platelet inhibition. \n \nPharmacodynamic effects \n \nRepeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation \nfrom the first day; this increased progressively and reached steady state between Day 3 and Day 7. At \nsteady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and \n60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within \n5 days after treatment was discontinued. \n \nClinical efficacy and safety \n \nThe safety and efficacy of clopidogrel have been evaluated in 5 double-blind studies involving over \n88,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY, \nCOMMIT and ACTIVE-A studies comparing clopidogrel to placebo, both medicinal products given in \ncombination with ASA and other standard therapy. \n \nRecent myocardial infarction (MI), recent stroke or established peripheral arterial disease \n \nThe CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent \nmyocardial infarction (<35 days), recent ischaemic stroke (between 7 days and 6 months) or \nestablished peripheral arterial disease (PAD). Patients were randomised to clopidogrel 75 mg/day or \nASA 325 mg/day, and were followed for 1 to 3 years. In the myocardial infarction subgroup, most of \nthe patients received ASA for the first few days following the acute myocardial infarction. \n \n\n11 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\nClopidogrel significantly reduced the incidence of new ischaemic events (combined end point of \nmyocardial infarction, ischaemic stroke and vascular death) when compared to ASA. In the intention \nto treat analysis, 939 events were observed in the clopidogrel group and 1,020 events with ASA \n(relative risk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4]; p=0.045), which corresponds, for every \n1000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients being prevented from \nexperiencing a new ischaemic event. Analysis of total mortality as a secondary endpoint did not show \nany significant difference between clopidogrel (5.8%) and ASA (6.0%). \n \nIn a subgroup analysis by qualifying condition (myocardial infarction, ischaemic stroke, and PAD) the \nbenefit appeared to be strongest (achieving statistical significance at p=0.003) in patients enrolled due \nto PAD (especially those who also had a history of myocardial infarction) (RRR = 23.7%; CI: 8.9 to \n36.2) and weaker (not significantly different from ASA) in stroke patients (RRR = 7.3%; CI: -5.7 to \n18.7 [p=0.258]). In patients who were enrolled in the trial on the sole basis of a recent myocardial \ninfarction, clopidogrel was numerically inferior, but not statistically different from ASA (RRR = -\n4.0%; CI: -22.5 to 11.7 [p=0.639]). In addition, a subgroup analysis by age suggested that the benefit \nof clopidogrel in patients over 75 years was less than that observed in patients ≤75 years. \n \nSince the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear \nwhether the differences in relative risk reduction across qualifying conditions are real, or a result of \nchance. \n \nAcute coronary syndrome \n \nThe CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome \n(unstable angina or non-Q-wave myocardial infarction), and presenting within 24 hours of onset of the \nmost recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to \nhave either ECG changes compatible with new ischaemia or elevated cardiac enzymes or troponin I or \nT to at least twice the upper limit of normal. Patients were randomised to clopidogrel (300 mg loading \ndose followed by 75 mg/day, N=6,259) or placebo (N=6,303), both given in combination with ASA \n(75-325 mg once daily) and other standard therapies. Patients were treated for up to one year. In \nCURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins \nwere administered in more than 90% of the patients and the relative rate of bleeding between \nclopidogrel and placebo was not significantly affected by the concomitant heparin therapy. \n \nThe number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardial \ninfarction (MI), or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the \nplacebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p=0.00009) for the \nclopidogrel-treated group (17% relative risk reduction when patients were treated conservatively, 29% \nwhen they underwent percutaneous transluminal coronary angioplasty (PTCA) with or without stent \nand 10% when they underwent coronary artery bypass graft (CABG)). New cardiovascular events \n(primary endpoint) were prevented, with relative risk reductions of 22% (CI: 8.6, 33.4), 32% (CI: 12.8, \n46.4), 4% (CI: -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI: -31.6, 44.2), during the 0-1, 1-3, 3-6, \n6-9 and 9-12 month study intervals, respectively. Thus, beyond 3 months of treatment, the benefit \nobserved in the clopidogrel + ASA group was not further increased, whereas the risk of haemorrhage \npersisted (see section 4.4). \n \nThe use of clopidogrel in CURE was associated with a decrease in the need of thrombolytic therapy \n(RRR = 43.3%; CI: 24.3%, 57.5%) and GPIIb/IIIa inhibitors (RRR = 18.2%; CI: 6.5%, 28.3%). \n \nThe number of patients experiencing the co-primary endpoint (CV death, MI, stroke or refractory \nischaemia) was 1,035 (16.5%) in the clopidogrel-treated group and 1,187 (18.8%) in the \nplacebo-treated group, a 14% relative risk reduction (95% CI of 6%-21%, p=0.0005) for the \nclopidogrel-treated group. This benefit was mostly driven by the statistically significant reduction in \nthe incidence of MI [287 (4.6%) in the clopidogrel treated group and 363 (5.8%) in the placebo treated \ngroup]. There was no observed effect on the rate of rehospitalisation for unstable angina. \n \n\n12 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\nThe results obtained in populations with different characteristics (e.g. unstable angina or non-Q-wave \nMI, low to high risk levels, diabetes, need for revascularisation, age, gender, etc.) were consistent with \nthe results of the primary analysis. In particular, in a post-hoc analysis in 2,172 patients (17% of the \ntotal CURE population) who underwent stent placement (Stent-CURE), the data showed that \nclopidogrel compared to placebo, demonstrated a significant RRR of 26.2% favouring clopidogrel for \nthe co-primary endpoint (CV death, MI, stroke) and also a significant RRR of 23.9% for the second \nco-primary endpoint (CV death, MI, stroke or refractory ischaemia). Moreover, the safety profile of \nclopidogrel in this subgroup of patients did not raise any particular concern. Thus, the results from this \nsubset are in line with the overall trial results. \n \nThe benefits observed with clopidogrel were independent of other acute and long-term cardiovascular \ntherapies (such as heparin/LMWH, GPIIb/IIIa antagonists, lipid lowering medicinal products, beta \nblockers, and ACE-inhibitors). The efficacy of clopidogrel was observed independently of the dose of \nASA (75-325 mg once daily). \n \nIn patients with acute ST-segment elevation MI, safety and efficacy of clopidogrel have been \nevaluated in 2 randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT. \n \nThe CLARITY trial included 3,491 patients presenting within 12 hours of the onset of a ST elevation \nMI and planned for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose, \nfollowed by 75 mg/day, n=1,752) or placebo (n=1,739), both in combination with ASA (150 to \n325 mg as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, \nheparin. The patients were followed for 30 days. The primary endpoint was the occurrence of the \ncomposite of an occluded infarct-related artery on the predischarge angiogram, or death or recurrent \nMI before coronary angiography. For patients who did not undergo angiography, the primary endpoint \nwas death or recurrent myocardial infarction by Day 8 or by hospital discharge. The patient population \nincluded 19.7% women and 29.2% patients ≥ 65 years. A total of 99.7% of patients received \nfibrinolytics (fibrin specific: 68.7%, non-fibrin specific: 31.1%), 89.5% heparin, 78.7% beta blockers, \n54.7% ACE inhibitors and 63% statins. \n \nFifteen percent (15.0%) of patients in the clopidogrel group and 21.7% in the placebo group reached \nthe primary endpoint, representing an absolute reduction of 6.7% and a 36 % odds reduction in favor \nof clopidogrel (95% CI: 24, 47%; p < 0.001), mainly related to a reduction in occluded infarct-related \narteries. This benefit was consistent across all prespecified subgroups including patients’ age and \ngender, infarct location, and type of fibrinolytic or heparin used. \n \nThe 2x2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the \nonset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, ST \ndepression or left bundle-branch block). Patients received clopidogrel (75 mg/day, n=22,961) or \nplacebo (n=22,891), in combination with ASA (162 mg/day), for 28 days or until hospital discharge. \nThe co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke \nor death. The population included 27.8% women, 58.4% patients ≥ 60 years (26% ≥ 70 years) and \n54.5% patients who received fibrinolytics. \n \nClopidogrel significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the \nrelative risk of the combination of re-infarction, stroke or death by 9% (p=0.002), representing an \nabsolute reduction of 0.5% and 0.9%, respectively. This benefit was consistent across age, gender and \nwith or without fibrinolytics, and was observed as early as 24 hours. \n \nAtrial fibrillation \n \nThe ACTIVE-W and ACTIVE-A studies, separate trials in the ACTIVE program, included patients \nwith atrial fibrillation (AF) who had at least one risk factor for vascular events. Based on enrollment \ncriteria, physicians enrolled patients in ACTIVE-W if they were candidates for vitamin K antagonist \n(VKA) therapy (such as warfarin). The ACTIVE-A study included patients who could not receive \nVKA therapy because they were unable or unwilling to receive the treatment. \n\n13 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n \nThe ACTIVE-W study demonstrated that anticoagulant treatment with vitamin K antagonists was \nmore effective than with clopidogrel and ASA. \n \nThe ACTIVE-A study (N=7,554) was a multicenter, randomized, double-blind, placebo-controlled \nstudy which compared clopidogrel 75 mg/day + ASA (N=3,772) to placebo + ASA (N=3,782). The \nrecommended dose for ASA was 75 to 100 mg/day. Patients were treated for up to 5 years. \n \nPatients randomized in the ACTIVE program were those presenting with documented AF, i.e., either \npermanent AF or at least 2 episodes of intermittent AF in the past 6 months, and had at least one of the \nfollowing risk factors: age 75 years or age 55 to 74 years and either diabetes mellitus requiring drug \ntherapy, or documented previous MI or documented coronary artery disease; treated for systemic \nhypertension; prior stroke, transient ischaemic attack (TIA), or non-CNS systemic embolus; left \nventricular dysfunction with left ventricular ejection fraction <45%; or documented peripheral \nvascular disease. The mean CHADS2 score was 2.0 (range 0-6). \n \nThe major exclusion criteria for patients were documented peptic ulcer disease within the previous \n6 months; prior intracerebral hemorrhage; significant thrombocytopenia (platelet count < 50 x 109/l); \nrequirement for clopidogrel or oral anticoagulants (OAC); or intolerance to any of the two compounds. \n \nSeventy-three percent (73%) of patients enrolled into the ACTIVE-A study were unable to take VKA \ndue to physician assessment, inability to comply with INR (international normalised ratio) monitoring, \npredisposition to falling or head trauma, or specific risk of bleeding; for 26% of the patients, the \nphysician’s decision was based on the patient’s unwillingness to take VKA. \n \nThe patient population included 41.8 % women. The mean age was 71 years, 41.6% of patients were \n≥75 years. A total of 23.0% of patients received anti-arrhythmics, 52.1% beta-blockers, 54.6% ACE \ninhibitors, and 25.4% statins. \n \nThe number of patients who reached the primary endpoint (time to first occurrence of stroke, MI, \nnon-CNS systemic embolism or vascular death) was 832 (22.1%) in the group treated with clopidogrel \n+ ASA and 924 (24.4%) in the placebo + ASA group (relative risk reduction of 11.1%; 95% CI of \n2.4% to 19.1%; p=0.013), primarily due to a large reduction in the incidence of strokes. Strokes \noccurred in 296 (7.8%) patients receiving clopidogrel + ASA and 408 (10.8%) patients receiving \nplacebo + ASA (relative risk reduction, 28.4%; 95% CI, 16.8% to 38.3%; p=0.00001). \n \nPaediatric population \nIn a dose escalation study of 86 neonates or infants up to 24 months of age at risk for thrombosis \n(PICOLO), clopidogrel was evaluated at consecutive doses of 0.01, 0.1 and 0.2 mg/kg in neonates and \ninfants and 0.15 mg/kg only in neonates. The dose of 0.2 mg/kg achieved the mean percent inhibition \nof 49.3% (5 µM ADP-induced platelet aggregation) which was comparable to that of adults taking \nClopidogrel 75 mg/day. \n \nIn a randomised, double-blind, parallel-group study (CLARINET), 906 paediatric patients (neonates \nand infants) with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial \nshunt were randomised to receive clopidogrel 0.2 mg/kg (n=467) or placebo (n=439) along with \nconcomitant background therapy up to the time of second stage surgery. The mean time between shunt \npalliation and first administration of study medicinal product was 20 days. Approximately 88% of \npatients received concomitant ASA (range of 1 to 23 mg/kg/day). There was no significant difference \nbetween groups in the primary composite endpoint of death, shunt thrombosis or cardiac-related \nintervention prior to 120 days of age following an event considered of thrombotic nature (89 [19.1%] \nfor the clopidogrel group and 90 [20.5%] for the placebo group) (see section 4.2). Bleeding was the \nmost frequently reported adverse reaction in both clopidogrel and placebo groups; however, there was \nno significant difference in the bleeding rate between groups. In the long-term safety follow-up of this \nstudy, 26 patients with the shunt still in place at one year of age received clopidogrel up to 18 months \nof age. No new safety concerns were noted during this long-term follow-up. \n\n14 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n \nThe CLARINET and the PICOLO trials were conducted using a constituted solution of clopidogrel. In \na relative bioavailability study in adults, the constituted solution of clopidogrel showed a similar extent \nand slightly higher rate of absorption of the main circulating (inactive) metabolite compared to the \nauthorised tablet. \n \n5.2 Pharmacokinetic properties \n \nAbsorption \nAfter single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak \nplasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/ml after a single 75 mg oral dose) \noccurred approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary \nexcretion of clopidogrel metabolites. \n \nDistribution \nClopidogrel and the main circulating (inactive) metabolite bind reversibly in vitro to human plasma \nproteins (98 % and 94 % respectively). The binding is non-saturable in vitro over a wide concentration \nrange. \n \nBiotransformation \nClopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised \naccording to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into \nits inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple \ncytochromes P450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite. \nSubsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the \nactive metabolite, a thiol derivative of clopidogrel. The active metabolite is formed mostly by \nCYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and \nCYP3A4. The active thiol metabolite which has been isolated in vitro, binds rapidly and irreversibly to \nplatelet receptors, thus inhibiting platelet aggregation. \n \nThe Cmax of the active metabolite is twice as high following a single 300-mg clopidogrel loading dose \nas it is after four days of 75-mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after \ndosing. \n \nElimination \nFollowing an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the \nurine and approximately 46% in the faeces in the 120-hour interval after dosing. After a single oral \ndose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination halflife of the \nmain circulating (inactive) metabolite was 8 hours after single and repeated administration. \n \nPharmacogenetics \nCYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel \nintermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as \nmeasured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. \n \nThe CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and \nCYP2C19*3 alleles are nonfunctional. The CYP2C19*2 and CYP2C19*3 alleles account for the \nmajority of reduced function alleles in Caucasian (85%) and Asian (99%) poor metabolisers. Other \nalleles associated with absent or reduced metabolism are less frequent and include CYP2C19*4, *5, \n*6, *7, and *8. A patient with poor metaboliser status will possess two loss-of-function alleles as \ndefined above. Published frequencies for the poor CYP2C19 metaboliser genotypes are approximately \n2% for Caucasians, 4% for Blacks and 14% for Chinese. Tests are available to determine a patient’s \nCYP2C19 genotype. \n \nA crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metaboliser groups (ultrarapid, \nextensive, intermediate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg \n\n15 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\nfollowed by 75 mg/day and 600 mg followed by 150 mg/day, each for a total of 5 days (steady state). \nNo substantial differences in active metabolite exposure and mean inhibition of platelet aggregation \n(IPA) were observed between ultrarapid, extensive and intermediate metabolisers. In poor \nmetabolisers, active metabolite exposure was decreased by 63-71% compared to extensive \nmetabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poor \nmetabolisers with mean IPA (5 μM ADP) of 24% (24 hours) and 37% (Day 5) as compared to IPA of \n39% (24 hours) and 58% (Day 5) in the extensive metabolisers and 37% (24 hours) and 60% (Day 5) \nin the intermediate metabolisers. When poor metabolisers received the 600 mg/150 mg regimen, active \nmetabolite exposure was greater than with the 300 mg/75 mg regimen. In addition, IPA was 32% \n(24 hours) and 61% (Day 5), which were greater than in the poor metabolisers receiving the \n300 mg/75 mg regimen, and were similar to the other CYP2C19 metaboliser groups receiving the \n300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been \nestablished in clinical outcome trials. \n \nConsistent with the above results, in a meta-analysis including 6 studies of 335 clopidogrel-treated \nsubjects at steady state, it was shown that active metabolite exposure was decreased by 28% for \nintermediate metabolisers, and 72% for poor metabolisers while platelet aggregation inhibition (5 μM \nADP) was decreased with differences in IPA of 5.9% and 21.4%, respectively, when compared to \nextensive metabolisers. \n \nThe influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not \nbeen evaluated in prospective, randomised, controlled trials. There have been a number of \nretrospective analyses, however, to evaluate this effect in patients treated with clopidogrel for whom \nthere are genotyping results: CURE (n=2721), CHARISMA (n=2428), CLARITY-TIMI 28 (n=227), \nTRITON-TIMI 38 (n=1477), and ACTIVE-A (n=601), as well as a number of published cohort \nstudies. \n \nIn TRITON-TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Giusti) the combined group of \npatients with either intermediate or poor metaboliser status had a higher rate of cardiovascular events \n(death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolisers. \n \nIn CHARISMA and one cohort study (Simon), an increased event rate was observed only in poor \nmetabolisers when compared to extensive metabolisers. \n \nIn CURE, CLARITY, ACTIVE-A and one of the cohort studies (Trenk), no increased event rate was \nobserved based on metaboliser status. \n \nNone of these analyses were adequately sized to detect differences in outcome in poor metabolisers. \n \nSpecial populations \n \nThe pharmacokinetics of the active metabolite of clopidogrel is not known in these special populations. \n \nRenal impairment \nAfter repeated doses of 75 mg clopidogrel per day in subjects with severe renal disease (creatinine \nclearance from 5 to 15 ml/min), inhibition of ADP-induced platelet aggregation was lower (25%) than \nthat observed in healthy subjects, however, the prolongation of bleeding time was similar to that seen \nin healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in \nall patients. \n \nHepatic impairment \nAfter repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic \nimpairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy \nsubjects. The mean bleeding time prolongation was also similar in the two groups. \n \nRace \n\n16 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\nThe prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs \naccording to race/ethnicity (see Pharmacogenetics). From literature, limited data in Asian populations \nare available to assess the clinical implication of genotyping of this CYP on clinical outcome events. \n \n5.3 Preclinical safety data \n \nDuring non clinical studies in rat and baboon, the most frequently observed effects were liver changes. \nThese occurred at doses representing at least 25 times the exposure seen in humans receiving the \nclinical dose of 75 mg/day and were a consequence of an effect on hepatic metabolising enzymes. No \neffect on hepatic metabolising enzymes was observed in humans receiving clopidogrel at the \ntherapeutic dose. \n \nAt very high doses, a poor gastric tolerability (gastritis, gastric erosions and/or vomiting) of \nclopidogrel was also reported in rat and baboon. \n \nThere was no evidence of carcinogenic effect when clopidogrel was administered for 78 weeks to \nmice and 104 weeks to rats when given at doses up to 77 mg/kg per day (representing at least 25 times \nthe exposure seen in humans receiving the clinical dose of 75 mg/day). \n \nClopidogrel has been tested in a range of in vitro and in vivo genotoxicity studies, and showed no \ngenotoxic activity. \n \nClopidogrel was found to have no effect on the fertility of male and female rats and was not \nteratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight delay in \nthe development of the offspring. Specific pharmacokinetic studies performed with radiolabelled \nclopidogrel have shown that the parent compound or its metabolites are excreted in the milk. \nConsequently, a direct effect (slight toxicity), or an indirect effect (low palatability) cannot be \nexcluded. \n \n \n6. PHARMACEUTICAL PARTICULARS \n \n6.1 List of excipients \n \nTablet core: \nCellulose, microcrystalline \nColloidal anhydrous silica \nCrospovidone (type A) \nMacrogol 6000 \nHydrogenated castor oil \n \nFilm coating: \nPolyvinyl alcohol \nTitanium dioxide (E171) \nRed iron oxide (E172) \nYellow iron oxide (E172) \nTalc \nMacrogol 3000 \n \n6.2 Incompatibilities \n \nNot applicable. \n \n6.3 Shelf life \n \n3 years. \n\n17 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n \n6.4 Special precautions for storage \n \nStore in the original package in order to protect from moisture and light. \n \n6.5 Nature and contents of container \n \nBlister of OPA/Al/PVC-Al containing 7, 14, 28, 30, 50, 56, 84, 90 and 100 film-coated tablets in the \nbox. \nPerforated unit dose blister of OPA/Al/PVC-Al containing 28x1 and 50x1 film-coated tablets in the \nbox. \n \nNot all pack sizes may be marketed. \n \n6.6 Special precautions for disposal \n \nAny unused medicinal product or waste material should be disposed of in accordance with local \nrequirements. \n \n \n7. MARKETING AUTHORISATION HOLDER \n \nTeva B.V. \nSwensweg 5 \n2031GA Haarlem \nThe Netherlands \n \n \n8. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/09/561/001 Cartons of 7 film-coated tablets in OPA/Al/PVC - Al blisters \nEU/1/09/561/002 Cartons of 14 film-coated tablets in OPA/Al/PVC - Al blisters \nEU/1/09/561/003 Cartons of 28 film-coated tablets in OPA/Al/PVC - Al blisters \nEU/1/09/561/004 Cartons of 30 film-coated tablets in OPA/Al/PVC - Al blisters \nEU/1/09/561/005 Cartons of 50 film-coated tablets in OPA/Al/PVC - Al blisters \nEU/1/09/561/006 Cartons of 56 film-coated tablets in OPA/Al/PVC - Al blisters \nEU/1/09/561/007 Cartons of 84 film-coated tablets in OPA/Al/PVC - Al blisters \nEU/1/09/561/008 Cartons of 90 film-coated tablets in OPA/Al/PVC - Al blisters \nEU/1/09/561/009 Cartons of 100 film-coated tablets in OPA/Al/PVC - Al blisters \nEU/1/09/561/010 Cartons of 28x1 film-coated tablets in OPA/Al/PVC - Al perforated unit-dose \n\nblisters \nEU/1/09/561/011 Cartons of 50x1 film-coated tablets in OPA/Al/PVC - Al perforated unit-dose \n\nblisters \n \n \n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n \nDate of first authorisation: 21 September 2009 \nDate of latest renewal: 8 May 2014 \n \n \n10. DATE OF REVISION OF THE TEXT \n \n \nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency http://www.ema.europa.eu/. \n\n18 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\nhttp://www.emea.europa.eu/\n\n\n \n\n19 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX II \n \nA. MANUFACTURERS RESPONSIBLE FOR BATCH \n\nRELEASE \n \n\nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY \nAND USE \n\n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE \n\nMARKETING AUTHORISATION \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO \n\nTHE SAFE AND EFFECTIVE USE OF THE MEDICINAL \nPRODUCT \n\n \n \n\n20 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\nA. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE \n \nName and address of the manufacturer responsible for batch release \n \nKRKA, d.d., Novo mesto \nŠmarješka cesta 6 \n8501 Novo mesto \nSlovenia \n \nTAD Pharma GmbH \nHeinz-Lohmann-Straße 5 \n27472 Cuxhaven \nGermany \n \nPharmachemie B.V. \nSwensweg 5, \n2031 GA Haarlem \nThe Netherlands \n \nThe printed package leaflet of the medicinal product must state the name and address of the \nmanufacturer responsible for the release of the concerned batch. \n \n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n \nMedicinal product subject to medical prescription. \n \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n \n Periodic Safety Update Reports \n \n\nThe PSUR submission schedule for Clopidogrel Teva Pharma film coated tablets should follow \nPSURs submission schedule for the reference medicinal product. \n \n Pharmacovigilance system \n \nThe MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1 of the \nMarketing Authorisation, is in place and functioning before and whilst the product is on the market. \n \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE \n\nAND EFFECTIVE USE OF THE MEDICINAL PRODUCT \n \n Risk Management Plan (RMP) \n \nRisk Management Plan was not submitted. The application is based on a reference medicinal product \nfor which no safety concerns requiring additional risk minimization activities have been identified. \n\n \n \n\n21 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n \n \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX III \n \n\nLABELLING AND PACKAGE LEAFLET \n\n22 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nA. LABELLING \n\n23 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n \nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nCARTON \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nClopidogrel Teva Pharma 75 mg film-coated tablets \n \nClopidogrel \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nEach film-coated tablet contains 75 mg of clopidogrel (as hydrochloride). \n \n \n3. LIST OF EXCIPIENTS \n \nIt also contains hydrogenated castor oil. \nSee leaflet for further information. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \n7 film-coated tablets \n14 film-coated tablets \n28 film-coated tablets \n30 film-coated tablets \n50 film-coated tablets \n56 film-coated tablets \n84 film-coated tablets \n90 film-coated tablets \n100 film-coated tablets \n28x1 film-coated tablets \n50x1 film-coated tablets \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nRead the package leaflet before use. \nOral use \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \n \n\n24 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nStore in the original package in order to protect from moisture and light. \n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nTeva B.V. \nSwensweg 5 \n2031GA Haarlem \nThe Netherlands \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/09/561/001 7 film-coated tablets \nEU/1/09/561/002 14 film-coated tablets \nEU/1/09/561/003 28 film-coated tablets \nEU/1/09/561/004 30 film-coated tablets \nEU/1/09/561/005 50 film-coated tablets \nEU/1/09/561/006 56 film-coated tablets \nEU/1/09/561/007 84 film-coated tablets \nEU/1/09/561/008 90 film-coated tablets \nEU/1/09/561/009 100 film-coated tablets \nEU/1/09/561/010 28x1 film-coated tablets \nEU/1/09/561/011 50x1 film-coated tablets \n \n \n13. BATCH NUMBER \n \nBatch \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \nMedicinal product subject to medical prescription. \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nClopidogrel Teva Pharma 75 mg \n\n25 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n \nMINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS \n \nBLISTER (7, 14, 28, 30, 50, 56, 84, 90, 100, 50x1 film-coated tablets) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nClopidogrel Teva Pharma 75 mg film-coated tablets \n \nClopidogrel \n \n \n2. NAME OF THE MARKETING AUTHORISATION HOLDER \n \nTeva B.V. \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nBatch \n \n \n5. OTHER \n \n\n26 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n \nMINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS \n \nBLISTER (28x1 film-coated tablets) \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nClopidogrel Teva Pharma 75 mg film-coated tablets \n \nClopidogrel \n \n \n2. NAME OF THE MARKETING AUTHORISATION HOLDER \n \nTeva B.V. \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nBatch \n \n \n5. OTHER \n \nCalendar days \nMon \nTue \nWed \nThu \nFri \nSat \nSun \n\n27 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nB. PACKAGE LEAFLET \n \n\n28 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\nPackage leaflet: Information for the user \n \n\nClopidogrel Teva Pharma 75 mg film-coated tablets \nClopidogrel \n\n \nRead all of this leaflet carefully before you start taking this medicine because it contains \nimportant information for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor or pharmacist. \n- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, \n\neven if their signs of illness are the same as yours. \n- If you have any of the side effects, including any side effects not listed in this leaflet, talk to \n\nyour doctor or pharmacist. See section 4. \n \n \nWhat is in this leaflet: \n1. What Clopidogrel Teva Pharma is and what it is used for \n2. What you need to know before you take Clopidogrel Teva Pharma \n3. How to take Clopidogrel Teva Pharma \n4. Possible side effects \n5. How to store Clopidogrel Teva Pharma \n6. Contents of the pack and other information \n \n \n1. What Clopidogrel Teva Pharma is and what it is used for \n \nClopidogrel Teva Pharma contains clopidogrel and belongs to a group of medicines called antiplatelet \nmedicinal products. Platelets are very small structures in the blood, which clump together during blood \nclotting. By preventing this clumping, antiplatelet medicinal products reduce the chances of blood \nclots forming (a process called thrombosis). \n \nClopidogrel Teva Pharma is taken by adults to prevent blood clots (thrombi) forming in hardened \nblood vessels (arteries), a process known as atherothrombosis, which can lead to atherothrombotic \nevents (such as stroke, heart attack, or death). \n \nYou have been prescribed Clopidogrel Teva Pharma to help prevent blood clots and reduce the risk of \nthese severe events because: \n- You have a condition of hardening of arteries (also known as atherosclerosis), and \n- You have previously experienced a heart attack, stroke or have a condition known as peripheral \n\narterial disease, or \n- You have experienced a severe type of chest pain known as ‘unstable angina’ or ‘myocardial \n\ninfarction’ (heart attack). For the treatment of this condition your doctor may have placed a stent \nin the blocked or narrowed artery to restore effective blood flow. You should also be given \nacetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever \nas well as to prevent blood clotting) by your doctor. \n\n- You have an irregular heartbeat, a condition called ‘atrial fibrillation’, and you cannot take \nmedicines known as ‘oral anticoagulants’ (vitamin K antagonists) which prevent new clots from \nforming and prevent existing clots from growing. You should have been told that ‘oral \nanticoagulants’ are more effective than acetylsalicylic acid or the combined use of Clopidogrel \nTeva Pharma and acetylsalicylic acid for this condition. Your doctor should have prescribed \nClopidogrel Teva Pharma plus acetylsalicylic acid if you cannot take ‘oral anticoagulants’ and \nyou do not have a risk of major bleeding \n\n \n \n2. What you need to know before you take Clopidogrel Teva Pharma \n \n\n29 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\nDo not take Clopidogrel Teva Pharma \n If you are allergic to clopidogrel or any of the other ingredients of this medicine (listed in \n\nsection 6). \n If you have a medical condition that is currently causing bleeding such as a stomach ulcer or \n\nbleeding within the brain. \n If you suffer from severe liver disease. \n \nIf you think any of these apply to you, or if you are in any doubt at all, consult your doctor before \ntaking Clopidogrel Teva Pharma. \n \nWarnings and precautions \nIf any of the situations mentioned below apply to you, you should tell your doctor before taking \nClopidogrel Teva Pharma: \n if you have a risk of bleeding such as \n\n- a medical condition that puts you at risk of internal bleeding (such as a stomach ulcer) \n- a blood disorder that makes you prone to internal bleeding (bleeding inside any tissues, organs \nor joints of your body). \n- a recent serious injury. \n- a recent surgery (including dental). \n- a planned surgery (including dental) in the next seven days. \n\n if you have had a clot in an artery of your brain (ischaemic stroke) which occurred within the \nlast seven days. \n\n if you have kidney or liver disease. \n if you have had an allergy or reaction to any medicine used to treat your disease. \n \nWhile you are taking Clopidogrel Teva Pharma: \n You should tell your doctor if a surgery (including dental) is planned. \n You should also tell your doctor immediately if you develop a medical condition (also known as \n\nThrombotic Thrombocytopenic Purpura or TTP) that includes fever and bruising under the skin \nthat may appear as red pinpoint dots, with or without unexplained extreme tiredness, confusion, \nyellowing of the skin or eyes (jaundice) (see section 4 ‘Possible side effects’). \n\n If you cut or injure yourself, it may take longer than usual for bleeding to stop. This is linked to \nthe way your medicine works as it prevents the ability of blood clots to form. For minor cuts \nand injuries e.g., cutting yourself, shaving, this is usually of no concern. However, if you are \nconcerned by your bleeding, you should contact your doctor straightaway (see section 4 \n‘Possible side effects’). \n\n Your doctor may order blood tests. \n \nChildren and adolescents \nDo not give this medicine to children because it does not work. \n \nOther medicines and Clopidogrel Teva Pharma \nTell your doctor or pharmacist if you are taking or have recently taken or might take any other \nmedicines, including medicines obtained without a prescription. \nSome other medicines may influence the use of Clopidogrel Teva Pharma or vice versa. \n \nYou should specifically tell your doctor if you take \n- medicines that may increase your risk of bleeding such as: \n\no oral anticoagulants, medicines used to reduce blood clotting, \no a non-steroidal anti-inflammatory medicine, usually used to treat painful and/or \n\ninflammatory conditions of muscle or joints, \no heparin or any other injectable medicine used to reduce blood clotting, \no ticlopidine, other antiplatelet agent, \no a selective serotonin reuptake inhibitor (including but not restricted to fluoxetine or \n\nfluvoxamine), medicines usually used to treat depression, \n- omeprazole or esomeprazole, medicines to treat upset stomach, \n\n30 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n- fluconazole or voriconazole, medicines to treat fungal infections, \n- efavirenz, a medicine to treat HIV (human immunodeficiency virus) infections, \n- carbamazepine, a medicine to treat some forms of epilepsy, \n- moclobemide, medicine to treat depression, \n- repaglinide, medicine to treat diabetes, \n- paclitaxel, medicine to treat cancer. \nIf you have experienced severe chest pain (unstable angina or heart attack), you may be prescribed \nClopidogrel Teva Pharma in combination with acetylsalicylic acid, a substance present in many \nmedicines used to relieve pain and lower fever. An occasional use of acetylsalicylic acid (no more \nthan 1,000 mg in any 24 hour period) should generally not cause a problem, but prolonged use in other \ncircumstances should be discussed with your doctor. \n \nPregnancy and breast-feeding \nIt is preferable not to take this medicine during pregnancy. \n \nIf you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist \nbefore taking Clopidogrel Teva Pharma. If you become pregnant while taking Clopidogrel Teva \nPharma, consult your doctor immediately as it is recommended not to take clopidogrel while you are \npregnant. \n \nYou should not breast-feed while taking this medicine. \nIf you are breast-feeding or planning to breast-feed, talk to your doctor before taking this medicine. \n \nAsk your doctor or pharmacist for advice before taking any medicine. \n \nDriving and using machines \nClopidogrel Teva Pharma is unlikely to affect your ability to drive or to use machines. \n \nClopidogrel Teva Pharma contains hydrogenated castor oil \nThis may cause stomach upset or diarrhoea. \n \n \n3. How to take Clopidogrel Teva Pharma \n \nAlways take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor \nor pharmacist if you are not sure. \n \nThe recommended dose, including for patients with a condition called ‘atrial fibrillation’ (an irregular \nheartbeat), is one 75 mg tablet of Clopidogrel Teva Pharma per day to be taken orally with or without \nfood, and at the same time each day. \n \nIf you have experienced severe chest pain (unstable angina or heart attack), your doctor may give you \n300 mg of Clopidogrel Teva Pharma (4 tablets of 75 mg) once at the start of treatment. Then, the \nrecommended dose is one 75 mg tablet of Clopidogrel Teva Pharma per day as described above. \n \nYou should take Clopidogrel Teva Pharma for as long as your doctor continues to prescribe it. \n \nIf you take more Clopidogrel Teva Pharma than you should \nContact your doctor or the nearest hospital emergency department because of the increased risk of \nbleeding. \n \nIf you forget to take Clopidogrel Teva Pharma \nIf you forget to take a dose of Clopidogrel Teva Pharma, but remember within 12 hours of your usual \ntime, take your tablet straightaway and then take your next tablet at the usual time. \n \n\n31 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\nIf you forget for more than 12 hours, simply take the next single dose at the usual time. Do not take a \ndouble dose to make up for a forgotten tablet. \n \nFor the 28x1 tablets pack size, you can check the day on which you last took the tablet by referring to \nthe calendar printed on the blister. \n \nIf you stop taking Clopidogrel Teva Pharma \nDo not stop the treatment unless your doctor tells you so. Contact your doctor or pharmacist before \nstopping. \n \nIf you have any further questions on the use of this medicine, ask your doctor or pharmacist. \n \n \n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. \n \nContact your doctor immediately if you experience: \n- fever, signs of infection or extreme tiredness. These may be due to rare decrease of some blood \n\ncells. \n- signs of liver problems such as yellowing of the skin and/or the eyes (jaundice), whether or not \n\nassociated with bleeding which appears under the skin as red pinpoint dots and/or confusion \n(see section 2 ‘Warnings and precautions’). \n\n- swelling in the mouth or skin disorders such as rashes and itching, blisters of the skin. These \nmay be the signs of an allergic reaction. \n\n \nThe most common side effect reported with Clopidogrel Teva Pharma is bleeding. \nBleeding may occur as bleeding in the stomach or bowels, bruising, haematoma (unusual bleeding or \nbruising under the skin), nose bleed, blood in the urine. In a small number of cases, bleeding in the \neye, inside the head, the lung or the joints has also been reported. \n \nIf you experience prolonged bleeding when taking Clopidogrel Teva Pharma \nIf you cut or injure yourself, it may take slightly longer than usual for bleeding to stop. This is linked \nto the way your medicine works as it prevents the ability of blood clots to form. For minor cuts and \ninjuries e.g., cutting yourself, shaving, this is usually of no concern. However, if you are concerned by \nyour bleeding, you should contact your doctor straightaway (see section 2 ‘Warnings and \nprecautions’). \n \nOther side effects include: \n \nCommon side effects (may affect up to 1 in 10 people): \nDiarrhoea, abdominal pain, indigestion or heartburn. \n \nUncommon side effects (may affect up to 1 in 100 people): \nHeadache, stomach ulcer, vomiting, nausea, constipation, excessive gas in stomach or intestines, \nrashes, itching, dizziness, sensation of tingling and numbness. \n \nRare side effect (may affect up to 1 in 1000 people): \nVertigo, enlarged breasts in males. \n \nVery rare side effects (may affect up to 1 in 10,000 people): \nJaundice; severe abdominal pain with or without back pain; fever, breathing difficulties sometimes \nassociated with cough; generalised allergic reactions (for example, overall sensation of heat with \nsudden general discomfort until fainting); swelling in the mouth; blisters of the skin; skin allergy; sore \nmouth (stomatitis); decrease in blood pressure; confusion; hallucinations; joint pain; muscular pain; \nchanges in taste of food. \n\n32 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n \nIn addition, your doctor may identify changes in your blood or urine test results. \n \nReporting of side effects \nIf you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects \nnot listed in this leaflet. You can also report side effects directly via the national reporting system \nlisted in Appendix V. By reporting side effects you can help provide more information on the safety of \nthis medicine. \n \n \n5. How to store Clopidogrel Teva Pharma \n \nKeep this medicine out of the sight and reach of children. \n \nDo not use this medicine after the expiry date which is stated on the carton and on the blister, after \nEXP. The expiry date refers to the last day of that month. \n \nStore in the original package in order to protect from moisture and light. \n \nDo not throw away any medicines via wastewater or household waste. Ask your pharmacist how to \nthrow away medicines you no longer use. These measures will help to protect the environment. \n \n \n6. Contents of the pack and other information \n \nWhat Clopidogrel Teva Pharma contains \nThe active substance is clopidogrel. Each film-coated tablet contains 75 mg of clopidogrel (as \nhydrochloride). \n \nThe other ingredients are (see section 2 ‘Clopidogrel Teva Pharma contains hydrogenated castor oil’): \n\n Tablet core: microcrystalline cellulose, colloidal anhydrous silica, crospovidone (type A), \nmacrogol 6000 and hydrogenated castor oil \n\n Tablet coating: Polyvinyl alcohol, titanium dioxide (E171), red iron oxide (E172), yellow \niron oxide (E172), talc and macrogol 3000. \n\n \nWhat Clopidogrel Teva Pharma looks like and contents of the pack \nThe film-coated tablets are pink, round and slightly convex. \nBoxes of 7, 14, 28, 30, 50, 56, 84, 90 and 100 film-coated tablets in blisters or boxes of 28x1 and 50x1 \nfilm-coated tablets in perforated unit dose blisters are available. \n \nNot all pack sizes may be marketed. \n \nMarketing Authorisation Holder \n \nTeva B.V. \nSwensweg 5 \n2031GA Haarlem \nThe Netherlands \n \nManufacturers \nKRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia \nTAD Pharma GmbH, Heinz-Lohmann-Straße 5, 27472 Cuxhaven, Germany \nPharmachemie B.V., Swensweg 5, 2031 GA Haarlem, The Netherlands \n \nFor any information about this medicinal product, please contact the local representative of the \nMarketing Authorisation Holder \n\n33 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n34 \n\n \nBelgië/Belgique/Belgien \nTeva Pharma Belgium N.V./S.A. /AG \nTel/Tél: +32 3 820 73 73 \n \n\nLietuva \nUAB “Sicor Biotech” \nTel: +370 5 266 02 03 \n\nБългария \nТева Фармасютикълс България ЕООД \nTeл: +359 2 489 95 82 \n\nLuxembourg/Luxemburg \nratiopharm GmbH \nAllemagne/Deutschland \nTél/Tel: +49 731 402 02 \n \n\nČeská republika \nTeva Pharmaceuticals CR, s.r.o. \nTel: +420 251 007 111 \n \n\nMagyarország \nTeva Gyógyszergyár Zrt. \nTel.: +36 1 288 64 00 \n\nDanmark \nTeva Denmark A/S \nTlf: +45 44 98 55 11 \n\nMalta \nTeva Pharmaceuticals Ireland \nL-Irlanda \nTel: +353 51 321740 \n \n\nDeutschland \nTEVA GmbH \nTel: (+49) 731 402 08 \n \n\nNederland \nTeva Nederland B.V. \nTel: +31 (0) 800 0228400 \n\nEesti \nTeva Eesti esindus UAB Sicor Biotech \nEesti filiaal \nTel: +372 6610801 \n \n\nNorge \nTeva Norway AS \nTlf: 47 66 77 55 90 \n\nΕλλάδα \nTeva Ελλάς Α.Ε. \nΤηλ: +30 210 72 79 099 \n \n\nÖsterreich \nratiopharm Arzneimittel Vertriebs-GmbH \nTel: +43/1/97007-0 \n\nEspaña \nTEVA PHARMA, S.L.U \nTel: +(34) 91 387 32 80 \n \n\nPolska \nTeva Pharmaceuticals Polska Sp. z o.o. \nTel.: +(48) 22 345 93 00 \n\nFrance \nTeva Santé \nTél: +(33) 1 55 91 7800 \n \n\nPortugal \nTeva Pharma - Produtos Farmacêuticos Lda \nTel: +351 21 476 75 50 \n\nHrvatska \nPliva Hrvatska d.o.o. \nTel:+ 385 1 37 20 000 \n \n\nRomânia \nTeva Pharmaceuticals S.R.L \nTel: +4021 230 65 24 \n\nIreland \nTeva Pharmaceuticals Ireland \nTel: +353 (0)51 321 740 \n \n\nSlovenija \nPliva Ljubljana d.o.o. \nTel: +386 1 58 90 390 \n\nÍsland \nratiopharm Oy \nFinnland \nSími: +358 20 180 5900 \n \n\nSlovenská republika \nTeva Pharmaceuticals Slovakia s.r.o. \nTel: +(421) 2 5726 7911 \n \n\nItalia \nTeva Italia S.r.l \nTel: +(39) 028917981 \n\nSuomi/Finland \nratiopharm Oy \nPuh/Tel: +358 20 180 5900 \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\n35 \n\n \n\nΚύπρος \nTeva Ελλάς Α.Ε. \nΕλλάδα \nΤηλ: +30 210 72 79 099 \n \n\nSverige \nTeva Sweden AB \nTel: +(46) 42 12 11 00 \n \n\nLatvija \nUAB Sicor Biotech filiāle Latvijā \nTel: +371 67 323 666 \n \n\nUnited Kingdom \nTeva UK Limited \nTel: +44(0) 1977 628500 \n \n\n \nThis leaflet was last revised in. \n \nDetailed information is available on the European Medicines Agency website: \nhttp://www.ema.europa.eu. \n \n\n \n \n \n\nMe\ndic\n\nina\nl p\n\nro\ndu\n\nct \nno\n\n lo\nng\n\ner\n au\n\nth\nor\n\nise\nd\n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT\n\tA. LABELLING\n\tB. PACKAGE LEAFLET"},"Section_1":{"kind":"string","value":"{'Title': '1. what clopidogrel teva pharma is and what it is used for', 'Section_Content': \"clopidogrel teva pharma contains clopidogrel and belongs to a group of medicines called antiplatelet medicinal products. platelets are very small structures in the blood, which clump together during blood clotting. by preventing this clumping, antiplatelet medicinal products reduce the chances of blood clots forming (a process called thrombosis). clopidogrel teva pharma is taken by adults to prevent blood clots (thrombi) forming in hardened blood vessels (arteries), a process known as atherothrombosis, which can lead to atherothrombotic events (such as stroke, heart attack, or death). you have been prescribed clopidogrel teva pharma to help prevent blood clots and reduce the risk of these severe events because: - you have a condition of hardening of arteries (also known as atherosclerosis), and - you have previously experienced a heart attack, stroke or have a condition known as peripheral arterial disease, or - you have experienced a severe type of chest pain known as 'unstable angina' or 'myocardial infarction' (heart attack). for the treatment of this condition your doctor may have placed a stent in the blocked or narrowed artery to restore effective blood flow. you should also be given acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever as well as to prevent blood clotting) by your doctor. - you have an irregular heartbeat, a condition called 'atrial fibrillation', and you cannot take medicines known as 'oral anticoagulants' (vitamin k antagonists) which prevent new clots from forming and prevent existing clots from growing. you should have been told that 'oral anticoagulants' are more effective than acetylsalicylic acid or the combined use of clopidogrel teva pharma and acetylsalicylic acid for this condition. your doctor should have prescribed clopidogrel teva pharma 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1895, 'EndOffset': 1899, 'Text': 'oral', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 63, 'BeginOffset': 1895, 'EndOffset': 1914, 'Score': 0.744521975517273, 'Text': 'oral anticoagulants', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'major bleeding', 'Type': 'PROBLEM', 'BeginOffset': 1946, 'EndOffset': 1960}]}"},"Section_2":{"kind":"string","value":"{'Title': '2. what you need to know before you take clopidogrel teva pharma', 'Section_Content': \"do not take clopidogrel teva pharma if you are allergic to clopidogrel or any of the other ingredients of this medicine (listed in section 6). if you have a medical condition that is currently causing bleeding such as a stomach ulcer or bleeding within the brain. if you suffer from severe liver disease. if you think any of these apply to you, or if you are in any doubt at all, consult your doctor before taking clopidogrel teva pharma. warnings and precautions if any of the situations mentioned below apply to you, you should tell your doctor before taking clopidogrel teva pharma: if you have a risk of bleeding such as - a medical condition that puts you at risk of internal bleeding (such as a stomach ulcer) - a blood disorder that makes you prone to internal bleeding (bleeding inside any tissues, organs or joints of your body). - a recent serious injury. - a recent surgery (including dental). - a planned surgery (including dental) in the next seven days. if you have had a clot in an artery of your brain (ischaemic stroke) which occurred within the last seven days. if you have kidney or liver disease. if you have had an allergy or reaction to any medicine used to treat your disease. while you are taking clopidogrel teva pharma: you should tell your doctor if a surgery (including dental) is planned. you should also tell your doctor immediately if you develop a medical condition (also known as thrombotic thrombocytopenic purpura or ttp) that includes fever and bruising under the skin that may appear as red pinpoint dots, with or without unexplained extreme tiredness, confusion, yellowing of the skin or eyes (jaundice) (see section 4 'possible side effects'). if you cut or injure yourself, it may take longer than usual for bleeding to stop. this is linked to the way your medicine works as it prevents the ability of blood clots to form. for minor cuts and injuries e.g., cutting yourself, shaving, this is usually of no concern. however, if you are concerned by your bleeding, you should contact your doctor straightaway (see section 4 'possible side effects'). your doctor may order blood tests. children and adolescents do not give this medicine to children because it does not work. other medicines and clopidogrel teva pharma tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines, including medicines obtained without a prescription. some other medicines may influence the use of clopidogrel teva pharma or vice versa. you should specifically tell your doctor if you take - medicines that may increase your risk of bleeding such as: o oral anticoagulants, medicines used to reduce blood clotting, o a non-steroidal anti-inflammatory medicine, usually used to treat painful and/or inflammatory conditions of muscle or joints, o heparin or any other injectable medicine used to reduce blood clotting, o ticlopidine, other antiplatelet agent, o a selective serotonin reuptake inhibitor (including but not restricted to fluoxetine or fluvoxamine), medicines usually used to treat depression, - omeprazole or esomeprazole, medicines to treat upset stomach, 30 - fluconazole or voriconazole, medicines to treat fungal infections, - efavirenz, a medicine to treat hiv (human immunodeficiency virus) infections, - carbamazepine, a medicine to treat some forms of epilepsy, - moclobemide, medicine to treat depression, - repaglinide, medicine to treat diabetes, - paclitaxel, medicine to treat cancer. if you have experienced severe chest pain (unstable angina or heart attack), you may be prescribed clopidogrel teva pharma in combination with acetylsalicylic acid, a substance present in many medicines used to relieve pain and lower fever. an occasional use of acetylsalicylic acid (no more than 1,000 mg in any 24 hour period) should generally not cause a problem, but prolonged use in other circumstances should be discussed with your doctor. pregnancy and breast-feeding it is preferable not to take this medicine during pregnancy. if you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist before taking clopidogrel teva pharma. if you become pregnant while taking clopidogrel teva pharma, consult your doctor immediately as it is recommended not to take clopidogrel while you are pregnant. you should not breast-feed while taking this medicine. if you are breast-feeding or planning to breast-feed, talk to your doctor before taking this medicine. ask your doctor or 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patients with a condition called 'atrial fibrillation' (an irregular heartbeat), is one 75 mg tablet of clopidogrel teva pharma per day to be taken orally with or without food, and at the same time each day. if you have experienced severe chest pain (unstable angina or heart attack), your doctor may give you 300 mg of clopidogrel teva pharma (4 tablets of 75 mg) once at the start of treatment. then, the recommended dose is one 75 mg tablet of clopidogrel teva pharma per day as described above. you should take clopidogrel teva pharma for as long as your doctor continues to prescribe it. if you take more clopidogrel teva pharma than you should contact your doctor or the nearest hospital emergency department because of the increased risk of bleeding. if you forget to take clopidogrel teva pharma if you forget to take a dose of clopidogrel teva pharma, but remember within 12 hours of your usual time, take your tablet straightaway and then take your next tablet at the usual time. if you forget for more than 12 hours, simply take the next single dose at the usual time. do not take a double dose to make up for a forgotten tablet. for the 28x1 tablets pack size, you can check the day on which you last took the tablet by referring to the calendar printed on the blister. if you stop taking clopidogrel teva pharma do not stop the treatment unless your doctor tells you so. contact your doctor or pharmacist before stopping. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.\", 'Entity_Recognition': [{'Text': 'clopidogrel teva pharma', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': 'a condition', 'Type': 'PROBLEM', 'BeginOffset': 185, 'EndOffset': 196}, {'Text': \"'atrial fibrillation\", 'Type': 'PROBLEM', 'BeginOffset': 204, 'EndOffset': 224}, {'Text': 'an irregular heartbeat', 'Type': 'PROBLEM', 'BeginOffset': 227, 'EndOffset': 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appears under the skin as red pinpoint dots and/or confusion (see section 2 'warnings and precautions'). - swelling in the mouth or skin disorders such as rashes and itching, blisters of the skin. these may be the signs of an allergic reaction. the most common side effect reported with clopidogrel teva pharma is bleeding. bleeding may occur as bleeding in the stomach or bowels, bruising, haematoma (unusual bleeding or bruising under the skin), nose bleed, blood in the urine. in a small number of cases, bleeding in the eye, inside the head, the lung or the joints has also been reported. if you experience prolonged bleeding when taking clopidogrel teva pharma if you cut or injure yourself, it may take slightly longer than usual for bleeding to stop. this is linked to the way your medicine works as it prevents the ability of blood clots to form. for minor cuts and injuries e.g., cutting yourself, shaving, this is usually of no concern. however, if you are concerned by your bleeding, you should contact your doctor straightaway (see section 2 'warnings and precautions'). other side effects include: common side effects (may affect up to 1 in 10 people): diarrhoea, abdominal pain, indigestion or heartburn. uncommon side effects (may affect up to 1 in 100 people): headache, stomach ulcer, vomiting, nausea, constipation, excessive gas in stomach or intestines, rashes, itching, dizziness, sensation of tingling and numbness. rare side effect (may affect up to 1 in 1000 people): vertigo, enlarged breasts in males. very rare side effects (may affect up to 1 in 10,000 people): jaundice; severe abdominal pain with or without back pain; fever, breathing difficulties sometimes associated with cough; generalised allergic reactions (for example, overall sensation of heat with sudden general discomfort until fainting); swelling in the mouth; blisters of the skin; skin allergy; sore mouth (stomatitis); decrease in blood pressure; confusion; hallucinations; joint pain; muscular pain; changes in taste of food. in addition, your doctor may identify changes in your blood or urine test results. reporting of side effects if you get any side effects, talk to your doctor or pharmacist. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.\", 'Entity_Recognition': [{'Text': 'clopidogrel teva pharma', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 24, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9625135660171509, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7366946339607239}]}, {'Id': 81, 'BeginOffset': 112, 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yellow iron oxide (e172), talc and macrogol 3000. what clopidogrel teva pharma looks like and contents of the pack the film-coated tablets are pink, round and slightly convex. boxes of 7, 14, 28, 30, 50, 56, 84, 90 and 100 film-coated tablets in blisters or boxes of 28x1 and 50x1 film-coated tablets in perforated unit dose blisters are available. not all pack sizes may be marketed.\", 'Entity_Recognition': [{'Text': 'clopidogrel teva pharma', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'clopidogrel teva pharma', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 28}, {'Id': 2, 'BeginOffset': 62, 'EndOffset': 73, 'Score': 0.9984283447265625, 'Text': 'clopidogrel', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.8767215013504028, 'RelationshipScore': 0.9916655421257019, 'RelationshipType': 'FORM', 'Id': 3, 'BeginOffset': 92, 'EndOffset': 98, 'Text': 'tablet', 'Category': 'MEDICATION', 'Traits': []}]}, 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\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX I \n \n\nSUMMARY OF PRODUCT CHARACTERISTICS \n \n\n \n \n \n\n\n\n2 \n\n1. NAME OF THE MEDICINAL PRODUCT \n \nPotactasol 1 mg powder for concentrate for solution for infusion \nPotactasol 4 mg powder for concentrate for solution for infusion \n \n \n2. QUALITATIVE AND QUANTITATIVE COMPOSITION \n \nPotactasol 1 mg powder for concentrate for solution for infusion \nEach vial contains 1 mg topotecan (as hydrochloride). \nAfter reconstitution, 1 ml concentrate contains 1 mg topotecan. \nExcipient with known effect \nEach vial contains 0.52 mg (0.0225 mmol) sodium. \n \nPotactasol 4 mg powder for concentrate for solution for infusion \nEach vial contains 4 mg topotecan (as hydrochloride). \nAfter reconstitution, 1 ml concentrate contains 1 mg topotecan. \nExcipient with known effect \nEach vial contains 2.07 mg (0.09 mmol) sodium. \n \n \nFor the full list of excipients, see section 6.1. \n \n \n3. PHARMACEUTICAL FORM \n \nPowder for concentrate for solution for infusion. \n \nYellow lyophilisate. \n \n \n4. CLINICAL PARTICULARS \n \n4.1 Therapeutic indications \n \nTopotecan monotherapy is indicated for the treatment of: \n- patients with metastatic carcinoma of the ovary after failure of first-line or subsequent therapy \n- patients with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first-line \n\nregimen is not considered appropriate (see section 5.1). \n \nTopotecan in combination with cisplatin is indicated for patients with carcinoma of the cervix \nrecurrent after radiotherapy and for patients with Stage IVB disease. Patients with prior exposure to \ncisplatin require a sustained treatment free interval to justify treatment with the combination (see \nsection 5.1). \n \n4.2 Posology and method of administration \n \nThe use of topotecan should be confined to units specialised in the administration of cytotoxic \nchemotherapy. Topotecan should only be administered under the supervision of a physician \nexperienced in the use of chemotherapy (see section 6.6). \n \nPosology \n \nWhen topotecan is used in combination with cisplatin, the full prescribing information for cisplatin \nshould be consulted. \n \n\n\n\n3 \n\nPrior to administration of the first course of topotecan, patients must have a baseline neutrophil count \nof ≥ 1.5 x 109/l, a platelet count of ≥ 100 x 109/l and a haemoglobin level of ≥ 9 g/dl (after transfusion \nif necessary). \n \nOvarian and small cell lung carcinoma \n \nInitial dose \nThe recommended dose of topotecan is 1.5 mg/m2 body surface area per day administered by \nintravenous infusion over 30 minutes daily for five consecutive days with a three week interval \nbetween the start of each course. If well tolerated, treatment may continue until disease progression \n(see sections 4.8 and 5.1). \n \nSubsequent doses \nTopotecan should not be re-administered unless the neutrophil count is ≥ 1 x 109/l, the platelet count \nis ≥ 100 x 109/l, and the haemoglobin level is ≥ 9 g/dl (after transfusion if necessary). \n \nStandard oncology practice for the management of neutropenia is either to administer topotecan with \nother medicinal products (e.g. G-CSF) or to reduce the dose to maintain neutrophil counts. \n \nIf dose reduction is chosen for patients who experience severe neutropenia (neutrophil \ncount < 0.5 x 109/l) for seven days or more, or severe neutropenia associated with fever or infection, or \nwho have had treatment delayed due to neutropenia, the dose should be reduced by 0.25 mg/m2/day to \n1.25 mg/m2/day (or subsequently down to 1.0 mg/m2/day if necessary). \n \nDoses should be similarly reduced if the platelet count falls below 25 x 109/l. In clinical studies, \ntopotecan was discontinued if the dose had been reduced to 1.0 mg/m2/day and a further dose \nreduction was required to manage adverse effects. \n \nCervical carcinoma \n \nInitial dose \nThe recommended dose of topotecan is 0.75 mg/m2/day administered as a 30-minute intravenous \ninfusion on days 1, 2 and 3. Cisplatin is administered as an intravenous infusion on day 1 at a dose of \n50 mg/m2/day and following the topotecan dose. This treatment schedule is repeated every 21 days for \nsix courses or until progressive disease. \n \nSubsequent doses \nTopotecan should not be re-administered unless the neutrophil count is ≥ 1.5 x 109/l, the platelet count \nis ≥ 100 x 109/l, and the haemoglobin level is ≥ 9 g/dl (after transfusion if necessary). \n \nStandard oncology practice for the management of neutropenia is either to administer topotecan with \nother medicinal products (e.g. G-CSF) or to reduce the dose to maintain neutrophil counts. \n \nIf dose reduction is chosen for patients who experience severe neutropenia (neutrophil count \n< 0.5 x 109/l) for seven days or more, or severe neutropenia associated with fever or infection or who \nhave had treatment delayed due to neutropenia, the dose should be reduced by 20 % to 0.60 mg/m2/day \nfor subsequent courses (or subsequently down to 0.45 mg/m2/day if necessary). \n \nDoses should be similarly reduced if the platelet count falls below 25 x 109/l. \n \nSpecial populations \n \nPatients with renal impairment \nMonotherapy (ovarian and small cell lung carcinoma) \nThere is insufficient experience with the use of topotecan in patients with severely impaired renal \nfunction (creatinine clearance <20 ml/min). Use of topotecan in this group of patients is not \nrecommended (see section 4.4). \n\n\n\n4 \n\nLimited data indicate that the dose should be reduced in patients with moderate renal impairment. The \nrecommended monotherapy dose of topotecan in patients with ovarian or small cell lung carcinoma \nand a creatinine clearance between 20 and 39 ml/min is 0.75 mg/m2/day for five consecutive days. \n \nCombination therapy (cervical carcinoma) \nIn clinical studies with topotecan in combination with cisplatin for the treatment of cervical cancer, \ntherapy was only initiated in patients with serum creatinine less than or equal to 1.5 mg/dl. If, during \ntopotecan/cisplatin combination therapy serum creatinine exceeds 1.5 mg/dl, it is recommended that \nthe full prescribing information be consulted for any advice on cisplatin dose reduction/continuation. \nIf cisplatin is discontinued, there are insufficient data regarding continuing monotherapy with \ntopotecan in patients with cervical cancer. \n \nPatients with hepatic impairment \nA small number of hepatically impaired patients (serum bilirubin between 1.5 and 10 mg/dl) were \ngiven intravenous topotecan at 1.5 mg/m2/day for five days every three weeks. A reduction in \ntopotecan clearance was observed. However, there are insufficient data available to make a dose \nrecommendation for this patient group (see section 4.4). \n \nThere is insufficient experience with the use of topotecan in patients with severely impaired hepatic \nfunction (serum bilirubin ≥ 10 mg/dl) due to cirrhosis. Topotecan is not recommended to be used in \nthis patient group (see section 4.4). \n \nPaediatric population \nCurrently available data are described in sections 5.1 and 5.2 but no recommendation on a posology \ncan be made. \n \nMethod of administration \n \nPotactasol is for intravenous infusion after reconstitution and dilution. It must be reconstituted and \nfurther diluted before use (see section 6.6). \n \nPrecautions to be taken before handling or administering the medicinal product \nReconstitution and dilution of the medicinal product must be performed by trained personnel. The \npreparation should be performed in a designated area under aseptic conditions. \nAdequate protective disposable gloves, goggles, gown and mask should be worn. Precautions should \nbe taken to avoid the medicinal product accidentally coming into contact with the eyes. In the event of \ncontact with the eyes, irrigate with large amounts of water. Then seek medical evaluation by a \nphysician. In case of skin contact, thoroughly wash the affected area with large amount of water. \nAlways wash hands after removing gloves. See section 6.6. \n \nPregnant staff should not handle the cytotoxic preparation. \n \n4.3 Contraindications \n \n- Severe hypersensitivity to the active substance or to any of the excipients listed in section 6.1 \n- Breast-feeding (see section 4.6) \n- Severe bone marrow depression prior to starting first course, as evidenced by baseline \n\nneutrophils < 1.5 x 109/l and/or a platelet count of < 100 x 109/l. \n \n4.4 Special warnings and precautions for use \n \nHaematological toxicity is dose-related and full blood count including platelets should be determined \nregularly (see section 4.2). \n \nAs with other cytotoxic medicinal products, topotecan can cause severe myelosuppression. \nMyelosuppression leading to sepsis and fatalities due to sepsis have been reported in patients treated \nwith topotecan (see section 4.8). \n\n\n\n5 \n\n \nTopotecan-induced neutropenia can cause neutropenic colitis. Fatalities due to neutropenic colitis have \nbeen reported in clinical studies with topotecan. In patients presenting with fever, neutropenia, and a \ncompatible pattern of abdominal pain, the possibility of neutropenic colitis should be considered. \n \nTopotecan has been associated with reports of interstitial lung disease (ILD), some of which have been \nfatal (see section 4.8). Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, \nthoracic exposure to radiation and use of pneumotoxic substances and/or colony stimulating factors. \nPatients should be monitored for pulmonary symptoms indicative of ILD (e.g. cough, fever, dyspnoea \nand/or hypoxia), and topotecan should be discontinued if a new diagnosis of ILD is confirmed. \n \nTopotecan monotherapy and topotecan in combination with cisplatin are commonly associated with \nclinically relevant thrombocytopenia. This should be taken into account, when prescribing topotecan, \ne.g. if patients at increased risk of tumour bleeds are considered for therapy. \n \nAs would be expected, patients with poor performance status (PS > 1) have a lower response rate and \nan increased incidence of complications such as fever, infection and sepsis (see section 4.8). Accurate \nassessment of performance status at the time therapy is given is important, to ensure that patients have \nnot deteriorated to PS 3. \n \nThere is insufficient experience of the use of topotecan in patients with severely impaired renal \nfunction (creatinine clearance < 20 ml/min) or severely impaired hepatic function (serum \nbilirubin ≥ 10 mg/dl) due to cirrhosis. Use of topotecan in these patient groups is not recommended \n(see section 4.2). \n \nA small number of hepatically impaired patients (serum bilirubin between 1.5 and 10 mg/dl) were \ngiven intravenous topotecan at 1.5 mg/m2/day for five days every three weeks. A reduction in \ntopotecan clearance was observed. However, there are insufficient data available to make a dose \nrecommendation for this patient group (see section 4.2). \n \nThis medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium-\nfree’. \n \n4.5 Interaction with other medicinal products and other forms of interaction \n \nNo in vivo human pharmacokinetic interaction studies have been performed. \n \nTopotecan does not inhibit human P450 enzymes (see section 5.2). In a population study using the \nintravenous route, the co-administration of granisetron, ondansetron, morphine or corticosteroids did \nnot appear to have a significant effect on the pharmacokinetics of total topotecan (active and inactive \nform). \n \nWhen combining topotecan with other chemotherapy agents, reduction of the doses of each medicinal \nproduct may be required to improve tolerability. However, when combining with platinum agents, \nthere is a distinct sequence-dependent interaction depending on whether the platinum agent is given on \nday 1 or 5 of the topotecan dosing. If either cisplatin or carboplatin is given on day 1 of the topotecan \ndosing, a lower dose of each agent must be given to improve tolerability compared to the dose of each \nagent which can be given if the platinum agent is given on day 5 of the topotecan dosing. \n \nWhen topotecan (0.75 mg/m2/day for 5 consecutive days) and cisplatin (60 mg/m2/day on day 1) were \nadministered in 13 patients with ovarian cancer, a slight increase in AUC (12 %, n = 9) and \nCmax (23 %, n = 11) was noted on day 5. This increase is considered unlikely to be of clinical \nrelevance. \n \n4.6 Fertility, pregnancy and lactation \n \nWomen of childbearing potential / Contraception in males and females \n\n\n\n6 \n\n \nTopotecan has been shown to cause embryo-foetal lethality and malformations in preclinical studies \n(see section 5.3). As with other cytotoxic medicinal products, topotecan may cause foetal harm and \ntherefore women of childbearing potential should be advised to avoid becoming pregnant during \ntherapy with topotecan. \n \nAs with all cytotoxic chemotherapy, patients being treated with topotecan must be advised that \nthey or their partner must use an effective method of contraception. \n \nPregnancy \n \nIf topotecan is used during pregnancy, or if the patient becomes pregnant during therapy with \ntopotecan, the patient must be warned of the potential hazards to the foetus. \n \nBreast-feeding \n \nTopotecan is contraindicated during breast-feeding (see section 4.3). Although it is not known whether \ntopotecan is excreted in human breast milk, breast-feeding should be discontinued at the start of \ntherapy. \n \nFertility \n \nNo effects on male or female fertility have been observed in reproductive toxicity studies in rats (see \nsection 5.3). However, as with other cytotoxic medicinal products topotecan is genotoxic and effects \non fertility, including male fertility, cannot be excluded. \n \n4.7 Effects on ability to drive and use machines \n \nNo studies of the effects on the ability to drive and use machines have been performed. However, \ncaution should be observed when driving or operating machines if fatigue and asthenia persist. \n \n4.8 Undesirable effects \n \nIn dose-finding studies involving 523 patients with relapsed ovarian cancer and 631 patients with \nrelapsed small cell lung cancer, the dose limiting toxicity of topotecan monotherapy was found to be \nhaematological. Toxicity was predictable and reversible. There were no signs of cumulative \nhaematological or non-haematological toxicity. \n \nThe safety profile of topotecan when given in combination with cisplatin in the cervical cancer clinical \nstudies is consistent with that seen with topotecan monotherapy. The overall haematological toxicity is \nlower in patients treated with topotecan in combination with cisplatin compared to topotecan \nmonotherapy, but higher than with cisplatin alone. \n \nAdditional adverse events were seen when topotecan was given in combination with cisplatin, \nhowever, these events were seen with cisplatin monotherapy and were not attributable to topotecan. \nThe prescribing information for cisplatin should be consulted for a full list of adverse events \nassociated with cisplatin use. \n \nThe integrated safety data for topotecan monotherapy are presented below. \n \nAdverse reactions are listed below, by system organ class and absolute frequency (all reported events). \nFrequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10); \nuncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) and not \nknown (cannot be estimated from the available data). \n \nWithin each frequency grouping, undesirable effects are presented in order of decreasing seriousness. \n \n\n\n\n7 \n\nInfections and infestations \nVery common: infection \nCommon: sepsis1 \n\n \nBlood and lymphatic system disorders \nVery common: febrile neutropenia \n\nneutropenia (see Gastrointestinal disorders below) \nthrombocytopenia \nanaemia \nleucopenia \n\nCommon: pancytopenia \nNot known: severe bleeding (associated with thrombocytopenia) \nImmune system disorders \nCommon: hypersensitivity reaction including rash \nRare: anaphylactic reaction \n\nangioedema \nurticaria \n\nMetabolism and nutrition disorders \nVery common: anorexia (which may be severe) \nRespiratory, thoracic and mediastinal disorders \nRare: interstitial lung disease (some cases have been fatal) \nGastrointestinal disorders \nVery common: \n \n\nnausea, vomiting and diarrhoea (all of which may be severe) \nconstipation \nabdominal pain2 \nmucositis \n\nNot known: gastrointestinal perforation \nHepatobiliary disorders \nCommon: hyperbilirubinaemia \nSkin and subcutaneous tissue disorders \nVery common: alopecia \nCommon: pruritus \nGeneral disorders and administration site conditions \nVery common: pyrexia \n\nasthenia \nfatigue \n\nCommon: malaise \nVery rare: extravasation3 \nNot known: mucosal inflammation \n\n \n1 Fatalities due to sepsis have been reported in patients treated with topotecan (see \nsection 4.4) \n2 Neutropenic colitis, including fatal neutropenic colitis, has been reported to occur as \na complication of topotecan-induced neutropenia (see section 4.4). \n3 Reactions have been mild and have not generally required specific therapy. \n \nThe adverse events listed above have the potential to occur with a higher frequency in patients who \nhave a poor performance status (see section 4.4). \n \nThe frequencies associated with the haematological and non-haematological adverse events listed \nbelow represent the adverse event reports considered to be related/possibly related to topotecan \ntherapy. \n \nHaematological \nNeutropenia: Severe (neutrophil count < 0.5 x 109/l) during course 1 in 55 % of patients, with \nduration ≥ seven days in 20 % and overall in 77 % of patients (39 % of courses). In association with \nsevere neutropenia, fever or infection occurred in 16 % of patients during course 1 and overall in 23 % \n\n\n\n8 \n\nof patients (6 % of courses). Median time to onset of severe neutropenia was nine days and the median \nduration was seven days. Severe neutropenia lasted beyond seven days in 11 % of courses overall. \nAmong all patients treated in clinical studies (including both those with severe neutropenia and those \nwho did not develop severe neutropenia), 11 % (4 % of courses) developed fever and 26 % (9 % of \ncourses) developed infection. In addition, 5 % of all patients treated (1 % of courses) developed sepsis \n(see section 4.4). \n \nThrombocytopenia: Severe (platelets < 25 x 109/l) in 25 % of patients (8 % of courses); moderate \n(platelets between 25.0 and 50.0 x 109/l) in 25 % of patients (15 % of courses). Median time to onset \nof severe thrombocytopenia was day 15 and the median duration was five days. Platelet transfusions \nwere given in 4 % of courses. Reports of significant sequelae associated with thrombocytopenia \nincluding fatalities due to tumour bleeds have been infrequent. \n \nAnaemia: Moderate to severe (Hb ≤ 8.0 g/dl) in 37 % of patients (14 % of courses). Red cell \ntransfusions were given in 52 % of patients (21 % of courses). \n \nNon-haematological \nFrequently reported non-haematological effects were gastrointestinal such as nausea (52 %), vomiting \n(32 %), diarrhoea (18 %), constipation (9 %) and mucositis (14 %). The incidence of severe \n(Grade 3 or 4) nausea, vomiting, diarrhoea and mucositis was 4, 3, 2 and 1 % respectively. \n \nMild abdominal pain was reported in 4 % of patients. \n \nFatigue was observed in approximately 25 % and asthenia in 16 % of patients receiving topotecan. \nSevere (Grade 3 or 4) fatigue and asthenia both occurred with an incidence of 3 %. \n \nTotal or pronounced alopecia was observed in 30 % of patients and partial alopecia in 15 % of \npatients. \n \nOther severe events that were recorded as related or possibly related to topotecan treatment were \nanorexia (12 %), malaise (3 %) and hyperbilirubinaemia (1 %). \n \nHypersensitivity reactions including rash, urticaria, angioedema and anaphylactic reactions have been \nreported rarely. In clinical studies, rash was reported in 4 % of patients and pruritus in 1.5 % of \npatients. \n \nReporting of suspected adverse reactions \nReporting suspected adverse reactions after authorisation of the medicinal product is important. It \nallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare \nprofessionals are asked to report any suspected adverse reactions via the national reporting system \nlisted in Appendix V. \n \n4.9 Overdose \n \nOverdoses have been reported in patients being treated with intravenous topotecan (up to 10 fold of \nthe recommended dose) and topotecan capsules (up to 5 fold of the recommended dose). The signs and \nsymptoms observed following overdose were consistent with the known undesirable events associated \nwith topotecan (see section 4.8). The primary complications of overdose are bone marrow suppression \nand mucositis. In addition, elevated hepatic enzymes have been reported with intravenous topotecan \noverdose. \n \nThere is no known antidote for topotecan overdose. Further management should be as clinically \nindicated or as recommended by the national poisons centre, where available. \n \n \n5. PHARMACOLOGICAL PROPERTIES \n \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n9 \n\n5.1 Pharmacodynamic properties \n \nPharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, ATC code: L01XX17. \n \nMechanism of action \n \nThe anti-tumour activity of topotecan involves the inhibition of topoisomerase-I, an enzyme intimately \ninvolved in DNA replication as it relieves the torsional strain introduced ahead of the moving \nreplication fork. Topotecan inhibits topoisomerase-I by stabilising the covalent complex of enzyme \nand strand-cleaved DNA which is an intermediate of the catalytic mechanism. The cellular sequela of \ninhibition of topoisomerase-I by topotecan is the induction of protein-associated DNA single-strand \nbreaks. \n \nClinical efficacy and safety \n \nRelapsed ovarian cancer \nIn a comparative study of topotecan and paclitaxel in patients previously treated for ovarian carcinoma \nwith platinum based chemotherapy (n = 112 and 114, respectively), the response rate (95 % CI) was \n20.5 % (13 %, 28 %) versus 14 % (8 %, 20 %) and median time to progression 19 weeks versus \n15 weeks (hazard ratio 0.7 [0.6, 1.0]), for topotecan and paclitaxel, respectively. Median overall \nsurvival was 62 weeks for topotecan versus 53 weeks for paclitaxel (hazard ratio 0.9 [0.6, 1.3]). \n \nThe response rate in the whole ovarian carcinoma programme (n = 392, all previously treated with \ncisplatin or cisplatin and paclitaxel) was 16 %. The median time to response in clinical studies was \n7.6-11.6 weeks. In patients refractory to, or relapsing within 3 months after cisplatin therapy (n = 186), \nthe response rate was 10 %. \n \nThese data should be evaluated in the context of the overall safety profile of the medicinal product, in \nparticular of the significant haematological toxicity (see section 4.8). \n \nA supplementary retrospective analysis was conducted on data from 523 patients with relapsed \novarian cancer. Overall, 87 complete and partial responses were observed, with 13 of these occurring \nduring cycles 5 and 6 and 3 occurring thereafter. Of the patients who received more than 6 cycles of \ntherapy, 91 % completed the study as planned or were treated until disease progression with only 3 % \nwithdrawn for adverse events. \n \nRelapsed SCLC \nA Phase III study (Study 478) compared oral topotecan plus best supportive care (BSC) (n = 71) with \nBSC alone (n = 70) in patients who had relapsed following first line therapy (median time to \nprogression [TTP] from first-line therapy: 84 days for oral topotecan plus BSC, 90 days for BSC \nalone) and for whom re-treatment with intravenous chemotherapy was not considered appropriate. In \nthe oral topotecan plus BSC group there was a statistically significant improvement in overall survival \ncompared with the BSC alone group (Log-rank p = 0.0104). The unadjusted hazard ratio for the oral \ntopotecan plus BSC group relative to the BSC alone group was 0.64 (95 % CI: 0.45, 0.90). Median \nsurvival in patients treated with oral topotecan plus BSC was 25.9 weeks (95 % CI 18.3, 31.6) \ncompared to 13.9 weeks (95 % CI 11.1, 18.6) for patients receiving BSC alone (p = 0.0104). \n \nPatient self-reports of symptoms using an unblinded assessment showed a consistent trend for \nsymptom benefit for oral topotecan plus BSC. \n \nOne Phase II study (Study 065) and one Phase III study (Study 396) were conducted to evaluate the \nefficacy of oral topotecan versus intravenous topotecan in patients who had relapsed ≥ 90 days after \ncompletion of one prior regimen of chemotherapy (see Table 1). Oral and intravenous topotecan were \nassociated with similar symptom palliation in patients with relapsed sensitive SCLC in patient self-\nreports on an unblinded symptom scale assessment in each of these two studies. \n \n\n\n\n10 \n\nTable 1. Summary of survival, response rate, and time to progression in SCLC patients treated \nwith oral or intravenous topotecan \n \n Study 065 Study 396 \n\nOral \ntopotecan \n\nIntravenous \ntopotecan \n\nOral topotecan Intravenous \ntopotecan \n\n(N = 52) (N = 54) (N = 153) (N = 151) \nMedian survival (weeks) 32.3 25.1 33.0 35.0 \n (95 % CI) (26.3, 40.9) (21.1, 33.0) (29.1, 42.4) (31.0, 37.1) \n Hazard ratio (95 % CI) 0.88 (0.59, 1.31) 0.88 (0.7, 1.11) \nResponse rate (%) 23.1 14.8 18.3 21.9 \n (95 % CI) (11.6, 34.5) (5.3, 24.3) (12.2, 24.4) (15.3, 28.5) \nDifference in response rate \n(95 % CI) \n\n8.3 (-6.6, 23.1) -3.6 (-12.6, 5.5) \n\nMedian time to \nprogression (weeks) \n\n14.9 13.1 11.9 14.6 \n\n (95 % CI) (8.3, 21.3) (11.6, 18.3) (9.7, 14.1) (13.3, 18.9) \n Hazard ratio (95 % CI) 0.90 (0.60, 1.35) 1.21 (0.96, 1.53) \n\nN = total number of patients treated. \nCI = confidence interval. \n \nIn another randomised Phase III study which compared intravenous (IV) topotecan to \ncyclophosphamide, doxorubicin and vincristine (CAV) in patients with relapsed, sensitive SCLC, the \noverall response rate was 24.3 % for topotecan compared to 18.3 % for the CAV group. Median time \nto progression was similar in the two groups (13.3 weeks and 12.3 weeks, respectively). Median \nsurvivals for the two groups were 25.0 and 24.7 weeks respectively. The hazard ratio for survival with \nIV topotecan relative to CAV was 1.04 (95 %, CI 0.78 -1.40). \n \nThe response rate to topotecan in the combined small cell lung cancer programme (n = 480) for \npatients with relapsed disease sensitive to first-line therapy, was 20.2 %. Median survival was \n30.3 weeks (95 % CI: 27.6, 33.4). \n \nIn a population of patients with refractory SCLC (those not responding to first-line therapy), the \nresponse rate to topotecan was 4.0 %. \n \nCervical carcinoma \nIn a randomised, comparative Phase III study conducted by the Gynecologic Oncology Group (GOG \n0179), topotecan plus cisplatin (n = 147) was compared with cisplatin alone (n = 146) for the treatment \nof histologically confirmed persistent, recurrent or Stage IVB carcinoma of the cervix where curative \ntreatment with surgery and/or radiation was not considered appropriate. Topotecan plus cisplatin had a \nstatistically significant benefit in overall survival relative to cisplatin monotherapy after adjusting for \ninterim analyses (Log-rank p = 0.033). \n \nTable 2. Study results Study GOG-0179 \n\n \nITT population \n\n Cisplatin 50 mg/m2 on day 1, \nevery 21 days \n\nCisplatin 50 mg/m2 on day 1, + \nTopotecan 0,75 mg/m2 on \n\ndays 1–3, every 21 days \nSurvival (months) (n = 146) (n = 147) \nMedian (95 % CI) 6.5 (5.8, 8.8) 9.4 (7.9, 11.9) \n\nHazard ratio (95 % CI) 0.76 (0.59, 0.98) \nLog rank p-value 0.033 \n\n \nPatients without prior cisplatin chemoradiotherapy \n\n Cisplatin Topotecan/Cisplatin \n\n\n\n11 \n\nSurvival (months) (n = 46) (n = 44) \nMedian (95 % CI) 8.8 (6.4, 11.5) 15.7 (11.9, 17.7) \n\nHazard ratio (95 % CI) 0.51 (0.31, 0.82) \n \n\nPatients with prior cisplatin chemoradiotherapy \n Cisplatin Topotecan/Cisplatin \n\nSurvival (months) (n = 72) (n = 69) \nMedian (95 % CI) 5.9 (4.7, 8.8) 7.9 (5.5, 10.9) \n\nHazard ratio (95 % CI) 0.85 (0.59, 1.21) \n \nIn patients (n = 39) with recurrence within 180 days after chemoradiotherapy with cisplatin, the \nmedian survival in the topotecan plus cisplatin arm was 4.6 months (95 % CI: 2.6, 6.1) versus \n4.5 months (95 % CI: 2.9, 9.6) for the cisplatin arm with a hazard ratio of 1.15 (0.59, 2.23). In those \npatients (n = 102) with recurrence after 180 days, median survival in the topotecan plus cisplatin arm \nwas 9.9 months (95 % CI: 7, 12.6) versus 6.3 months (95 % CI: 4.9, 9.5) for the cisplatin arm with a \nhazard ratio of 0.75 (0.49, 1.16). \n \nPaediatric population \nTopotecan was also evaluated in the paediatric population; however, only limited data on efficacy and \nsafety are available. \n \nIn an open-label study involving children (n = 108, age range: infant to 16 years) with recurrent or \nprogressive solid tumours, topotecan was administered at a starting dose of 2.0 mg/m2 given as a \n30 minute infusion for 5 days repeated every 3 weeks for up to one year depending on response to \ntherapy. Tumour types included were Ewing's sarcoma/primitive neuroectodermal tumour, \nneuroblastoma, osteoblastoma, and rhabdomyosarcoma. Anti-tumour activity was demonstrated \nprimarily in patients with neuroblastoma. Toxicities of topotecan in paediatric patients with recurrent \nand refractory solid tumours were similar to those historically seen in adult patients. In this study, \nforty-six (43 %) patients received G-CSF over 192 (42.1 %) courses; sixty-five (60 %) received \ntransfusions of packed red blood cells and fifty (46 %) of platelets over 139 and 159 courses (30.5 % \nand 34.9 %), respectively. Based on the dose-limiting toxicity of myelosuppression, the maximum \ntolerated dose (MTD) was established at 2.0 mg/m2/day with G-CSF and 1.4 mg/m2/day without \nG-CSF in a pharmacokinetic study in paediatric patients with refractory solid tumours (see \nsection 5.2). \n \n5.2 Pharmacokinetic properties \n \nDistribution \n \nFollowing intravenous administration of topotecan at doses of 0.5 to 1.5 mg/m2 as a 30 minute \ninfusion daily for five days, topotecan demonstrated a high plasma clearance of 62 l/h (SD 22), \ncorresponding to approximately 2/3 of liver blood flow. Topotecan also had a high volume of \ndistribution, about 132 l, (SD 57), and a relatively short half-life of 2-3 hours. Comparison of \npharmacokinetic parameters did not suggest any change in pharmacokinetics over the 5 days of \ndosing. Area under the curve increased approximately in proportion to the increase in dose. There is \nlittle or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change \nin the pharmacokinetics after multiple doses. Preclinical studies indicate plasma protein binding of \ntopotecan is low (35 %) and distribution between blood cells and plasma was fairly homogeneous. \n \nBiotransformation \n \nThe elimination of topotecan has only been partly investigated in man. A major route of clearance of \ntopotecan was by hydrolysis of the lactone ring to form the ring-opened carboxylate. \n \nMetabolism accounts for < 10 % of the elimination of topotecan. An N-desmethyl metabolite, which \nwas shown to have similar or less activity than the parent in a cell-based assay, was found in urine, \nplasma, and faeces. The mean metabolite:parent AUC ratio was < 10 % for both total topotecan and \n\n\n\n12 \n\ntopotecan lactone. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has been \nidentified in the urine. \n \nElimination \n \nOverall recovery of topotecan-related material following five daily doses of topotecan was 71 to 76 % \nof the administered IV dose. Approximately 51 % was excreted as total topotecan and 3 % was \nexcreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted for \n18 % while faecal elimination of N-desmethyl topotecan was 1.7 %. Overall, the N-desmethyl \nmetabolite contributed a mean of less than 7 % (range 4-9 %) of the total topotecan-related material \naccounted for in the urine and faeces. The topotecan-O-glucuronide and N-desmethyl \ntopotecan-O-glucuronide in the urine were less than 2.0 %. \n \nIn vitro data using human liver microsomes indicate the formation of small amounts of \nN-demethylated topotecan. In vitro, topotecan did not inhibit human P450 enzymes CYP1A2, \nCYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A or CYP4A nor did it inhibit the human \ncytosolic enzymes dihydropyrimidine or xanthine oxidase. \n \nWhen given in combination with cisplatin (cisplatin day 1, topotecan days 1 to 5), the clearance of \ntopotecan was reduced on day 5 compared to day 1 (19.1 l/h/m2 compared to 21.3 l/h/m2 [n = 9]) (see \nsection 4.5). \n \nSpecial populations \n \nHepatic impairment \nPlasma clearance in patients with hepatic impairment (serum bilirubin between 1.5 and 10 mg/dl) \ndecreased to about 67 % when compared with a control group of patients. Topotecan half-life was \nincreased by about 30 % but no clear change in volume of distribution was observed. Plasma clearance \nof total topotecan (active and inactive form) in patients with hepatic impairment only decreased by \nabout 10 % compared with the control group of patients. \n \nRenal impairment \nPlasma clearance in patients with renal impairment (creatinine clearance 41-60 ml/min.) decreased to \nabout 67 % compared with control patients. Volume of distribution was slightly decreased and thus \nhalf-life only increased by 14 %. In patients with moderate renal impairment topotecan plasma \nclearance was reduced to 34 % of the value in control patients. Mean half-life increased from 1.9 hours \nto 4.9 hours. \n \nAge/weight \nIn a population study, a number of factors including age, weight and ascites had no significant effect \non clearance of total topotecan (active and inactive form). \n \nPaediatric population \nThe pharmacokinetics of topotecan given as a 30-minute infusion for 5 days were evaluated in two \nstudies. One study included a dose range of 1.4 to 2.4 mg/m2 in children (aged 2 up to 12 years, \nn = 18), adolescents (aged 12 up to 16 years, n = 9) and young adults (aged 16 to 21 years, n = 9) with \nrefractory solid tumours. The second study included a dose range of 2.0 to 5.2 mg/m2 in children \n(n = 8), adolescents (n = 3) and young adults (n = 3) with leukaemia. In these studies, there were no \napparent differences in the pharmacokinetics of topotecan among children, adolescents, and young \nadult patients with solid tumours or leukaemia, but data are too limited to draw definite conclusions. \n \n5.3 Preclinical safety data \n \nResulting from its mechanism of action, topotecan is genotoxic to mammalian cells (mouse lymphoma \ncells and human lymphocytes) in vitro and mouse bone marrow cells in vivo. Topotecan was also \nshown to cause embryo-foetal lethality when given to rats and rabbits. \n \n\n\n\n13 \n\nIn reproductive toxicity studies with topotecan in rats there was no effect on male or female fertility; \nhowever, in females super-ovulation and slightly increased pre-implantation loss were observed. \n \nThe carcinogenic potential of topotecan has not been studied. \n \n \n6. PHARMACEUTICAL PARTICULARS \n \n6.1 List of excipients \n \nMannitol (E421) \nTartaric acid (E334) \nSodium hydroxide \nHydrochloric acid (E507) \n \n6.2 Incompatibilities \n \nThis medicinal product must not be mixed with other medicinal products except those mentioned in \nsection 6.6. \n \n6.3 Shelf life \n \nVials \n4 years. \n \nReconstituted and diluted solution \nChemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2°C in \nnormal light conditions, and for 24 hours at 2°C to 8°C when protected from light. \n \nChemical and physical stability of the solution obtained after dilution of the concentrate in sodium \nchloride 9 mg/ml (0.9 %) solution for injection or 50 mg/ml (5 %) glucose solution for infusion has \nbeen demonstrated for 4 hours at 25 ± 2°C, in normal lighting conditions. The concentrates tested were \nstored at 25 ± 2°C for 12 hours and 24 hours respectively after reconstitution, and then diluted. \n \nFrom a microbiological point of view, the product should be used immediately. If not used \nimmediately, in-use storage times and conditions prior to use are the responsibility of the user and \nwould normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution/dilution has taken \nplace in controlled and validated aseptic conditions. \n \n6.4 Special precautions for storage \n \nKeep the vial in the outer carton in order to protect from light. \n \nFor storage conditions of the reconstituted and diluted medicinal product, see section 6.3. \n \n6.5 Nature and contents of container \n \nPotactasol 1 mg powder for concentrate for solution for infusion \nType I colourless glass vial (5 ml) with grey bromobutylic stopper and aluminium seal with plastic \nflip-off cap containing 1 mg topotecan. \n \nPotactasol 4 mg powder for concentrate for solution for infusion \nType I colourless glass vial (8 ml), with grey bromobutylic stopper and aluminium seal with plastic \nflip-off cap containing 4 mg topotecan. \n \nVials may or may not be sheathed in a protective sleeve. \n \n\n\n\n14 \n\nPotactasol is available in cartons containing 1 vial. \n \n6.6 Special precautions for disposal and other handling \n \nPotactasol 1 mg powder for concentrate for solution for infusion \nPotactasol 1 mg vials must be reconstituted with 1.1 ml water for injections. The clear concentrate is \npale yellow in colour and provides 1 mg per ml of topotecan, as Potactasol 1 mg contains a 10 % \noverage of fill. \nFurther dilution of the appropriate volume of the reconstituted solution with either sodium chloride 9 \nmg/ml (0.9 %) or 5 % w/v glucose is required to give a final concentration of between 25 and \n50 microgram/ml. \n \nPotactasol 4 mg powder for concentrate for solution for infusion \nPotactasol 4 mg vials must be reconstituted with 4 ml water for injections. The clear concentrate is \npale yellow in colour and provides 1 mg per ml of topotecan. \nFurther dilution of the appropriate volume of the reconstituted solution with either sodium chloride 9 \nmg/ml (0.9 %) or 5 % w/v glucose is required to give a final concentration of between 25 and \n50 microgram/ml. \n \nThe normal procedures for proper handling and disposal of anticancer medicinal products should be \nadopted, namely: \n\n− Personnel should be trained to reconstitute and dilute the the medicinal product. \n− Pregnant staff should be excluded from working with this medicinal product. \n− Personnel handling this medicinal product during reconstitution and dilution should wear \n\nprotective clothing including mask, goggles and gloves. \n− Accidental contact with the skin or eyes should be treated immediately with copious amounts of \n\nwater. \n− All items for administration or cleaning, including gloves, should be placed in high-risk, waste \n\ndisposal bags for high-temperature incineration. \n \n \n7. MARKETING AUTHORISATION HOLDER \n \nActavis Group PTC ehf. \nReykjavíkurvegi 76-78 \nIS-220 Hafnarfjörður \nIceland \n \n \n8. MARKETING AUTHORISATION NUMBER(S) \n \nPotactasol 1 mg powder for concentrate for solution for infusion \nEU/1/10/660/001 \n \nPotactasol 4 mg powder for concentrate for solution for infusion \nEU/1/10/660/002 \n \n \n9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION \n \nDate of first authorisation: 6 January 2011 \nDate of latest renewal: 5 October 2015 \n \n \n10. DATE OF REVISION OF THE TEXT \n \n\n\n\n15 \n\n \n \nDetailed information on this medicinal product is available on the website of the European Medicines \nAgency http://www.ema.europa.eu/. \n \n \n\nhttp://www.ema.europa.eu/\n\n\n16 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX II \n \n\nA. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE \n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND \n\nUSE \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE \n\nMARKETING AUTHORISATION \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE \n\nSAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT \n \n\n\n\n17 \n\nA. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE \n \nName and address of the manufacturer responsible for batch release \n \nS.C. Sindan-Pharma S.R.L. \n11 Ion Mihalache Blvd. \n011171 Bucharest \nRomania \n \n \nB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE \n \nMedicinal product subject to restricted medical prescription (See Annex I: Summary of Product \nCharacteristics, section 4.2). \n \n \nC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING \n\nAUTHORISATION \n \n• Periodic Safety Update Reports \n \nThe requirements for submission of periodic safety update reports for this medicinal product are set \nout in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive \n2001/83/EC and any subsequent updates published on the European medicines web-portal. \n \n \nD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND \n\nEFFECTIVE USE OF THE MEDICINAL PRODUCT \n \n• Risk Management Plan (RMP) \n\n \nNot applicable. \n \n\n\n\n18 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nANNEX III \n \n\nLABELLING AND PACKAGE LEAFLET \n \n\n\n\n19 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nA. LABELLING \n \n\n\n\n20 \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nOuter Carton \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nPotactasol 1 mg powder for concentrate for solution for infusion \ntopotecan \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nEach vial contains 1 mg topotecan (as hydrochloride). \nAfter reconstitution, 1 ml concentrate contains 1 mg topotecan. \n \n \n3. LIST OF EXCIPIENTS \n \nContains mannitol (E421), tartaric acid (E334), hydrochloric acid (E507) and sodium hydroxide. See \nleaflet for further information. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nPowder for concentrate for solution for infusion. \n1 x 1 mg vial \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nRead the package leaflet before use. \nFor intravenous use as infusion, after reconstitution and dilution. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \nCytotoxic, special handling instructions (see package leaflet). \nCytotoxic \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nKeep the vial in the outer carton in order to protect from light. \n\n\n\n21 \n\n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused product or waste material should be disposed of in accordance with local requirements. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nActavis Group PTC ehf. \n220 Hafnarfjörður \nIceland \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/10/660/001 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nJustification for not including Braille accepted \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: \nSN: \nNN: \n \n \n\n\n\n22 \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVial \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n \nPotactasol 1 mg powder for concentrate for solution for infusion \ntopotecan \nIV \n \n \n2. METHOD OF ADMINISTRATION \n \nRead the package leaflet before use. \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n1 mg \n \n \n6. OTHER \n \nCytotoxic \n\n\n\n23 \n\nPARTICULARS TO APPEAR ON THE OUTER PACKAGING \n \nOuter Carton \n \n \n1. NAME OF THE MEDICINAL PRODUCT \n \nPotactasol 4 mg powder for concentrate for solution for infusion \ntopotecan \n \n \n2. STATEMENT OF ACTIVE SUBSTANCE(S) \n \nEach vial contains 4 mg topotecan (as hydrochloride). \nAfter reconstitution, 1 ml concentrate contains 1 mg topotecan. \n \n \n3. LIST OF EXCIPIENTS \n \nContains mannitol (E421), tartaric acid (E334), hydrochloric acid (E507) and sodium hydroxide. See \nleaflet for further information. \n \n \n4. PHARMACEUTICAL FORM AND CONTENTS \n \nPowder for concentrate for solution for infusion. \n1 x 4 mg vial \n \n \n5. METHOD AND ROUTE(S) OF ADMINISTRATION \n \nRead the package leaflet before use. \nFor intravenous use as infusion, after reconstitution and dilution. \n \n \n6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT \n\nOF THE SIGHT AND REACH OF CHILDREN \n \nKeep out of the sight and reach of children. \n \n \n7. OTHER SPECIAL WARNING(S), IF NECESSARY \n \nCytotoxic, special handling instructions (see package leaflet). \nCytotoxic \n \n \n8. EXPIRY DATE \n \nEXP \n \n \n9. SPECIAL STORAGE CONDITIONS \n \nKeep the vial in the outer carton in order to protect from light. \n\n\n\n24 \n\n \n \n10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS \n\nOR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF \nAPPROPRIATE \n\n \nAny unused product or waste material should be disposed of in accordance with local requirements. \n \n \n11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER \n \nActavis Group PTC ehf. \n220 Hafnarfjörður \nIceland \n \n \n12. MARKETING AUTHORISATION NUMBER(S) \n \nEU/1/10/660/002 \n \n \n13. BATCH NUMBER \n \nLot \n \n \n14. GENERAL CLASSIFICATION FOR SUPPLY \n \n \n15. INSTRUCTIONS ON USE \n \n \n16. INFORMATION IN BRAILLE \n \nJustification for not including Braille accepted \n \n \n17. UNIQUE IDENTIFIER – 2D BARCODE \n \n2D barcode carrying the unique identifier included. \n \n \n18. UNIQUE IDENTIFIER – HUMAN READABLE DATA \n \nPC: \nSN: \nNN: \n \n \n\n\n\n25 \n\nMINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS \n \nVial \n \n \n1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION \n \nPotactasol 4 mg powder for concentrate for solution for infusion \ntopotecan \nIV \n \n \n2. METHOD OF ADMINISTRATION \n \nRead the package leaflet before use. \n \n \n3. EXPIRY DATE \n \nEXP \n \n \n4. BATCH NUMBER \n \nLot \n \n \n5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT \n \n4 mg \n \n \n6. OTHER \n \nCytotoxic \n\n\n\n26 \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\nB. PACKAGE LEAFLET \n \n\n\n\n27 \n\nPackage leaflet: Information for the user \n \n\nPotactasol 1 mg powder for concentrate for solution for infusion \nPotactasol 4 mg powder for concentrate for solution for infusion \n\ntopotecan \n \n\nRead all of this leaflet carefully before you start using this medicine because it contains \nimportant information for you. \n- Keep this leaflet. You may need to read it again. \n- If you have any further questions, ask your doctor or nurse. \n- If you get any side effects, talk to your doctor or nurse. This includes any possible side effects \n\nnot listed in this leaflet. See section 4. \n \nWhat is in this leaflet \n1. What Potactasol is and what it is used for \n2. What you need to know before you use Potactasol \n3. How to use Potactasol \n4. Possible side effects \n5. How to store Potactasol \n6. Contents of the pack and other information \n \n \n1. What Potactasol is and what it is used for \n \nPotactasol contains the active substance topotecan which helps to kill tumour cells. \n \nPotactasol is used to treat: \n- ovarian cancer or small cell lung cancer that has come back after chemotherapy \n- advanced cervical cancer if surgery or radiotherapy is not possible. In this case Potactasol \n\ntreatment is combined with medicines containing cisplatin. \n \n \n2. What you need to know before you use Potactasol \n \nDo not use Potactasol \n- if you are allergic to topotecan or any of the other ingredients of this medicine (listed in \n\nsection 6); \n- if you are breast-feeding.; \n- if your blood cell counts are too low. Your doctor will tell you whether this is the case, based on \n\nthe results of your last blood test. \nTell you doctor if you think any of these could apply to you. \n \nWarnings and precautions \nTalk to your doctor before using Potactasol: \n- if you have any kidney problems. Your dose of Potactasol may need to be adjusted. Potactasol is \n\nnot recommended in case of severe kidney impairment; \n- if you have liver problems. Potactasol is not recommended in case of severe liver impairment; \n- if you suffer from lung inflammation with signs such as cough, fever and difficulties in \n\nbreathing, see also section 4 “Possible side effects”. \n \nPotactasol may cause a decrease in the number of blood clotting cells (platelets). This can lead to \nsevere bleeding from relatively small injuries such as a small cut. Rarely, it can lead to more severe \nbleeding (haemorrhage). Talk to your doctor for advice on how to minimize the risk of bleeding. \n \nThe incidence of side effects is more frequent in patients who are in poor general health. The doctor \nwill evaluate your general health during the treatment and you should tell him/her in case you have \nfever, infection or are in some ways feeling unwell. \n\n\n\n28 \n\n \nUse in children and adolescents \nThe experience in children and adolescents is limited and treatment is therefore not recommended. \n \nOther medicines and Potactasol \nTell your doctor if you are taking, have recently taken or might take any other medicines. \n \nPregnancy and breast-feeding \nPotactasol should not be used in pregnant women, unless clearly necessary. If you are or think you \nmight be pregnant, tell your doctor immediately. \n \nEffective contraception methods should be used to avoid becoming pregnant or fathering a child while \non treatment with Potactasol. Ask your doctor for advice. \n \nPatients who are concerned about their fertility should ask their doctor for counselling on fertility and \nfamily planning options prior to starting treatment. \n \nYou must not breast-feed while on treatment with Potactasol. \n \nDriving and using machines \nPotactasol can make you feel tired or weak. If you experience this, do not drive or use machines. \n \nPotactasol contains sodium \nThis medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium-free’. \n \n \n3. How to use Potactasol \n \nYour dose of Potactasol will depend on: \n- the disease being treated, \n- your body surface area (m2), \n- the results of blood tests carried out before and during treatment, \n- how well you tolerate treatment. \n \nAdults \nOvarian cancer and small cell lung cancer \nThe usual dose is 1.5 mg per m2 of body surface area once daily for 5 days. This treatment cycle will \nnormally be repeated every three weeks. \n \nCervical cancer \nThe usual dose is 0.75 mg per m2 of body surface area once daily for 3 days. This treatment cycle will \nnormally be repeated every three weeks. \nFor cervical cancer, it will be used together with another anticancer medicines containing cisplatin. \nFor more information about cisplatin, please refer to the corresponding package leaflet. \n \nPatients with impaired kidney function \nYour doctor might need to reduce your dose based on your kidney function. \n \nHow Potactasol is prepared \nTopotecan is supplied as a powder for concentrate for solution for infusion. The powder must be \ndissolved, and the resulting concentrate further diluted before administration. \n \nHow Potactasol is given \nA doctor or nurse will give you the reconstituted and diluted Potactasol solution as an infusion (drip), \nusually into your arm, over about 30 minutes. \n \nIf you are given too much Potactasol \n\n\n\n29 \n\nAs this medicine is being given by your doctor or nurse, it is unlikely that you will be given too much. \nIn the unlikely event of an overdose, your doctor will monitor you for side effects. Tell your doctor or \nnurse if you have any concerns about the amount of medicine that you receive. \n \n \n4. Possible side effects \n \nLike all medicines, this medicine can cause side effects, although not everybody gets them. \n \nSerious side effects \nYou must tell your doctor immediately if you experience any of the following serious side effects. \nThey may require hospitalisation and could even be life-threatening. \n \n- Infections (very common; may affect more than 1 in 10 people), with signs such as: \n\n- fever \n- serious decline of your general condition \n- local symptoms, such as sore throat or burning sensation when urinating \n- severe stomach pain, fever and possibly diarrhoea (rarely with blood) can be signs of bowel \n\ninflammation (neutropenic colitis) \nPotactasol may reduce your ability to fight infections. \n \n- Lung inflammation (rare; may affect up to 1 in 1,000 people), with signs such as: \n\n- difficulty breathing \n- cough \n- fever \n\nThe risk of developing this severe condition (interstitial lung disease) is higher if you currently have \nlung problems, or if you have received previous radiation treatment or medicines that affected your \nlungs, see also section 2 “Warnings and precautions”. This condition can be fatal. \n \n- Severe allergic (anaphylactic) reactions (rare; may affect up to 1 in 1,000 people), with signs \n\nsuch as: \n- swelling of the face, lips, tongue or throat, difficulty breathing, low blood pressure, dizziness \n\nand itchy rash. \n \nOther side effects with Potactasol include: \n \nVery common side effects (may affect more than 1 in 10 people) \n- Feeling generally weak and tired, which can be symptoms of a decrease in the number of red \n\nblood cells (anaemia). In some cases you may need a blood transfusion. \n- Decrese in number of circulating white blood cells (leucotyes) in the blood. Abnormal low \n\nnumber of neutrophil granulocytes (a type of white blood cell) in the blood, with or without \nfever. \n\n- Unusual bruising or bleeding, sometimes severe, caused by a decrease in the number of blood \nclotting cells (platelets). \n\n- Weight loss and loss of appetite (anorexia); tiredness; weakness. \n- Feeling sick (nausea), vomiting; diarrhoea; stomach pain; constipation. \n- Inflammation of the lining of the mouth and digestive tract. \n- Fever. \n- Hair loss. \n \nCommon side effects (may affect up to 1 in 10 people) \n- Allergic (hypersensitivity) reactions (including rash). \n- Abnormal high level of bilirubin, a waste product produced by the liver during breakdown of \n\nred blood cells. Symptoms may include yellow skin (jaundice). \n- Decrease in the number of all blood cells (pancytopenia). \n- Feeling unwell. \n- Serious blood infection, which can be fatal. \n\n\n\n30 \n\n- Itching (pruritus). \n \nRare side effects (may affect up to 1 in 1,000 people) \n- Swelling caused by fluid build-up (angioedema) e.g. around the eyes and lips as well as hands, \n\nfeet and throat. If severe it may cause breathing difficulties. \n- Itchy rash (or hives). \n \nVery rare side effects (may affect up to 1 in 10,000 people) \n- Mild pain and inflammation at the site of injection due to accidental administration of the \n\nmedicinal product into the surrounding tissue (extravasation) e.g. by leakage. \n \nNot known (frequency cannot be estimated from the available data) \n- Severe stomach pain, nausea, vomiting of blood, black or bloody stools (possible symptoms of \n\ngastrointestinal perforation). \n- Mouth sores, difficulty swallowing, abdominal pain, nausea, vomiting, diarrhoea, bloody stools \n\n(possible signs and symptoms of inflammation of the inner lining of the mouth, stomach and/or \ngut [mucosal inflammation]). \n\n \nIf you are being treated for cervical cancer, you may get side effects from the other medicine \n(cisplatin) that you will be given along with Potactasol. \n \nReporting of side effects \nIf you get any side effects, talk to your doctor or nurse. This includes any possible side effects not \nlisted in this leaflet. You can also report side effects directly via the national reporting system listed in \nAppendix V. By reporting side effects you can help provide more information on the safety of this \nmedicine. \n \n \n5. How to store Potactasol \n \nKeep this medicine out of the sight and reach of children. \n \nDo not use this medicine after the expiry date which is stated on the vial and carton after EXP. The \nexpiry date refers to the last day of that month. \n \nKeep the vial in the outer carton in order to protect from light. \n \nStorage after reconstitution and dilution \nChemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2°C, in \nnormal light conditions and 24 hours at 2°C to 8°C, protected from light. \n \nThe physico-chemical stability of the medicinal product solution obtained after dilution in solutions \nfor infusion (NaCl 0.9 % and Glucose 5 %) has been demonstrated for 4 hours at room temperature, in \nnormal lighting conditions, on samples reconstituted and stored for 12 hours and respectively 24 hours \nat 25oC ± 2oC and then diluted. \n \nFrom a microbiological point of view, the product should be used immediately. If not used \nimmediately, in-use storage times and conditions prior to use are the responsibility of the user and \nwould normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution/dilution has taken \nplace in controlled and validated aseptic conditions. \n \nAny unused product or waste material should be disposed of in accordance with local requirements for \ncytotoxic material. \n \n \n6. Contents of the pack and other information \n \n\nhttp://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc\n\n\n31 \n\nWhat Potactasol contains \n- The active substance is topotecan. Each vial contains 1 mg or 4 mg topotecan (as \n\nhydrochloride). After reconstitution 1 ml concentrate contains 1 mg topotecan. \n- The other ingredients are: mannitol (E421), tartaric acid (E334), hydrochloric acid (E507) and \n\nsodium hydroxide (see section 2). \n \nWhat Potactasol looks like and contents of the pack \nPotactasol is supplied in type I colourless glass vials with grey bromobutylic stopper and aluminium \nseals with plastic flip-off caps. Vials may or may not be sheathed in a protective sleeve. Vials contain \neither 1 mg or 4 mg of topotecan. \n \nEach pack contains one vial. \n \nMarketing Authorisation Holder \nActavis Group PTC ehf. \nReykjavíkurvegi 76-78 \n220 Hafnarfjörður \nIceland \n \nManufacturer \nS.C. Sindan-Pharma S.R.L. \n11 Ion Mihalache Blvd \nBucharest \nRomania \n \nFor any information about this medicine, please contact the local representative of the Marketing \nAuthorisation Holder: \n \nBelgië/Belgique/Belgien \nActavis Group PTC ehf. \nIJsland/Islande/Island \nTél/Tel: +354 5503300 \n \n\nLietuva \nUAB Teva Baltics \nTel: +370 52660203 \n \n\nБългария \nТева Фарма ЕАД \nTeл: +359 24899585 \n \n\nLuxembourg/Luxemburg \nActavis Group PTC ehf. \nIslande/Island \nTél/Tel: +354 5503300 \n \n\nČeská republika \nTeva Pharmaceuticals CR, s.r.o. \nTel: +420 251007111 \n \n\nMagyarország \nTeva Gyógyszergyár Zrt. \nTel: +36 12886400 \n \n\nDanmark \nTeva Denmark A/S \nTlf: +45 44985511 \n \n\nMalta \nActavis Ltd. \nTel: +356 21693533 \n \n\nDeutschland \nPUREN Pharma GmbH & Co. KG \nTel: +49 895589090 \n\n \n\nNederland \nActavis Group PTC ehf. \nIJsland \nTel: +354 5503300 \n \n\nEesti \nUAB Teva Baltics Eesti filiaal \nTel: +372 6610801 \n \n\nNorge \nTeva Norway AS \nTlf: +47 66775590 \n \n\n\n\n32 \n\nΕλλάδα \nSpecifar A.B.E.E. \nΤηλ: +30 2118805000 \n \n\nÖsterreich \nratiopharm Arzneimittel Vertriebs-GmbH \nTel: +43 1970070 \n \n\nEspaña \nActavis Group PTC ehf. \nIslandia \nTel: +354 5503300 \n \n\nPolska \nTeva Pharmaceuticals Polska Sp. z o.o. \nTel: +48 223459300 \n \n\nFrance \nActavis Group PTC ehf. \nIslande \nTél: +354 5503300 \n \n\nPortugal \nTeva Pharma - Produtos Farmacêuticos, Lda. \nTel: +351 214767550 \n \n\nHrvatska \nPliva Hrvatska d.o.o. \nTel: +385 13720000 \n \n\nRomânia \nTeva Pharmaceuticals S.R.L. \nTel: +40 212306524 \n \n\nIreland \nTeva Pharmaceuticals Ireland \nTel: +353 19127700 \n \n\nSlovenija \nPliva Ljubljana d.o.o. \nTel: +386 15890390 \n \n\nÍsland \nTeva Pharma Iceland ehf. \nSími: +354 5503300 \n \n\nSlovenská republika \nTEVA Pharmaceuticals Slovakia s.r.o. \nTel: +421 257267911 \n \n\nItalia \nTeva Italia S.r.l. \nTel: +39 028917981 \n \n\nSuomi/Finland \nTeva Finland Oy \nPuh/Tel: +358 201805900 \n \n\nΚύπρος \nSpecifar A.B.E.E. \nΕλλάδα \nΤηλ: +30 2118805000 \n \n\nSverige \nTeva Sweden AB \nTel: +46 42121100 \n \n\nLatvija \nUAB Teva Baltics filiāle Latvijā \nTel: +371 67323666 \n \n\nUnited Kingdom \nActavis UK Limited \nTel: +44 1271385257 \n \n\n \nThis leaflet was last revised in {MM/YYYY}. \n \nDetailed information on this medicine is available on the European Medicines Agency web site: \nhttp://www.ema.europa.eu/. \n \n-------------------------------------------------------------------------------------------------------------------------- \nThe following information is intended for healthcare professionals only: \n \n \n\nPotactasol \n \n\nINSTRUCTIONS ON USE \n \n\n \nReconstitution and dilution prior to administration \n \n\nhttp://www.ema.europa.eu/\n\n\n33 \n\nBefore infusion, Potactasol powder for concentrate for solution for infusion must be reconstituted with \nan appropriate volume of water for injections, as follows: \n \n- Potactasol 1 mg with 1.1 ml water for injections (as it contains 10 % overage of fill) \n- Potactasol 4 mg with 4 ml water for injections \n \nReconstitution will result in a concentrate containing 1 mg topotecan per ml. \nThis concentrate (1 mg/ml) must be diluted prior to administration. \n \nThe volume of reconstituted concentrate corresponding to the calculated individual dose should be \nfurther diluted with either sodium chloride 9 mg/ml (0.9 %) or 5 % w/v glucose, to give a final \nconcentration of between 25 and 50 microgram per ml in the solution for infusion, for example: \n \n Volume for \n\n25 microgram/ml solution \nVolume for \n50 microgram/ml solution \n\n1 ml of 1 mg/ml topotecan solution Add 39 ml to give 40 ml Add 19 ml to give 20 ml \n4 ml of 1 mg/ml topotecan solution Add 156 ml to give 160 ml Add 76 ml to give 80 ml \n\n \n \nStorage after reconstitution and dilution \nChemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2°C in \nnormal light conditions, and for 24 hours at 2°C to 8°C when protected from light. \n \nChemical and physical stability of the solution obtained after dilution of the concentrate in sodium \nchloride 9 mg/ml (0.9 %) solution for injection or 50 mg/ml (5 %) glucose solution for infusion has \nbeen demonstrated for 4 hours at 25 ± 2°C, in normal lighting conditions .The concentrates tested were \nreconstituted and stored at 25 ± 2°C for 12 hours and 24 hours respectively after reconstitution, and \nthen diluted. \n \nFrom a microbiological point of view, the product should be used immediately. If not used \nimmediately, in-use storage times and conditions prior to use are the responsibility of the user and \nwould normally not be longer than 24 hours at 2°C to 8°C, unless reconstitution/dilution has taken \nplace in controlled and validated aseptic conditions. \n \nHandling and disposal \nThe normal procedures for proper handling and disposal of anti-tumour medicinal products should be \nadopted: \n− Staff should be trained to reconstitute and dilute the the medicinal product. \n− Pregnant staff should be excluded from working with this medicinal product. \n− Staff handling this medicinal product during reconstitution and dilution should wear protective \n\nclothing including mask, goggles and gloves. \n− Accidental contact with the skin or eyes should be treated immediately with copious amounts of \n\nwater. \n− All items for administration or cleaning, including gloves, should be placed in high-risk, waste \n\ndisposal bags for high-temperature incineration. \n \n\n\n\tSUMMARY OF PRODUCT CHARACTERISTICS\n\tA. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE\n\tB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE\n\tC. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION\n\tD. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT \n\tA. LABELLING\n\tB. PACKAGE LEAFLET"},"Section_1":{"kind":"string","value":"{'Title': '1. what potactasol is and what it is used for', 'Section_Content': 'potactasol contains the active substance topotecan which helps to kill tumour cells. potactasol is used to treat: - ovarian cancer or small cell lung cancer that has come back after chemotherapy - advanced cervical cancer if surgery or radiotherapy is not possible. in this case potactasol treatment is combined with medicines containing cisplatin.', 'Entity_Recognition': [{'Text': 'potactasol', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 1, 'BeginOffset': 0, 'EndOffset': 10, 'Score': 0.9170990586280823, 'Text': 'potactasol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the active substance topotecan', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 50}, {'Id': 3, 'BeginOffset': 85, 'EndOffset': 95, 'Score': 0.8877561688423157, 'Text': 'potactasol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 6, 'BeginOffset': 116, 'EndOffset': 130, 'Score': 0.9513476490974426, 'Text': 'ovarian cancer', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9743806719779968}]}, {'Id': 7, 'BeginOffset': 134, 'EndOffset': 156, 'Score': 0.5611948370933533, 'Text': 'small cell lung cancer', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9797528982162476}]}, {'Id': 0, 'BeginOffset': 145, 'EndOffset': 149, 'Score': 0.9419222474098206, 'Text': 'lung', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 9, 'BeginOffset': 182, 'EndOffset': 194, 'Score': 0.8671510815620422, 'Text': 'chemotherapy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'advanced cervical cancer', 'Type': 'PROBLEM', 'BeginOffset': 197, 'EndOffset': 221}, {'Id': 10, 'BeginOffset': 225, 'EndOffset': 232, 'Score': 0.631624698638916, 'Text': 'surgery', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'PROCEDURE_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 236, 'EndOffset': 248, 'Score': 0.980496883392334, 'Text': 'radiotherapy', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}, {'Text': 'this case potactasol treatment', 'Type': 'TREATMENT', 'BeginOffset': 269, 'EndOffset': 299}, {'Text': 'medicines', 'Type': 'TREATMENT', 'BeginOffset': 317, 'EndOffset': 326}, {'Id': 5, 'BeginOffset': 338, 'EndOffset': 347, 'Score': 0.9950214624404907, 'Text': 'cisplatin', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}]}"},"Section_2":{"kind":"string","value":"{'Title': '2. what you need to know before you use potactasol', 'Section_Content': 'do not use potactasol - if you are allergic to topotecan or any of the other ingredients of this medicine (listed in section 6); - if you are breast-feeding.; - if your blood cell counts are too low. your doctor will tell you whether this is the case, based on the results of your last blood test. tell you doctor if you think any of these could apply to you. warnings and precautions talk to your doctor before using potactasol: - if you have any kidney problems. your dose of potactasol may need to be adjusted. potactasol is not recommended in case of severe kidney impairment; - if you have liver problems. potactasol is not recommended in case of severe liver impairment; - if you suffer from lung inflammation with signs such as cough, fever and difficulties in breathing, see also section 4 \"possible side effects\". potactasol may cause a decrease in the number of blood clotting cells (platelets). this can lead to severe bleeding from relatively small injuries such as a small cut. rarely, it can lead to more severe bleeding (haemorrhage). talk to your doctor for advice on how to minimize the risk of bleeding. the incidence of side effects is more frequent in patients who are in poor general health. the doctor will evaluate your general health during the treatment and you should tell him/her in case you have fever, infection or are in some ways feeling unwell. use in children and adolescents the experience in children and adolescents is limited and treatment is therefore not recommended. other medicines and potactasol tell your doctor if you are taking, have recently taken or might take any other medicines. pregnancy and breast-feeding potactasol should not be used in pregnant women, unless clearly necessary. if you are or think you might be pregnant, tell your doctor immediately. effective contraception methods should be used to avoid becoming pregnant or fathering a child while on treatment with potactasol. ask your doctor for advice. patients who are concerned about their fertility should ask their doctor for counselling on fertility and family planning options prior to starting treatment. you must not breast-feed while on treatment with potactasol. driving and using machines potactasol can make you feel tired or weak. if you experience this, do not drive or use machines. potactasol contains sodium this medicine contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially \\'sodium-free\\'.', 'Entity_Recognition': [{'Text': 'potactasol', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 6, 'BeginOffset': 11, 'EndOffset': 21, 'Score': 0.9582926034927368, 'Text': 'potactasol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.873885452747345}]}, {'Text': 'allergic', 'Type': 'PROBLEM', 'BeginOffset': 35, 'EndOffset': 43}, {'Id': 7, 'BeginOffset': 47, 'EndOffset': 56, 'Score': 0.9814700484275818, 'Text': 'topotecan', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [{'Name': 'NEGATION', 'Score': 0.40107232332229614}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 92, 'EndOffset': 105}, {'Id': 16, 'BeginOffset': 142, 'EndOffset': 156, 'Score': 0.37611132860183716, 'Text': 'breast-feeding', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.5001035332679749}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.8592559099197388, 'RelationshipScore': 0.9671362638473511, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 0, 'BeginOffset': 142, 'EndOffset': 148, 'Text': 'breast', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 17, 'BeginOffset': 169, 'EndOffset': 198, 'Score': 0.3967021703720093, 'Text': 'blood cell counts are too low', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': []}, {'Text': 'your last blood test', 'Type': 'TEST', 'BeginOffset': 276, 'EndOffset': 296}, {'Id': 8, 'BeginOffset': 418, 'EndOffset': 428, 'Score': 0.849562406539917, 'Text': 'potactasol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'any kidney problems', 'Type': 'PROBLEM', 'BeginOffset': 444, 'EndOffset': 463}, {'Id': 9, 'BeginOffset': 478, 'EndOffset': 488, 'Score': 0.9673286080360413, 'Text': 'potactasol', 'Category': 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0.7383295297622681}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9778123497962952, 'RelationshipScore': 0.9026370644569397, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 5, 'BeginOffset': 698, 'EndOffset': 702, 'Text': 'lung', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'signs', 'Type': 'PROBLEM', 'BeginOffset': 721, 'EndOffset': 726}, {'Id': 23, 'BeginOffset': 735, 'EndOffset': 740, 'Score': 0.9948416352272034, 'Text': 'cough', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.860716700553894}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9778123497962952, 'RelationshipScore': 0.6416801810264587, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 5, 'BeginOffset': 698, 'EndOffset': 702, 'Text': 'lung', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 24, 'BeginOffset': 742, 'EndOffset': 747, 'Score': 0.9906700849533081, 'Text': 'fever', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 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0.4978671669960022, 'Text': 'poor general health', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.741027295589447}]}, {'Text': 'the treatment', 'Type': 'TREATMENT', 'BeginOffset': 1265, 'EndOffset': 1278}, {'Id': 35, 'BeginOffset': 1324, 'EndOffset': 1329, 'Score': 0.9953051805496216, 'Text': 'fever', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8192696571350098}]}, {'Id': 36, 'BeginOffset': 1331, 'EndOffset': 1340, 'Score': 0.9957791566848755, 'Text': 'infection', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.64882892370224}]}, {'Id': 37, 'BeginOffset': 1361, 'EndOffset': 1375, 'Score': 0.6471028923988342, 'Text': 'feeling unwell', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9053089618682861}]}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 1467, 'EndOffset': 1476}, {'Text': 'other medicines', 'Type': 'TREATMENT', 'BeginOffset': 1507, 'EndOffset': 1522}, {'Id': 13, 'BeginOffset': 1527, 'EndOffset': 1537, 'Score': 0.9231066703796387, 'Text': 'potactasol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'any other medicines', 'Type': 'TREATMENT', 'BeginOffset': 1608, 'EndOffset': 1627}, {'Id': 38, 'BeginOffset': 1629, 'EndOffset': 1638, 'Score': 0.938140869140625, 'Text': 'pregnancy', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9155068397521973}]}, {'Text': 'breast-feeding potactasol', 'Type': 'TREATMENT', 'BeginOffset': 1643, 'EndOffset': 1668}, {'Id': 39, 'BeginOffset': 1691, 'EndOffset': 1699, 'Score': 0.9745855927467346, 'Text': 'pregnant', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9146111011505127}]}, {'Id': 40, 'BeginOffset': 1766, 'EndOffset': 1774, 'Score': 0.995789110660553, 'Text': 'pregnant', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9393665194511414}]}, {'Id': 49, 'BeginOffset': 1793, 'EndOffset': 1804, 'Score': 0.9999725818634033, 'Text': 'immediately', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'DX_NAME', 'Score': 0.995789110660553, 'RelationshipScore': 0.7190786600112915, 'RelationshipType': 'OVERLAP', 'Id': 40, 'BeginOffset': 1766, 'EndOffset': 1774, 'Text': 'pregnant', 'Category': 'MEDICAL_CONDITION', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9393665194511414}]}]}, {'Text': 'effective contraception methods', 'Type': 'TREATMENT', 'BeginOffset': 1806, 'EndOffset': 1837}, {'Id': 41, 'BeginOffset': 1871, 'EndOffset': 1879, 'Score': 0.9937688708305359, 'Text': 'pregnant', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9530273675918579}]}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 1910, 'EndOffset': 1919}, {'Id': 15, 'BeginOffset': 1925, 'EndOffset': 1935, 'Score': 0.86746746301651, 'Text': 'potactasol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 2113, 'EndOffset': 2122}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 2158, 'EndOffset': 2167}, {'Id': 50, 'BeginOffset': 2173, 'EndOffset': 2183, 'Score': 0.8543952703475952, 'Text': 'potactasol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'machines potactasol', 'Type': 'TREATMENT', 'BeginOffset': 2203, 'EndOffset': 2222}, {'Id': 57, 'BeginOffset': 2241, 'EndOffset': 2246, 'Score': 0.9795240759849548, 'Text': 'tired', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6874260902404785}]}, {'Id': 58, 'BeginOffset': 2250, 'EndOffset': 2254, 'Score': 0.8656396269798279, 'Text': 'weak', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8151910901069641}]}, {'Id': 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cervical cancer, it will be used together with another anticancer medicines containing cisplatin. for more information about cisplatin, please refer to the corresponding package leaflet. patients with impaired kidney function your doctor might need to reduce your dose based on your kidney function. how potactasol is prepared topotecan is supplied as a powder for concentrate for solution for infusion. the powder must be dissolved, and the resulting concentrate further diluted before administration. how potactasol is given a doctor or nurse will give you the reconstituted and diluted potactasol solution as an infusion (drip), usually into your arm, over about 30 minutes. if you are given too much potactasol 29 as this medicine is being given by your doctor or nurse, it is unlikely that you will be given too much. in the unlikely event of an overdose, your doctor will monitor you for side effects. tell your doctor or nurse if you have any concerns about the amount of medicine that you receive.', 'Entity_Recognition': [{'Text': 'potactasol', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 4, 'BeginOffset': 13, 'EndOffset': 23, 'Score': 0.7917085886001587, 'Text': 'potactasol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the disease', 'Type': 'PROBLEM', 'BeginOffset': 42, 'EndOffset': 53}, {'Id': 25, 'BeginOffset': 117, 'EndOffset': 128, 'Score': 0.798937976360321, 'Text': 'blood tests', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TEST_NAME', 'Traits': []}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 159, 'EndOffset': 168}, {'Text': 'treatment', 'Type': 'TREATMENT', 'BeginOffset': 194, 'EndOffset': 203}, {'Text': 'adults ovarian cancer', 'Type': 'PROBLEM', 'BeginOffset': 205, 'EndOffset': 226}, {'Text': 'small cell lung cancer', 'Type': 'PROBLEM', 'BeginOffset': 231, 'EndOffset': 253}, {'Text': '1.5', 'Type': 'NUMBER', 'BeginOffset': 272, 'EndOffset': 275}, {'Text': 'body surface area', 'Type': 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as: - fever - serious decline of your general condition - local symptoms, such as sore throat or burning sensation when urinating - severe stomach pain, fever and possibly diarrhoea (rarely with blood) can be signs of bowel inflammation (neutropenic colitis) potactasol may reduce your ability to fight infections. - lung inflammation (rare; may affect up to 1 in 1,000 people), with signs such as: - difficulty breathing - cough - fever the risk of developing this severe condition (interstitial lung disease) is higher if you currently have lung problems, or if you have received previous radiation treatment or medicines that affected your lungs, see also section 2 \"warnings and precautions\". this condition can be fatal. - severe allergic (anaphylactic) reactions (rare; may affect up to 1 in 1,000 people), with signs such as: - swelling of the face, lips, tongue or throat, difficulty breathing, low blood pressure, dizziness and itchy rash. other side effects with potactasol include: very common side effects (may affect more than 1 in 10 people) - feeling generally weak and tired, which can be symptoms of a decrease in the number of red blood cells (anaemia). in some cases you may need a blood transfusion. - decrese in number of circulating white blood cells (leucotyes) in the blood. abnormal low number of neutrophil granulocytes (a type of white blood cell) in the blood, with or without fever. - unusual bruising or bleeding, sometimes severe, caused by a decrease in the number of blood clotting cells (platelets). - weight loss and loss of appetite (anorexia); tiredness; weakness. - feeling sick (nausea), vomiting; diarrhoea; stomach pain; constipation. - inflammation of the lining of the mouth and digestive tract. - fever. - hair loss. common side effects (may affect up to 1 in 10 people) - allergic (hypersensitivity) reactions (including rash). - abnormal high level of bilirubin, a waste product produced by the liver during breakdown of red blood cells. symptoms may include yellow skin (jaundice). - decrease in the number of all blood cells (pancytopenia). - feeling unwell. - serious blood infection, which can be fatal. - itching (pruritus). rare side effects (may affect up to 1 in 1,000 people) - swelling caused by fluid build-up (angioedema) e.g. around the eyes and lips as well as hands, feet and throat. if severe it may cause breathing difficulties. - itchy rash (or hives). very rare side effects (may affect up to 1 in 10,000 people) - mild pain and inflammation at the site of injection due to accidental administration of the medicinal product into the surrounding tissue (extravasation) e.g. by leakage. not known (frequency cannot be estimated from the available data) - severe stomach pain, nausea, vomiting of blood, black or bloody stools (possible symptoms of gastrointestinal perforation). - mouth sores, difficulty swallowing, abdominal pain, nausea, vomiting, diarrhoea, bloody stools (possible signs and symptoms of inflammation of the inner lining of the mouth, stomach and/or gut [mucosal inflammation]). if you are being treated for cervical cancer, you may get side effects from the other medicine (cisplatin) that you will be given along with potactasol. reporting of side effects if you get any side effects, talk to your doctor or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'potactasol', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 13, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9666258096694946, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': 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'PROBLEM', 'BeginOffset': 2367, 'EndOffset': 2388}, {'Text': 'all blood cells', 'Type': 'PROBLEM', 'BeginOffset': 2419, 'EndOffset': 2434}, {'Id': 106, 'BeginOffset': 2436, 'EndOffset': 2448, 'Score': 0.9433385729789734, 'Text': 'pancytopenia', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.8178742527961731}]}, {'Id': 107, 'BeginOffset': 2453, 'EndOffset': 2467, 'Score': 0.7565804719924927, 'Text': 'feeling unwell', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9314295053482056}]}, {'Text': 'serious blood infection', 'Type': 'PROBLEM', 'BeginOffset': 2471, 'EndOffset': 2494}, {'Id': 109, 'BeginOffset': 2518, 'EndOffset': 2525, 'Score': 0.9901211261749268, 'Text': 'itching', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8842194080352783}]}, {'Id': 110, 'BeginOffset': 2527, 'EndOffset': 2535, 'Score': 0.9828593134880066, 'Text': 'pruritus', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7986676692962646}]}, {'Text': 'rare side effects', 'Type': 'PROBLEM', 'BeginOffset': 2538, 'EndOffset': 2555}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 2574, 'EndOffset': 2575}, {'Text': '1,000', 'Type': 'NUMBER', 'BeginOffset': 2579, 'EndOffset': 2584}, {'Id': 112, 'BeginOffset': 2595, 'EndOffset': 2603, 'Score': 0.8941961526870728, 'Text': 'swelling', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7435885667800903}]}, {'Id': 113, 'BeginOffset': 2614, 'EndOffset': 2628, 'Score': 0.3641243577003479, 'Text': 'fluid build-up', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7492251396179199}], 'Attributes': [{'Type': 'DIRECTION', 'Score': 0.5124379992485046, 'RelationshipScore': 0.7452263236045837, 'RelationshipType': 'DIRECTION', 'Id': 72, 'BeginOffset': 2647, 'EndOffset': 2653, 'Text': 'around', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9968185424804688, 'RelationshipScore': 0.8649080991744995, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 73, 'BeginOffset': 2658, 'EndOffset': 2662, 'Text': 'eyes', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9976630210876465, 'RelationshipScore': 0.7997550368309021, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 74, 'BeginOffset': 2667, 'EndOffset': 2671, 'Text': 'lips', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9970989227294922, 'RelationshipScore': 0.7498077750205994, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 75, 'BeginOffset': 2683, 'EndOffset': 2688, 'Text': 'hands', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9960886240005493, 'RelationshipScore': 0.7710645198822021, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 76, 'BeginOffset': 2690, 'EndOffset': 2694, 'Text': 'feet', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.997273862361908, 'RelationshipScore': 0.9213598966598511, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 77, 'BeginOffset': 2699, 'EndOffset': 2705, 'Text': 'throat', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 114, 'BeginOffset': 2630, 'EndOffset': 2640, 'Score': 0.9858047366142273, 'Text': 'angioedema', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.7115841507911682}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9970989227294922, 'RelationshipScore': 0.5221203565597534, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 75, 'BeginOffset': 2683, 'EndOffset': 2688, 'Text': 'hands', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.997273862361908, 'RelationshipScore': 0.6794143319129944, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 77, 'BeginOffset': 2699, 'EndOffset': 2705, 'Text': 'throat', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 73, 'BeginOffset': 2658, 'EndOffset': 2662, 'Score': 0.9968185424804688, 'Text': 'eyes', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 74, 'BeginOffset': 2667, 'EndOffset': 2671, 'Score': 0.9976630210876465, 'Text': 'lips', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 75, 'BeginOffset': 2683, 'EndOffset': 2688, 'Score': 0.9970989227294922, 'Text': 'hands', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 76, 'BeginOffset': 2690, 'EndOffset': 2694, 'Score': 0.9960886240005493, 'Text': 'feet', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 77, 'BeginOffset': 2699, 'EndOffset': 2705, 'Score': 0.997273862361908, 'Text': 'throat', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 115, 'BeginOffset': 2730, 'EndOffset': 2752, 'Score': 0.977290153503418, 'Text': 'breathing difficulties', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9169715642929077}]}, {'Id': 116, 'BeginOffset': 2756, 'EndOffset': 2766, 'Score': 0.8468033075332642, 'Text': 'itchy rash', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8864212036132812}]}, {'Id': 117, 'BeginOffset': 2771, 'EndOffset': 2776, 'Score': 0.9430474638938904, 'Text': 'hives', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6289052963256836}]}, {'Text': 'very rare side effects', 'Type': 'PROBLEM', 'BeginOffset': 2779, 'EndOffset': 2801}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 2820, 'EndOffset': 2821}, {'Id': 143, 'BeginOffset': 2825, 'EndOffset': 2831, 'Score': 0.6733601689338684, 'Text': '10,000', 'Category': 'TIME_EXPRESSION', 'Type': 'TIME_TO_DX_NAME', 'Traits': [], 'Attributes': [{'Type': 'DX_NAME', 'Score': 0.9935890436172485, 'RelationshipScore': 0.5216392874717712, 'RelationshipType': 'OVERLAP', 'Id': 119, 'BeginOffset': 2847, 'EndOffset': 2851, 'Text': 'pain', 'Category': 'MEDICAL_CONDITION', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.814214289188385}]}]}, {'Text': 'mild pain', 'Type': 'PROBLEM', 'BeginOffset': 2842, 'EndOffset': 2851}, {'Id': 120, 'BeginOffset': 2856, 'EndOffset': 2868, 'Score': 0.9924658536911011, 'Text': 'inflammation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6300987005233765}]}, {'Text': 'injection', 'Type': 'TREATMENT', 'BeginOffset': 2884, 'EndOffset': 2893}, {'Text': 'the medicinal product', 'Type': 'TREATMENT', 'BeginOffset': 2930, 'EndOffset': 2951}, {'Id': 78, 'BeginOffset': 2961, 'EndOffset': 2979, 'Score': 0.3908141553401947, 'Text': 'surrounding tissue', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 121, 'BeginOffset': 3004, 'EndOffset': 3011, 'Score': 0.7042087316513062, 'Text': 'leakage', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6469743847846985}], 'Attributes': [{'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.3908141553401947, 'RelationshipScore': 0.8415420651435852, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 78, 'BeginOffset': 2961, 'EndOffset': 2979, 'Text': 'surrounding tissue', 'Category': 'ANATOMY', 'Traits': []}]}, {'Text': 'severe stomach pain', 'Type': 'PROBLEM', 'BeginOffset': 3081, 'EndOffset': 3100}, {'Id': 123, 'BeginOffset': 3102, 'EndOffset': 3108, 'Score': 0.997687578201294, 'Text': 'nausea', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9484823942184448}]}, {'Text': 'vomiting of blood', 'Type': 'PROBLEM', 'BeginOffset': 3110, 'EndOffset': 3127}, {'Id': 125, 'BeginOffset': 3129, 'EndOffset': 3151, 'Score': 0.7112383246421814, 'Text': 'black or bloody stools', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9565806984901428}]}, {'Text': 'symptoms', 'Type': 'PROBLEM', 'BeginOffset': 3162, 'EndOffset': 3170}, {'Id': 126, 'BeginOffset': 3174, 'EndOffset': 3202, 'Score': 0.9665869474411011, 'Text': 'gastrointestinal perforation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.822681188583374}]}, {'Id': 127, 'BeginOffset': 3207, 'EndOffset': 3218, 'Score': 0.7346341013908386, 'Text': 'mouth sores', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9464032649993896}]}, {'Id': 128, 'BeginOffset': 3220, 'EndOffset': 3241, 'Score': 0.9911728501319885, 'Text': 'difficulty swallowing', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9738150238990784}]}, {'Id': 129, 'BeginOffset': 3243, 'EndOffset': 3257, 'Score': 0.9820615649223328, 'Text': 'abdominal pain', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.9756803512573242}]}, {'Id': 130, 'BeginOffset': 3259, 'EndOffset': 3265, 'Score': 0.9993188381195068, 'Text': 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'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6301027536392212}], 'Attributes': [{'Type': 'DIRECTION', 'Score': 0.8191272616386414, 'RelationshipScore': 0.9999843835830688, 'RelationshipType': 'DIRECTION', 'Id': 81, 'BeginOffset': 3354, 'EndOffset': 3359, 'Text': 'inner', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9079734683036804, 'RelationshipScore': 0.9989591836929321, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 82, 'BeginOffset': 3360, 'EndOffset': 3379, 'Text': 'lining of the mouth', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9889876246452332, 'RelationshipScore': 0.9960015416145325, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 83, 'BeginOffset': 3381, 'EndOffset': 3388, 'Text': 'stomach', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9907638430595398, 'RelationshipScore': 0.9618145823478699, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 84, 'BeginOffset': 3396, 'EndOffset': 3399, 'Text': 'gut', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 82, 'BeginOffset': 3360, 'EndOffset': 3379, 'Score': 0.9079734683036804, 'Text': 'lining of the mouth', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 83, 'BeginOffset': 3381, 'EndOffset': 3388, 'Score': 0.9889876246452332, 'Text': 'stomach', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 84, 'BeginOffset': 3396, 'EndOffset': 3399, 'Score': 0.9907638430595398, 'Text': 'gut', 'Category': 'ANATOMY', 'Type': 'SYSTEM_ORGAN_SITE', 'Traits': []}, {'Id': 135, 'BeginOffset': 3401, 'EndOffset': 3421, 'Score': 0.8728171586990356, 'Text': 'mucosal inflammation', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.4048217535018921}, {'Name': 'DIAGNOSIS', 'Score': 0.4619597792625427}], 'Attributes': [{'Type': 'DIRECTION', 'Score': 0.8191272616386414, 'RelationshipScore': 0.7426785826683044, 'RelationshipType': 'DIRECTION', 'Id': 81, 'BeginOffset': 3354, 'EndOffset': 3359, 'Text': 'inner', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9079734683036804, 'RelationshipScore': 0.7820868492126465, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 82, 'BeginOffset': 3360, 'EndOffset': 3379, 'Text': 'lining of the mouth', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9889876246452332, 'RelationshipScore': 0.9399741888046265, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 83, 'BeginOffset': 3381, 'EndOffset': 3388, 'Text': 'stomach', 'Category': 'ANATOMY', 'Traits': []}, {'Type': 'SYSTEM_ORGAN_SITE', 'Score': 0.9907638430595398, 'RelationshipScore': 0.6822801828384399, 'RelationshipType': 'SYSTEM_ORGAN_SITE', 'Id': 84, 'BeginOffset': 3396, 'EndOffset': 3399, 'Text': 'gut', 'Category': 'ANATOMY', 'Traits': []}]}, {'Id': 136, 'BeginOffset': 3454, 'EndOffset': 3469, 'Score': 0.9533217549324036, 'Text': 'cervical cancer', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9636351466178894}]}, {'Id': 137, 'BeginOffset': 3483, 'EndOffset': 3495, 'Score': 0.9125102162361145, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6527734994888306}]}, {'Text': 'the other medicine (cisplatin)', 'Type': 'TREATMENT', 'BeginOffset': 3501, 'EndOffset': 3531}, {'Id': 87, 'BeginOffset': 3566, 'EndOffset': 3576, 'Score': 0.9569910168647766, 'Text': 'potactasol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 138, 'BeginOffset': 3591, 'EndOffset': 3603, 'Score': 0.9454371929168701, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7773797512054443}]}, {'Id': 139, 'BeginOffset': 3619, 'EndOffset': 3631, 'Score': 0.92707759141922, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7638394832611084}]}, {'Id': 140, 'BeginOffset': 3690, 'EndOffset': 3702, 'Score': 0.959625780582428, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.6577098965644836}]}, {'Id': 141, 'BeginOffset': 3751, 'EndOffset': 3763, 'Score': 0.8630843758583069, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7130597829818726}]}, {'Id': 142, 'BeginOffset': 3817, 'EndOffset': 3828, 'Score': 0.3529776334762573, 'Text': 'appendix v.', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.7306555509567261}]}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 3910, 'EndOffset': 3923}]}"},"Section_5":{"kind":"string","value":"{'Title': '5. how to store potactasol', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the vial and carton after exp. the expiry date refers to the last day of that month. keep the vial in the outer carton in order to protect from light. storage after reconstitution and dilution chemical and physical stability of the concentrate has been demonstrated for 24 hours at 25 ± 2, in normal light conditions and 24 hours at 2 to 8, protected from light. the physico-chemical stability of the medicinal product solution obtained after dilution in solutions for infusion (nacl 0.9 % and glucose 5 %) has been demonstrated for 4 hours at room temperature, in normal lighting conditions, on samples reconstituted and stored for 12 hours and respectively 24 hours at 25oc ± 2oc and then diluted. from a microbiological point of view, the product should be used immediately. if not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions. any unused product or waste material should be disposed of in accordance with local requirements for cytotoxic material.', 'Entity_Recognition': [{'Text': 'potactasol', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 70, 'EndOffset': 83}, {'Text': 'the outer carton', 'Type': 'TREATMENT', 'BeginOffset': 227, 'EndOffset': 243}, {'Text': 'reconstitution', 'Type': 'TREATMENT', 'BeginOffset': 290, 'EndOffset': 304}, {'Text': 'dilution chemical', 'Type': 'TREATMENT', 'BeginOffset': 309, 'EndOffset': 326}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 395, 'EndOffset': 397}, {'Text': '25', 'Type': 'NUMBER', 'BeginOffset': 407, 'EndOffset': 409}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 412, 'EndOffset': 413}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 446, 'EndOffset': 448}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 458, 'EndOffset': 459}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 463, 'EndOffset': 464}, {'Text': 'the medicinal product solution', 'Type': 'TREATMENT', 'BeginOffset': 522, 'EndOffset': 552}, {'Text': 'dilution in solutions', 'Type': 'TREATMENT', 'BeginOffset': 568, 'EndOffset': 589}, {'Text': 'infusion (nacl', 'Type': 'TREATMENT', 'BeginOffset': 594, 'EndOffset': 608}, {'Text': '0.9', 'Type': 'NUMBER', 'BeginOffset': 609, 'EndOffset': 612}, {'Text': 'glucose', 'Type': 'TREATMENT', 'BeginOffset': 619, 'EndOffset': 626}, {'Text': '5', 'Type': 'NUMBER', 'BeginOffset': 627, 'EndOffset': 628}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 658, 'EndOffset': 659}, {'Text': '12', 'Type': 'NUMBER', 'BeginOffset': 758, 'EndOffset': 760}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 784, 'EndOffset': 786}, {'Text': '24', 'Type': 'NUMBER', 'BeginOffset': 1050, 'EndOffset': 1052}, {'Text': '2', 'Type': 'NUMBER', 'BeginOffset': 1062, 'EndOffset': 1063}, {'Text': '8', 'Type': 'NUMBER', 'BeginOffset': 1067, 'EndOffset': 1068}, {'Text': 'reconstitution/dilution', 'Type': 'TREATMENT', 'BeginOffset': 1077, 'EndOffset': 1100}, {'Text': 'any unused product or waste material', 'Type': 'PROBLEM', 'BeginOffset': 1165, 'EndOffset': 1201}, {'Text': 'cytotoxic material', 'Type': 'TREATMENT', 'BeginOffset': 1266, 'EndOffset': 1284}]}"},"Section_6":{"kind":"string","value":"{'Title': '6. contents of the pack and other information', 'Section_Content': 'what potactasol contains - the active substance is topotecan. each vial contains 1 mg or 4 mg topotecan (as hydrochloride). after reconstitution 1 ml concentrate contains 1 mg topotecan. - the other ingredients are: mannitol (e421), tartaric acid (e334), hydrochloric acid (e507) and sodium hydroxide (see section 2). what potactasol looks like and contents of the pack potactasol is supplied in type i colourless glass vials with grey bromobutylic stopper and aluminium seals with plastic flip-off caps. vials may or may not be sheathed in a protective sleeve. vials contain either 1 mg or 4 mg of topotecan. each pack contains one vial.', 'Entity_Recognition': [{'Text': 'potactasol', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 5, 'EndOffset': 15, 'Score': 0.37037527561187744, 'Text': 'potactasol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 1, 'BeginOffset': 51, 'EndOffset': 60, 'Score': 0.9918953776359558, 'Text': 'topotecan', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9419365525245667, 'RelationshipScore': 0.99893718957901, 'RelationshipType': 'DOSAGE', 'Id': 2, 'BeginOffset': 81, 'EndOffset': 85, 'Text': '1 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 81, 'EndOffset': 82}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 89, 'EndOffset': 90}, {'Id': 4, 'BeginOffset': 94, 'EndOffset': 103, 'Score': 0.9961233735084534, 'Text': 'topotecan', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.8393182158470154, 'RelationshipScore': 0.9994053840637207, 'RelationshipType': 'DOSAGE', 'Id': 3, 'BeginOffset': 89, 'EndOffset': 93, 'Text': '4 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.9895880222320557, 'RelationshipScore': 0.9308471083641052, 'RelationshipType': 'DOSAGE', 'Id': 6, 'BeginOffset': 145, 'EndOffset': 149, 'Text': '1 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Id': 5, 'BeginOffset': 108, 'EndOffset': 121, 'Score': 0.9745477437973022, 'Text': 'hydrochloride', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9895880222320557, 'RelationshipScore': 0.9990712404251099, 'RelationshipType': 'DOSAGE', 'Id': 6, 'BeginOffset': 145, 'EndOffset': 149, 'Text': '1 ml', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'reconstitution', 'Type': 'TREATMENT', 'BeginOffset': 130, 'EndOffset': 144}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 145, 'EndOffset': 146}, {'Text': '1', 'Type': 'NUMBER', 'BeginOffset': 171, 'EndOffset': 172}, {'Id': 8, 'BeginOffset': 176, 'EndOffset': 185, 'Score': 0.9973711967468262, 'Text': 'topotecan', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9895880222320557, 'RelationshipScore': 0.908437192440033, 'RelationshipType': 'DOSAGE', 'Id': 6, 'BeginOffset': 145, 'EndOffset': 149, 'Text': '1 ml', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.5739544034004211, 'RelationshipScore': 0.9940750598907471, 'RelationshipType': 'DOSAGE', 'Id': 7, 'BeginOffset': 150, 'EndOffset': 175, 'Text': 'concentrate contains 1 mg', 'Category': 'MEDICATION', 'Traits': []}]}, {'Text': 'mannitol (e', 'Type': 'TREATMENT', 'BeginOffset': 216, 'EndOffset': 227}, {'Id': 10, 'BeginOffset': 233, 'EndOffset': 246, 'Score': 0.9833803176879883, 'Text': 'tartaric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 11, 'BeginOffset': 255, 'EndOffset': 272, 'Score': 0.9969274401664734, 'Text': 'hydrochloric acid', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 12, 'BeginOffset': 284, 'EndOffset': 300, 'Score': 0.9996688365936279, 'Text': 'sodium hydroxide', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 13, 'BeginOffset': 323, 'EndOffset': 333, 'Score': 0.76901775598526, 'Text': 'potactasol', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'the pack potactasol', 'Type': 'TREATMENT', 'BeginOffset': 361, 'EndOffset': 380}, {'Text': 'grey bromobutylic stopper', 'Type': 'TREATMENT', 'BeginOffset': 431, 'EndOffset': 456}, {'Id': 15, 'BeginOffset': 461, 'EndOffset': 476, 'Score': 0.6696465611457825, 'Text': 'aluminium seals', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': [], 'Attributes': [{'Type': 'FORM', 'Score': 0.6586731672286987, 'RelationshipScore': 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17, 'BeginOffset': 583, 'EndOffset': 587, 'Text': '1 mg', 'Category': 'MEDICATION', 'Traits': []}, {'Type': 'DOSAGE', 'Score': 0.8192265629768372, 'RelationshipScore': 0.999971866607666, 'RelationshipType': 'DOSAGE', 'Id': 18, 'BeginOffset': 591, 'EndOffset': 595, 'Text': '4 mg', 'Category': 'MEDICATION', 'Traits': 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85533BAC69E6E3BBF78B96DE98B9E212 | https://www.ema.europa.eu/documents/product-information/litak-epar-product-information_en.pdf | Litak | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
LITAK 2 mg/ml solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of solution contains 2 mg of cladribine (2-CdA)... | {'Title': '1. what litak is and what it is used for', 'Section_Content': 'litak contains the active substance cladribine. cladribine is a cytostatic agent. it affects the growth of malignant (cancerous) white blood cells which play a role in hairy cell leukaemia. litak is used to treat this disease.', 'Entity_Recogniti... | {'Title': '2. what you need to know before you use litak', 'Section_Content': 'do not use litak - if you are allergic to cladribine or any of the other ingredients of litak (listed in section 6) - if you are pregnant or breast-feeding - if you are less than 18 years of age - if you have moderate to severe kidney or liv... | {'Title': '3. how to use litak', 'Section_Content': 'always use litak as your doctor has told you. you should check with your doctor or pharmacist if you are not sure. your doctor will calculate your dose according to your body weight and explain the treatment schedule in detail. the recommended daily dose is 0.14 mg p... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines, litak can cause side effects, although not everybody gets them. tell your doctor immediately if you have any of the following during or after treatment with litak: - any signs of infections (such as flu-like symptoms) - fever repeated occurre... | {'Title': '5. how to store litak', 'Section_Content': 'keep out of the sight and reach of children. store in a refrigerator (2c-8c). do not freeze. do not use litak after the expiry date which is stated on the vial label and the outer carton after exp. the expiry date refers to the last day of that month. from a microb... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what litak contains - the active substance is cladribine. each ml solution contains 2 mg cladribine. each vial contains 10 mg cladribine in 5 ml solution. - the other ingredients are sodium chloride, sodium hydroxide (for ph adjustment), hyd... |
D0CC9635D229DB1D224636A7078CA5D9 | https://www.ema.europa.eu/documents/product-information/ribavirin-teva-pharma-bv-epar-product-information_en.pdf | Ribavirin Teva Pharma B.V. | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Ribavirin Teva Pharma B.V. 200 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Ribavirin Teva Pharma B.V. tablet contains 200 mg of ribavirin
F... | {'Title': '1. what ribavirin teva pharma b.v. is and what it is used for', 'Section_Content': 'ribavirin teva pharma b.v. contains the active substance ribavirin. this medicine stops the multiplication of many types of viruses, including hepatitis c virus. this medicine must not be used without interferon alfa-2b, i.e.... | {'Title': '2. what you need to know before you use ribavirin teva pharma b.v.', 'Section_Content': 'do not take ribavirin teva pharma b.v. do not take ribavirin teva pharma b.v. if any of the following apply to you or the child you are caring for. if you are not sure, talk to your doctor or pharmacist before taking rib... | {'Title': '3. how to use ribavirin teva pharma b.v.', 'Section_Content': 'general information about taking this medicine: always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. do not take more than the recommended dosage and take the medicine for as lon... | {'Title': '4. possible side effects', 'Section_Content': None, 'Entity_Recognition': [{'Text': 'ribavirin teva pharma b.v.', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 19, 'BeginOffset': 26, 'EndOffset': 38, 'Score': 0.8618642091751099, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Ty... | {'Title': '5. how to store ribavirin teva pharma b.v.', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the outer packaging. the expiry date refers to the last day of that month. this medicinal product requires no special s... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what ribavirin teva pharma b.v. contains the active substance is ribavirin. each film-coated tablet contains 200 mg of ribavirin. the other ingredients are tablet core; calcium hydrogen phosphate anhydrous, croscarmellose sodium, povidone, m... |
D3495F6E62BF7176BF1803F4DB89AC41 | https://www.ema.europa.eu/documents/product-information/velphoro-epar-product-information_en.pdf | Velphoro | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Velphoro 500 mg chewable tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each chewable tablet contains 500 mg iron as sucroferric oxyhydroxide also known as a mix... | {'Title': '1. what velphoro is and what it is used for', 'Section_Content': 'velphoro is a medicine that contains the active substance sucroferric oxyhydroxide, which is made up from iron, sugar (sucrose) and starches. velphoro is for use by adult patients who undergo haemodialysis or peritoneal dialysis (procedures to... | {'Title': '2. what you need to know before you take velphoro', 'Section_Content': "do not take velphoro: if you are allergic to sucroferric oxyhydroxide or any of the other ingredients of this medicine (listed in section 6) if you have a history of abnormal iron build-up in your organs (haemochromatosis) if you have an... | {'Title': '3. how to take velphoro', 'Section_Content': 'always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the usual recommended starting dose is the equivalent of 1,500 mg iron per day (3 tablets). the maximum recommended dose is 3,00... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. black stools may occur very commonly in patients taking velphoro. if you also have symptoms like increasing tiredness and breathlessness contact your doctor immediately (... | {'Title': '5. how to store velphoro', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date stated on the carton, bottle or blister after "exp". the expiry date refers to the last day of that month. after first opening of the bottle the chewable ta... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what velphoro contains the active substance is iron as sucroferric oxyhydroxide also known as a mixture of polynuclear iron(iii)-oxyhydroxide, sucrose, and starches. each chewable tablet contains 500 mg iron as sucroferric oxyhydroxide. each... |
92375E51FA395F8F8CBDC47C7D2FFD9B | https://www.ema.europa.eu/documents/product-information/aprovel-epar-product-information_en.pdf | Aprovel | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Aprovel 75 mg tablets.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 75 mg of irbesartan.
Excipient with known effect: 15.37 mg of lactose monohydr... | {'Title': '1. what aprovel is and what it is used for', 'Section_Content': 'aprovel belongs to a group of medicines known as angiotensin-ii receptor antagonists. angiotensin-ii is a substance produced in the body which binds to receptors in blood vessels causing them to tighten. this results in an increase in blood pre... | {'Title': '2. what you need to know before you take aprovel', 'Section_Content': 'do not take aprovel if you are allergic to irbesartan or any other ingredients of this medicine (listed in section 6) if you are more than 3 months pregnant. (it is also better to avoid aprovel in early pregnancy see pregnancy section) if... | {'Title': '3. how to take aprovel', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. method of administration aprovel is for oral use. swallow the tablets with a sufficient amount of fluid (e.g. one glass of water). you can take... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. some of these effects may be serious and may require medical attention. as with similar medicines, rare cases of allergic skin reactions (rash, urticaria), as well as loc... | {'Title': '5. how to store aprovel', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and on the blister after exp. the expiry date refers to the last day of that month. do not store above 30. do not throw away an... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what aprovel contains the active substance is irbesartan. each tablet of aprovel 75 mg contains 75 mg irbesartan. the other ingredients are microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, magnesium stearate, colloidal... |
872F0A92D7E5CA03CBF88E6EC8A5FDE6 | https://www.ema.europa.eu/documents/product-information/kiovig-epar-product-information_en.pdf | Kiovig | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
KIOVIG 100 mg/ml solution for infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Human normal immunoglobulin (IVIg)
One ml contains:
Human normal immunoglobulin ……………100 mg
(purity of at least 98% IgG)
Each vial of 10 ml conta... | {'Title': '1. what kiovig is and what it is used for', 'Section_Content': 'kiovig belongs to a class of medications called immunoglobulins. these medicines contain human antibodies, which are also present in your blood. antibodies help your body to fight infections. medicines like kiovig are used in patients who do not... | {'Title': '2. what you need to know before you use kiovig', 'Section_Content': "do not use kiovig if you are allergic to immunoglobulins or to any other ingredients of this medicine (listed in section 6). for example, if you have an immunoglobulin a deficiency, you may have antibodies against immunoglobulin a in your b... | {'Title': '3. how to use kiovig', 'Section_Content': 'kiovig is intended for intravenous administration (infusion into a vein). it is given to you by your doctor or nurse. dose and frequency of the infusion will vary depending on your condition and your body weight. at the beginning of your infusion you will receive ki... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. certain side effects, e.g. headache or flushing, may be reduced by slowing the infusion rate. below is a list of side effects reported with kiovig: very common side effec... | {'Title': '5. how to store kiovig', 'Section_Content': ' keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is printed on the label and carton after exp. the expiry date refers to the last day of that month. do not use this medicine if you notice particulate ... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what kiovig contains the active substance of kiovig is human normal immunoglobulin. 1 ml of kiovig contains 100 mg of human protein of which at least 98% is immunoglobulin g (igg). the other ingredients (excipients) are glycine and water for... |
656C3533BF06E19D8AF505AF291867F2 | https://www.ema.europa.eu/documents/product-information/lorviqua-epar-product-information_en.pdf | Lorviqua | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspect... | {'Title': '1. what lorviqua is and what it is used for', 'Section_Content': 'what lorviqua is lorviqua contains the active substance lorlatinib, a medicine that is used for treatment of adults with advanced stages of a form of lung cancer called non-small cell lung cancer (nsclc). lorviqua belongs to the group of medic... | {'Title': '2. what you need to know before you take lorviqua', 'Section_Content': "do not take lorviqua - if you are allergic to lorlatinib or any of the other ingredients of this medicine (listed in section 6). - if you are taking any of these medicines: rifampicin (used to treat tuberculosis) carbamazepine, phenytoin... | {'Title': '3. how to take lorviqua', 'Section_Content': 'always take this medicine exactly as your doctor, pharmacist or nurse has told you. check with your doctor, pharmacist or nurse if you are not sure. - the recommended dose is one tablet of 100 mg taken by mouth once daily. - take the dose at about the same time e... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. some side effects could be serious. tell your doctor straight away if you notice any of the following side effects (also section 2 what you need to know before you take l... | {'Title': '5. how to store lorviqua', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister foil and carton after "exp". the expiry date refers to the last day of that month. this medicine does not require any special... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what lorviqua contains - the active substance is lorlatinib. lorviqua 25 mg: each film-coated tablet (tablet) contains 25 mg lorlatinib. lorviqua 100 mg: each film-coated tablet (tablet) contains 100 mg lorlatinib. - the other ingredients ar... |
FF20679A00B6324E35178EF95C3BEED4 | https://www.ema.europa.eu/documents/product-information/pifeltro-epar-product-information_en.pdf | Pifeltro | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
1. NAM... | {'Title': '1. what pifeltro is and what it is used for', 'Section_Content': "what pifeltro is pifeltro is used to treat hiv ('human immunodeficiency virus') infection. it belongs to a group of medicines called 'antiretroviral medicines'. pifeltro contains the active substance doravirine - a non-nucleoside reverse trans... | {'Title': '2. what you need to know before you take pifeltro', 'Section_Content': 'do not take pifeltro: if you are allergic to doravirine or any of the other ingredients of this medicine listed in section 6. if you are taking the following medicines: carbamazepine, oxcarbazepine, phenobarbital, phenytoin (medicines fo... | {'Title': '3. how to take pifeltro', 'Section_Content': 'always take this medicine exactly as your doctor, pharmacist, or nurse has told you. check with your doctor, pharmacist, or nurse if you are not sure. this medicine must be used in combination with other medicines for hiv. how much to take the recommended dose is... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. do not stop taking this medicine without first talking to your doctor. common: may affect up to 1 in 10 people: abnormal dreams, difficulty in sleeping (insomnia) headach... | {'Title': '5. how to store pifeltro', 'Section_Content': ' keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the bottle after exp. this medicine should be used within 35 days after first opening of the bottle. the bottle contains a desiccant pro... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what pifeltro contains the active substance is doravirine 100 mg. the other ingredients are croscarmellose sodium e468; hypromellose acetate succinate; lactose monohydrate; magnesium stearate e470b; microcrystalline cellulose e460; and silic... |
F633DD14B429B6B0E65E2DC3F1DCE6FA | https://www.ema.europa.eu/documents/product-information/shingrix-epar-product-information_en.pdf | Shingrix | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See sectio... | {'Title': '1. what shingrix is and what it is used for', 'Section_Content': "what shingrix is used for shingrix is a vaccine that helps to protect adults against shingles (herpes zoster) and post-herpetic neuralgia (phn), the long-lasting nerve pain that follows shingles. shingrix is given to adults 50 years and above.... | {'Title': '2. what you need to know before you receive shingrix', 'Section_Content': "you should not receive shingrix if you are allergic (hypersensitive) to the active substances or any of the other ingredients of this vaccine (listed in section 6). signs of an allergic reaction may include itchy skin rash, shortness ... | {'Title': '3. how shingrix is given', 'Section_Content': ' shingrix is given as an injection into a muscle (usually in the upper arm). you will receive 2 injections with an interval of 2 months. if flexibility in the vaccination schedule is necessary, the second dose can be administered between 2 and 6 months after the... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this vaccine can cause side effects, although not everybody gets them. side effects reported during clinical trials with shingrix: very common (these may occur with more than 1 in 10 doses of the vaccine): headache stomach and digestive compl... | {'Title': '5. how to store shingrix', 'Section_Content': ' keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label and carton. the expiry date refers to the last day of that month. store in a refrigerator (2 8). do not freeze. store in the o... | {'Title': '6. contents of the pack and other information', 'Section_Content': "what shingrix contains the active substances are: after reconstitution, one dose (0.5 ml) contains: varicella zoster virus1 glycoprotein e antigen2 50 micrograms 1 varicella zoster virus = vzv 2 adjuvanted with as01b containing: plant extrac... |
19D1556A958E1BF6BEC9BD88A12A46CF | https://www.ema.europa.eu/documents/product-information/tegsedi-epar-product-information_en.pdf | Tegsedi | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See Sectio... | {'Title': '1. what tegsedi is and what it is used for', 'Section_Content': 'tegsedi contains the active substance inotersen. it is used to treat adults with hereditary transthyretin amyloidosis. hereditary transthyretin amyloidosis is a genetic disease, which causes build-up of small fibres of a protein called transthy... | {'Title': '2. what you need to know before you use tegsedi', 'Section_Content': 'do not use tegsedi if: - you are allergic to inotersen or any of the other ingredients of this medicine (listed in section 6). - tests show you have excessively low numbers of platelets, the cells in your blood which stick together helping... | {'Title': '3. how to use tegsedi', 'Section_Content': 'always use this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. the recommended dose of tegsedi is one dose of 284 mg inotersen. doses should be administered once every week. all subsequent doses should be inj... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects if you get any of the following side effects, stop using tegsedi and contact your doctor immediately: - symptoms that could indicate glomerulonephrit... | {'Title': '5. how to store tegsedi', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date, which is stated on the carton, tray and on the pre-filled syringe after "exp". the expiry date refers to the last day of that month. store in a refrigerator... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what tegsedi contains - the active substance is inotersen. - each pre-filled syringe contains 284mg of inotersen. - the other ingredients are water for injections, sodium hydroxide, and hydrochloric acid. what tegsedi looks like and contents... |
1A8CFDB034D73903CD7A466779FC69FD | https://www.ema.europa.eu/documents/product-information/xyrem-epar-product-information_en.pdf | Xyrem | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Xyrem 500 mg/mL oral solution
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each mL of solution contains 500 mg of sodium oxybate.
For the full list of exci... | {'Title': '1. what xyrem is and what it is used for', 'Section_Content': 'xyrem contains the active substance sodium oxybate. xyrem works by consolidating night-time sleep, though its exact mechanism of action is unknown. xyrem is used to treat narcolepsy with cataplexy in adults, adolescents and children from 7 years ... | {'Title': '2. what you need to know before you take xyrem', 'Section_Content': "do not take xyrem - if you are allergic to sodium oxybate or any of the other ingredients of this medicine (listed in section 6); - if you have succinic semialdehyde dehydrogenase deficiency (a rare metabolic disorder); - if you suffer from... | {'Title': '3. how to take xyrem', 'Section_Content': "always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. it is important that you only use the syringe provided in the box when preparing doses of xyrem. the xyrem syringe has two differen... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. these are usually mild to moderate.. adults - most common side effects observed in clinical studies (occurring in 10% to 20% of patients): dizziness nausea headache. if y... | {'Title': '5 how to store xyrem', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date stated on the bottle after (exp). the expiry date refers to the last day of that month. after dilution in the dosing cups, the preparation should be used within... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what xyrem contains - the active substance is sodium oxybate. each ml contains 500 mg of sodium oxybate. - the other ingredients are purified water, malic acid and sodium hydroxyde. what xyrem looks like and contents of the pack xyrem is sup... |
B5F4B1A6811BA7FB9024E509326CEA8B | https://www.ema.europa.eu/documents/product-information/intrarosa-epar-product-information_en.pdf | Intrarosa | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See sectio... | {'Title': '1. what intrarosa is and what it is used for', 'Section_Content': 'intrarosa contains the active substance prasterone. what intrarosa is used for intrarosa is used to treat postmenopausal women having moderate to severe symptoms of vulvar and vaginal atrophy. it is used to relieve menopausal symptoms in the ... | {'Title': '2. what you need to know before you use intrarosa', 'Section_Content': 'the use of hrt carries risks which need to be considered when deciding whether to start taking it, or whether to carry on taking it. the experience in treating women with a premature menopause (due to ovarian failure or surgery) is limit... | {'Title': '3. how to use intrarosa', 'Section_Content': 'always use this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. your doctor will aim to prescribe the lowest dose to treat your symptom for as short as necessary. speak to your doctor if you th... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the following diseases are reported more often in women using hrt medicines which circulate in the blood compared to women not using hrt. these risks apply less to vagina... | {'Title': '5. how to store intrarosa', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and blisters after exp. the expiry date refers to the last day of that month. store below 30 . do not freeze. do not throw aw... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what intrarosa contains - the active substance is prasterone. each pessary contains 6.5 mg of prasterone. - the only other ingredient is the hard fat (adeps solidus). what intrarosa looks like and contents of the pack intrarosa is a white to... |
F06CB0C715721E3C777AF60468921DA1 | https://www.ema.europa.eu/documents/product-information/pretomanid-fgk-epar-product-information_en.pdf | Pretomanid FGK | ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
... | {'Title': '1. what pretomanid fgk is and what it is used for', 'Section_Content': 'pretomanid fgk contains the active substance pretomanid, a type of antibiotic. antibiotics are medicines used to kill bacteria that cause diseases. pretomanid fgk is used in combination with two other medicines called linezolid and bedaq... | {'Title': '2. what you need to know before you take pretomanid fgk', 'Section_Content': 'do not take pretomanid fgk if you are allergic to pretomanid, antibiotics of the group called nitroimidazoles, or any of the other ingredients of this medicine (listed in section 6) since pretomanid must be used in combination with... | {'Title': '3. how to take pretomanid fgk', 'Section_Content': "always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. pretomanid fgk is used in combination with linezolid and bedaquiline. please also read the package leaflets from these med... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. when pretomanid fgk is used together with linezolid and bedaquiline the following side effects have been reported: contact your doctor immediately if you experience any o... | {'Title': '5. how to store pretomanid fgk', 'Section_Content': None, 'Entity_Recognition': None} | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what pretomanid fgk contains the active substance is pretomanid. each tablet contains 200 mg pretomanid. the other ingredients are lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, silica colloidal... |
C201632ED6452685184B4EB7A592C624 | https://www.ema.europa.eu/documents/product-information/beovu-epar-product-information_en.pdf | Beovu | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adve... | {'Title': '1. what beovu is and what it is used for', 'Section_Content': "what beovu is beovu contains the active substance brolucizumab, which belongs to a group of medicines called antineovascularisation agents. beovu is injected into the eye by your doctor to treat an eye disorder called neovascular (wet) age-relate... | {'Title': '2. what you need to know before you are given beovu', 'Section_Content': 'you must not be given beovu: - if you are allergic to brolucizumab or any of the other ingredients of this medicine (listed in section 6). - if you have an active or suspected infection in or around the eye. - if you have pain or redne... | {'Title': '3. how beovu is given', 'Section_Content': 'how much and how often beovu is given the recommended dose is 6 mg brolucizumab. - you will be treated with one injection every month for the first 3 months. - after that, you may get one injection every 3 months. your doctor will determine your treatment interval ... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the side effects with beovu injection are either from the medicine itself or from the injection procedure and they mostly affect the eye. some side effects could be serio... | {'Title': '5. how to store beovu', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and label after exp. the expiry date refers to the last day of that month. store in a refrigerator (2 - 8). do not freeze. keep t... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what beovu contains - the active substance is brolucizumab. one ml solution for injection contains 120 mg brolucizumab. each pre-filled syringe contains 19.8 mg brolucizumab in 0.165 ml solution. this provides a usable amount to deliver a si... |
3E57A488CE288770BB41B0A0DF239588 | https://www.ema.europa.eu/documents/product-information/hyqvia-epar-product-information_en.pdf | HyQvia | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
1. NAME OF ... | {'Title': '1. what hyqvia is and what it is used for', 'Section_Content': 'what hyqvia is hyqvia contains two solutions for infusion (drip) under the skin (subcutaneous or sc infusion). it is supplied as a package containing one vial of human normal immunoglobulin 10% (the active substance) and one vial of recombinant ... | {'Title': '2. what you need to know before you use hyqvia', 'Section_Content': 'do not inject or infuse hyqvia - if you are allergic to immunoglobulins, hyaluronidase, recombinant hyaluronidase or any of the other ingredients of this medicine (listed in section 6, "contents of the pack and other information"). - if you... | {'Title': '3. how to use hyqvia', 'Section_Content': None, 'Entity_Recognition': [{'Text': 'hyqvia', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 24}, {'Id': 1, 'BeginOffset': 106, 'EndOffset': 112, 'Score': 0.4246278405189514,... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can have side effects, although not everybody gets them. certain side effects, such as headache, chills, or body aches, may be reduced by slowing the infusion rate. serious side effects infusions of medicines like hyqvia can occ... | {'Title': '5. how to store hyqvia', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label and carton after exp. the expiry date refers to the last day of that month. store in a refrigerator (2 to 8). do not freeze. do n... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what hyqvia contains hyqvia is a dual vial unit containing: - a solution of recombinant human hyaluronidase (step 1 of hyqvia/infuse first) and - a solution of human normal immunoglobulin 10% (step 2 of hyqvia/infuse second). the contents of... |
182A6C29142B01CD4402579AF2BDA7AE | https://www.ema.europa.eu/documents/product-information/ionsys-epar-product-information_en.pdf | Ionsys | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Me
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o l
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uth
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2
1. NAME OF THE MEDICINAL PRODUCT
IONSYS 40 micrograms per dose transdermal system
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each IONSYS system contains fentanyl hydrochloride equivalent to ... | {'Title': '1. what ionsys is and what it is used for', 'Section_Content': 'what ionsys is ionsys is a transdermal system (to be applied on intact skin) that contains a strong analgesic (pain reliever) medicine called fentanyl. what ionsys is used for ionsys is used to treat short-term moderate to severe pain in adults ... | {'Title': '2. before you use ionsys', 'Section_Content': "do not use ionsys: if you are allergic (hypersensitive) to fentanyl, or any of the other ingredients of ionsys (listed in section 6). if you suffer from severe breathing problems or cystic fibrosis. warnings and precautions talk to your doctor or nurse before us... | {'Title': '3. how to use ionsys', 'Section_Content': 'always use this medicine exactly as your doctor or nurse has told you. check with your doctor or nurse if you are not sure about how to use ionsys or forget your instructions. the recommended dose each dose of ionsys delivers 40 micrograms of fentanyl. you control y... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. if you feel faint or if you have difficulty in breathing while being treated with ionsys, tell a doctor or nurse immediately. the following side effects may occur whilst ... | {'Title': '5. how to store ionsys', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton, or tray or sachet label, after "exp". the expiry date refers to the last day of that month. do not store above 25. do not refri... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what ionsys contains the active substance in ionsys is fentanyl hydrochloride. each ionsys system contains fentanyl hydrochloride equivalent to 9.7 mg of fentanyl and delivers 40 micrograms fentanyl per dose, to a maximum of 80 doses (3.2 mg... |
7283A4BA0162D5172DA35B90FFE48B36 | https://www.ema.europa.eu/documents/product-information/zyprexa-velotab-epar-product-information_en.pdf | Zyprexa Velotab | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
ZYPREXA VELOTAB 5 mg orodispersible tablets
ZYPREXA VELOTAB 10 mg orodispersible tablets
ZYPREXA VELOTAB 15 mg orodispersible tablets
ZYPREXA VELOTAB 20 mg orodispersible t... | {'Title': '1. what zyprexa velotab is and what it is used for', 'Section_Content': 'zyprexa velotab contains the active substance olanzapine. zyprexa velotab belongs to a group of medicines called antipsychotics and is used to treat the following conditions: schizophrenia, a disease with symptoms such as hearing, seein... | {'Title': '2. what you need to know before you take zyprexa velotab', 'Section_Content': 'do not take zyprexa velotab if you are allergic (hypersensitive) to olanzapine or any of the other ingredients of this medicine (listed in section 6). an allergic reaction may be recognised as a rash, itching, a swollen face, swol... | {'Title': '3. how to take zyprexa velotab', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. your doctor will tell you how many zyprexa velotab tablets to take and how long you should continue to take them. the daily dose of zyp... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor immediately if you have: unusual movement (a common side effect that may affect up to 1 in 10 people) mainly of the face or tongue; blood clots in the ve... | {'Title': '5. how to store zyprexa velotab', 'Section_Content': 'keep this medicine out of sight and reach of children. do not use this medicine after the expiry date, which is stated on the carton. zyprexa velotab should be stored in its original pack in order to protect from light and moisture. do not throw away any ... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what zyprexa velotab contains the active substance is olanzapine. each zyprexa velotab orodispersible tablet contains either 5 mg, 10 mg, 15 mg or 20 mg of the active substance. the exact amount is shown on your zyprexa velotab pack. the oth... |
C18EFFA40A73A83A1C1FBDB12BC03949 | https://www.ema.europa.eu/documents/product-information/azarga-epar-product-information_en.pdf | Azarga | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
AZARGA 10 mg/ml + 5 mg/ml eye drops, suspension
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml of suspension contains 10 mg brinzolamide a... | {'Title': '1. what azarga is and what it is used for', 'Section_Content': 'azarga contains two active substances, brinzolamide and timolol, which work together to reduce pressure within the eye. azarga is used to treat high pressure in the eyes, also called glaucoma or ocular hypertension, in adult patients that are mo... | {'Title': '2. what you need to know before you use azarga', 'Section_Content': "do not use azarga if you are allergic to brinzolamide, medicines called sulphonamides (examples include medicines used to treat diabetes, infections and also diuretics (water tablets)), timolol, beta- blockers (medicines used to lower blood... | {'Title': '3. how to use azarga', 'Section_Content': "always use this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. if you are changing from another eye drop medicine used to treat glaucoma to azarga, you should stop using the other medicine and st... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects although not everybody gets them. stop using this medicine and contact your doctor immediately if you develop skin rash, severe skin reaction, or severe redness and itching of the eye. these could be the s... | {'Title': '5. how to store azarga', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the bottle and the carton after exp. the expiry date refers to the last day of that month. this medicine does not require any special stora... | {'Title': '6. contents of the pack and other information', 'Section_Content': "what azarga contains the active substances are brinzolamide and timolol. one ml of suspension contains 10 mg of brinzolamide and 5 mg of timolol (as maleate). the other ingredients are benzalkonium chloride (see section 2 'azarga contains be... |
9A41613B51C2B72D58D71772D83A306A | https://www.ema.europa.eu/documents/product-information/aripiprazole-zentiva-epar-product-information_en.pdf | Aripiprazole Zentiva | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Aripiprazole Zentiva 5 mg tablets
Aripiprazole Zentiva 10 mg tablets
Aripiprazole Zentiva 15 mg tablets
Aripiprazole Zentiva 30 mg tablets
2. QUALITATIVE AND QUANTITATIVE C... | {'Title': '1. what aripiprazole zentiva is and what it is used for', 'Section_Content': 'aripiprazole zentiva contains the active substance aripiprazole and belong to a group of medicines called antipsychotics. it is used to treat adults and adolescents aged 15 years and older who suffer from a disease characterised by... | {'Title': '2. what you need to know before you take aripiprazole zentiva', 'Section_Content': 'do not take aripiprazole zentiva if you are allergic to aripiprazole or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor before taking aripiprazole zentiva. sui... | {'Title': '3. how to take aripiprazole zentiva', 'Section_Content': 'always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the recommended dose for adults is 15 mg once a day. however your doctor may prescribe a lower or higher dose to a m... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. common side effects (may affect up to 1 in 10 people): diabetes mellitus, difficulty sleeping, feeling anxious, feeling restless and unable to keep still, difficulty sitt... | {'Title': '5. how to store aripiprazole zentiva', 'Section_Content': None, 'Entity_Recognition': None} | {'Title': '6. contents of the pack and other information', 'Section_Content': "what aripiprazole zentiva contains the active substance is aripiprazole. each tablet contains 5 mg/10 mg/15 mg/30 mg of aripiprazole. the other ingredients are lactose monohydrate, microcrystalline cellulose, crospovidone, hydroxypropyl cell... |
EDCEDBE56018CE371FD5D66B4DDE9CC8 | https://www.ema.europa.eu/documents/product-information/xermelo-epar-product-information_en.pdf | Xermelo | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See ... | {'Title': '1. what xermelo is and what it is used for', 'Section_Content': "what xermelo is this medicine contains the active substance telotristat ethyl. what xermelo is used for this medicine is used in adults with a condition called 'carcinoid syndrome'. this is when a tumour, called a 'neuroendocrine tumour', relea... | {'Title': '2. what you need to know before you take xermelo', 'Section_Content': 'do not take xermelo - if you are allergic to telotristat or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor or pharmacist before taking xermelo: if you have liver problems.... | {'Title': '3. how to take xermelo', 'Section_Content': 'always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. how much to take the recommended dose is one tablet (250 mg) three times a day. the maximum dose of xermelo is 750 mg in 24 hours... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor immediately if you notice any of the following side effects: feeling or being sick, abnormally dark urine, yellow skin or eyes, pain in the upper right b... | {'Title': '5. how to store xermelo', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and the blister after exp. the expiry date refers to the last day of that month. do not throw away any medicines via wastewater... | {'Title': '6. contents of the pack and other information', 'Section_Content': "what xermelo contains the active substance is telotristat ethyl. each tablet contains telotristat etiprate equivalent to 250 mg telotristat ethyl. the other ingredients are: lactose anhydrous (see section 2 under 'xermelo contains lactose'),... |
6B783065FFDD65D778AFD71E2DBD5029 | https://www.ema.europa.eu/documents/product-information/imatinib-medac-epar-product-information_en.pdf | Imatinib medac | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Me
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1. NAME OF THE MEDICINAL PRODUCT
Imatinib medac 100 mg hard capsules
Imatinib medac 400 mg hard capsules
2. QUALITATIVE AND QUANTITATIVE COMP... | {'Title': '1. what imatinib medac is and what it is used for', 'Section_Content': 'imatinib medac is a medicine containing an active substance called imatinib. this medicine works by inhibiting the growth of abnormal cells in the diseases listed below. these include some types of cancer. imatinib medac is a treatment f... | {'Title': '2. what you need to know before you take imatinib medac', 'Section_Content': "imatinib medac will only be prescribed to you by a doctor with experience in medicines to treat blood cancers or solid tumours. follow all your doctor's instructions carefully, even if they differ from the general information conta... | {'Title': '3. how to take imatinib medac', 'Section_Content': "your doctor has prescribed imatinib medac because you suffer from a serious condition. imatinib medac can help you to fight this condition. however, always take this medicine exactly as your doctor, pharmacist or nurse has told you. it is important that you... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. they are usually mild to moderate. some side effects may be serious. tell your doctor straight away if you get any of the following: very common (may affect more than 1 i... | {'Title': '5. how to store imatinib medac', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister and carton after exp. do not store above 30 . do not use any pack that is damaged or shows signs of tampering. do not t... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what imatinib medac contains the active substance is imatinib (as mesilate). each 100 mg hard capsule of imatinib medac contains 100 mg imatinib (as mesilate). each 400 mg hard capsule of imatinib medac contains 400 mg imatinib (as mesilate)... |
6CEDC70614C3A802A5692D9CE10694A3 | https://www.ema.europa.eu/documents/product-information/grasustek-epar-product-information_en.pdf | Grasustek | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See ... | {'Title': '1. what grasustek is and what it is used for', 'Section_Content': 'grasustek is for use in adults aged 18 and over. grasustek contains the active substance pegfilgrastim. pegfilgrastim is a protein produced by biotechnology in bacteria called e. coli. it belongs to a group of proteins called cytokines and is... | {'Title': '2. what you need to know before you use grasustek', 'Section_Content': 'do not use grasustek if you are allergic to pegfilgrastim, filgrastim, e. coli derived proteins, or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor, pharmacist or nurse be... | {'Title': '3. how to use grasustek', 'Section_Content': 'always use grasustek exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. the usual dose is one 6 mg subcutaneous injection (injection under your skin) using a pre-filled syringe and it should be given at least 24 hours a... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine may have side effects, although not everybody gets them. please tell your doctor immediately if you have any of the following or combination of the following side effects: swelling or puffiness, which may be associated with pass... | {'Title': '5. how to store grasustek', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and on the syringe label after exp. the expiry date refers to the last day of that month. store in a refrigerator (2-8). you ... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what grasustek contains − the active substance is pegfilgrastim. each pre-filled syringe contains 6 mg of pegfilgrastim in 0.6 ml of solution. − the other ingredients are sodium acetate, sorbitol (e420), polysorbate 20 and water for injectio... |
3C92CFC7FF68FF6393EA2F4405A40B29 | https://www.ema.europa.eu/documents/product-information/epclusa-epar-product-information_en.pdf | Epclusa | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See sec... | {'Title': '1. what epclusa is and what it is used for', 'Section_Content': 'epclusa is a medicine that contains the active substances sofosbuvir and velpatasvir in a single tablet. it is given to treat a chronic (long-term) viral infection of the liver called hepatitis c in adults of 18 years and older. the active subs... | {'Title': '2. what you need to know before you take epclusa', 'Section_Content': 'do not take epclusa if you are allergic to sofosbuvir, velpatasvir or any of the other ingredients of this medicine (listed in section 6 of this leaflet). if this applies to you, do not take epclusa and tell your doctor immediately. if yo... | {'Title': '3. how to take epclusa', 'Section_Content': "always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. recommended dose the recommended dose is one tablet once a day for 12 weeks. swallow the tablet whole with or without food. do not chew, crush ... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine may cause side effects, although not everybody gets them. common side effects (may affect up to 1 in 10 people) rash uncommon side effects (may affect up to 1 in 100 people) swelling of the face, lips, tongue or throat (angioede... | {'Title': '5. how to store epclusa', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the bottle and carton after "exp". the expiry date refers to the last day of that month. this medicine does not require any special storag... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what epclusa contains the active substances are sofosbuvir and velpatasvir. each film-coated tablet contains 400 mg sofosbuvir and 100 mg velpatasvir. the other ingredients are tablet core: copovidone, microcrystalline cellulose, croscarmell... |
0AA9B4EF46C83A76DDB04D916CDF4EAC | https://www.ema.europa.eu/documents/product-information/imnovid-epar-product-information_en.pdf | Imnovid | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of new
safety information. Healthcare professionals are asked to report any suspected adverse r... | {'Title': '1. what imnovid is and what it is used for', 'Section_Content': "what imnovid is imnovid contains the active substance 'pomalidomide'. this medicine is related to thalidomide and belongs to a group of medicines which affect the immune system (the body's natural defences). what imnovid is used for imnovid is ... | {'Title': '2. what you need to know before you take imnovid', 'Section_Content': 'do not take imnovid: if you are pregnant or think you may be pregnant or are planning to become pregnant this is because imnovid is expected to be harmful to an unborn child. (men and women taking this medicine must read the section "preg... | {'Title': '3. how to take imnovid', 'Section_Content': "imnovid must be given to you by a doctor with experience in treating multiple myeloma. always take your medicines exactly as your doctor has told you. check with your doctor, pharmacist or nurse if you are not sure. when to take imnovid with other medicines imnovi... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects stop taking imnovid and see a doctor straight away if you notice any of the following serious side effects you may need urgent medical treatment: fev... | {'Title': '5. how to store imnovid', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister and carton after exp. the expiry date refers to the last day of that month. this medicine does not require any special storage... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what imnovid contains the active substance is pomalidomide. the other ingredients are mannitol (e421), starch, pregelatinised, and sodium stearyl fumarate. imnovid 1 mg hard capsule: each capsule contains 1 mg of pomalidomide. the capsule sh... |
4544B30A5E4E78127A7EFDDB2609CA65 | https://www.ema.europa.eu/documents/product-information/nordimet-epar-product-information_en.pdf | Nordimet | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1 NAME OF THE MEDICINAL PRODUCT
Nordimet 7.5 mg solution for injection in pre-filled pen
Nordimet 10 mg solution for injection in pre-filled pen
Nordimet 12.5 mg solution for ... | {'Title': '1. what nordimet is and what it is used for', 'Section_Content': "nordimet contains the active substance methotrexate which works by: - reducing inflammation or swelling, and - reducing the activity of the immune system (the body's own defense mechanism). an overactive immune system has been linked to inflam... | {'Title': '2. what you need to know before you use nordimet', 'Section_Content': 'do not use nordimet if: - you are allergic to methotrexate or any of the other ingredients of this medicine (listed in section 6) - you have severe kidney disease (your doctor will be able to tell you if you have severe kidney disease) - ... | {'Title': '3. how to use nordimet', 'Section_Content': 'important warning about the dose of nordimet use nordimet only once a week for the treatment of rheumatoid arthritis, active juvenile idiopathic arthritis, psoriasis and psoriatic arthritis requiring dosing once a week. using too much of nordimet may be fatal. ple... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor straight away if you get any sudden wheeziness, difficulty in breathing, swelling of the eyelids, face or lips, rash or itching (especially affecting you... | {'Title': '5. how to store nordimet', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label of the pre-filled pen and the carton after exp. the expiry date refers to the last day of that month. store below 25. keep the ... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what nordimet contains the active substance is methotrexate. 1 ml of solution contains 25 mg methotrexate. the other ingredients are sodium chloride, sodium hydroxide and water for injections. the following pens are available: pre-filled pen... |
860E463689856EBCE34DA2F48D8F5CBC | https://www.ema.europa.eu/documents/product-information/arikayce-liposomal-product-information_en.pdf | Arikayce liposomal | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
ARIKAYCE liposomal 590 mg nebuliser dispersion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains amikacin sulfate equivalent to 590 mg amikacin in a lip... | {'Title': '1. what arikayce liposomal is and what it is used for', 'Section_Content': 'arikayce liposomal is an antibiotic that contains the active ingredient amikacin. amikacin belongs to a group of antibiotics called aminoglycosides which stop the growth of certain bacteria that cause infections. arikayce liposomal i... | {'Title': '2. what you need to know before you use arikayce liposomal', 'Section_Content': 'do not use arikayce liposomal - if you are allergic to amikacin or other aminoglycosides, soya or any of the other ingredients of this medicine (listed in section 6) - if you are taking any other aminoglycosides (oral or for inj... | {'Title': '3. how to use arikayce liposomal', 'Section_Content': 'always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure. the recommended dose is one vial of arikayce liposomal inhaled in your mouth once a day, using the lamira nebuliser. after 6 months of treatment you... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor immediately if: - you experience any hypersensitivity or severe allergic reactions when taking arikayce liposomal (e.g. with low blood pressure, loss of ... | {'Title': '5. how to store arikayce liposomal', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the vial after exp. the expiry date refers to the last day of that month. store in a refrigerator (2 8 ). do not freeze, discar... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what arikayce liposomal contains - the active substance is amikacin. each vial contains amikacin sulfate equivalent to 590 mg amikacin in a liposomal formulation. the mean delivered dose per vial is approximately 312 mg of amikacin. - the ot... |
2FACB377F58985B93B438528E7B24319 | https://www.ema.europa.eu/documents/product-information/gazyvaro-epar-product-information_en.pdf | Gazyvaro | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Gazyvaro 1,000 mg concentrate for solution for infusion.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial of 40 mL concentrate contains 1,000 mg obinu... | {'Title': '1. what gazyvaro is and what it is used for', 'Section_Content': 'what gazyvaro is gazyvaro contains the active substance obinutuzumab, which belongs to a group of medicines called "monoclonal antibodies". antibodies work by attaching themselves to specific targets in your body. what gazyvaro is used for gaz... | {'Title': '2. what you need to know before you are given gazyvaro', 'Section_Content': 'you must not be given gazyvaro if: you are allergic to obinutuzumab or any of the other ingredients of this medicine (listed in section 6). if you are not sure talk to your doctor or nurse before being given gazyvaro. warnings and p... | {'Title': '3. how gazyvaro is given', 'Section_Content': 'how gazyvaro is given gazyvaro is given under the supervision of a doctor experienced in such treatment. it is given into a vein as a drip (intravenous infusion) over several hours. the gazyvaro treatment chronic lymphocytic leukaemia you will be given 6 treatme... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the following side effects have been reported with this medicine: serious side effects infusion related reactions tell your doctor or nurse straight away if you get any o... | {'Title': '5. how to store gazyvaro', 'Section_Content': 'gazyvaro will be stored by the healthcare professionals at the hospital or clinic. the storage details are as follows: keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton after e... | {'Title': '6. content of the pack and other information', 'Section_Content': 'what gazyvaro contains the active substance is obinutuzumab: 1,000 mg/40 ml per vial corresponding to a concentration before dilution of 25 mg/ml. the other ingredients are histidine, histidine hydrochloride monohydrate, trehalose dihydrate, ... |
08B331006615DBC9DCA92C36C72E1C49 | https://www.ema.europa.eu/documents/product-information/bemfola-epar-product-information_en.pdf | Bemfola | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Bemfola 75 IU/0.125 mL solution for injection in pre-filled pen
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each mL of the solution contains 600 IU (equivalent to 4... | {'Title': '1. what bemfola is and what it is used for', 'Section_Content': 'what bemfola is this medicine contains the active substance follitropin alfa, which is almost identical to a natural hormone produced by your body called "follicle-stimulating hormone" (fsh). fsh is a gonadotropin, a type of hormone that plays ... | {'Title': '2. what you need to know before you use bemfola', 'Section_Content': 'you and your partner\'s fertility should be evaluated before the treatment is started by a doctor experienced in treating fertility disorders. do not use bemfola if you are allergic to follicle stimulating hormone or any of the other ingre... | {'Title': '3. how to use bemfola', 'Section_Content': 'always use this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. using this medicine bemfola is intended to be given by injection just under the skin (subcutaneously). use the pre- filled pen only once then it ... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects in women lower abdominal pain together with nausea or vomiting may be the symptoms of ovarian hyper-stimulation syndrome (ohss). this may indicate th... | {'Title': '5. how to store bemfola', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date, which is stated on the pen label and carton after exp. the expiry date refers to the last day of that month. store in a refrigerator (2 - 8). do not freeze.... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what bemfola contains the active substance is follitropin alfa. bemfola 75 iu/0.125 ml: each cartridge contains 75 iu (equivalent to 5.5 micrograms) follitropin alfa in 0.125 ml solution. bemfola 150 iu/0.25 ml: each cartridge contains 150 i... |
284AEF4A93DF6030B4AB6CEC34042E38 | https://www.ema.europa.eu/documents/product-information/epoetin-alfa-hexal-epar-product-information_en.pdf | Epoetin Alfa Hexal | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Epoetin alfa HEXAL 1,000 IU/0.5 mL solution for injection in a pre-filled syringe
Epoetin alfa HEXAL 2,000 IU/1 mL solution for injection in a pre-filled syringe
Epoetin alfa... | {'Title': '1. what epoetin alfa hexal is and what it is used for', 'Section_Content': 'epoetin alfa hexal contains the active substance epoetin alfa, a protein that stimulates the bone marrow to produce more red blood cells which carry haemoglobin (a substance that transports oxygen). epoetin alfa is a copy of the huma... | {'Title': '2. what you need to know before you use epoetin alfa hexal', 'Section_Content': 'do not use epoetin alfa hexal: if you are allergic to epoetin alfa or any of the other ingredients of this medicine (listed in section 6). if you have been diagnosed with pure red cell aplasia (the bone marrow cannot produce eno... | {'Title': '3. how to use epoetin alfa hexal', 'Section_Content': "always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure. your doctor has carried out blood tests and decided you need epoetin alfa hexal. epoetin alfa hexal may be given by injection: either into a vein or... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor or nurse immediately if you notice any of the effects in this list. very common side effects these may affect more than 1 in 10 people. diarrhoea feeling... | {'Title': '5. how to store epoetin alfa hexal', 'Section_Content': ' keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label and carton after exp. store and transport refrigerated (2-8). you may take epoetin alfa hexal out of the refrigerato... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what epoetin alfa hexal contains - the active substance is: epoetin alfa (for quantity see the table below). - the other ingredients are: sodium dihydrogen phosphate dihydrate, disodium phosphate dihydrate, sodium chloride, glycine, polysorb... |
D151F97A5AD8B5F9FF3AF280F2883C51 | https://www.ema.europa.eu/documents/product-information/farydak-epar-product-information_en.pdf | Farydak | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Farydak 10 mg hard capsules
Farydak 15 mg hard capsules
Farydak 20 mg hard capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Farydak 10 mg hard capsules
Ea... | {'Title': '1. what farydak is and what it is used for', 'Section_Content': 'what farydak is farydak is an anti-cancer medicine that contains the active substance panobinostat, which belongs to a group of medicines called pan-deacetylase inhibitors. what farydak is used for farydak is used to treat adult patients with a... | {'Title': '2. what you need to know before you take farydak', 'Section_Content': "do not take farydak: - if you are allergic to panobinostat or any of the other ingredients of this medicine (listed in section 6). - if you are breast-feeding warnings and precautions follow all your doctor's instructions carefully. talk ... | {'Title': '3. how to take farydak', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor or your 42 pharmacist if you are not sure. how much to take - farydak is taken over 21 days (2 weeks on and 1 week off) this is called a treatment cycle. - you do not take the me... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. some side effects could be serious stop taking farydak and seek medical help immediately if you experience any of the following: difficulty in breathing or swallowing, sw... | {'Title': '5. how to store farydak', 'Section_Content': '- keep this medicine out of the sight and reach of children. - do not take this medicine after the expiry date, which is stated on the carton and blister foil. - do not store above 30. - store in the original package in order to protect from moisture. - do not ta... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what farydak contains - the active substance of farydak is panobinostat. - each farydak 10 mg hard capsule contains panobinostat lactate anhydrous equivalent to 10 mg panobinostat. the other ingredients are: magnesium stearate, mannitol, mic... |
936476B9D52F5CDC9529480E5B920534 | https://www.ema.europa.eu/documents/product-information/aripiprazole-mylan-pharma-epar-product-information_en.pdf | Aripiprazole Mylan Pharma | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Aripiprazole Mylan Pharma 5 mg tablets
Aripiprazole Mylan Pharma 10 mg tablets
Aripiprazole Mylan Pharma 15 mg tablets
Aripiprazole Mylan Phar... | {'Title': '1. what aripiprazole mylan pharma is and what it is used for', 'Section_Content': 'aripiprazole mylan pharma contains the active substance aripiprazole and belong to a group of medicines called antipsychotics. it is used to treat adults and adolescents aged 15 years and older who suffer from a disease charac... | {'Title': '2. what you need to know before you take aripiprazole mylan pharma', 'Section_Content': 'do not take aripiprazole mylan pharma if you are allergic to aripiprazole or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor before taking aripiprazole my... | {'Title': '3. how to take aripiprazole mylan pharma', 'Section_Content': 'always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the recommended dose for adults is 15 mg once a day. however, your doctor may prescribe a lower or higher dose ... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. common side effects (may affect up to 1 in 10 people): diabetes mellitus, difficulty sleeping, feeling anxious, feeling restless and unable to keep still, difficulty sitt... | {'Title': '5. how to store aripiprazole mylan pharma', 'Section_Content': None, 'Entity_Recognition': None} | {'Title': '6. contents of the pack and other information', 'Section_Content': "what aripiprazole mylan pharma contains the active substance is aripiprazole. each tablet of 5, 10, 15, 30 mg containing 5, 10, 15, 30 mg of aripiprazole respectively. the other ingredients for 5 mg are crystalline maltose, microcrystalline ... |
75BE3B140AA61F85E17ECDEEC52C5598 | https://www.ema.europa.eu/documents/product-information/episalvan-epar-product-information_en.pdf | Episalvan | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick
identification of new safety information. Healthcare professionals are asked to report
any suspected adverse reactions. Se... | {'Title': '1. what episalvan is and what it is used for', 'Section_Content': 'episalvan gel is a herbal medicinal product which contains dry extract from birch bark. it is used in adults for the treatment of skin wounds, resulting for example from grade 2a burn wounds or from surgical skin graft transplantation. there ... | {'Title': '2. what you need to know before you use episalvan', 'Section_Content': 'do not use episalvan - if you are allergic to birch bark or any of the other ingredients of this medicine (listed in section 6). episalvan does not contain birch pollen, so it may be used by people with birch pollen allergy. warnings and... | {'Title': '3. how to use episalvan', 'Section_Content': "always use this medicine exactly as your doctor or nurse has told you. check with your doctor or nurse if you are not sure. method of administration if necessary, wounds should be cleansed using a suitable antiseptic solution prior to application of episalvan epi... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the most frequently reported side effects are: common side effects (may affect up to 1 in 10 people): - painful skin - itching - complications in the wound healing proces... | {'Title': '5. how to store episalvan', 'Section_Content': "keep this medicine out of the sight and reach of children. store below 30. do not use this medicine after the expiry date which is stated on the carton and tube after 'exp'. the expiry date refers to the last day of that month. this product is for single use on... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what episalvan contains the active substance is a dry extract from birch bark. 1 g gel contains: 100 mg extract (as dry extract, refined) from birch bark from betula pendula, betula pubescens as well as hybrids of both species (equivalent to... |
3AC9F22A3B04A8DC8C0550DA9CE0C0D0 | https://www.ema.europa.eu/documents/product-information/comirnaty-epar-product-information_en.pdf | Comirnaty | ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
1.... | {'Title': '1. what comirnaty is and what it is used for', 'Section_Content': "comirnaty is a vaccine used for preventing covid-19 caused by sars-cov-2 virus. comirnaty is given to adults and adolescents from 16 years of age and older. the vaccine causes the immune system (the body's natural defences) to produce antibod... | {'Title': '2. what you need to know before you receive comirnaty', 'Section_Content': "comirnaty should not be given if you are allergic to the active substance or any of the other ingredients of this medicine (listed in section 6) warnings and precautions talk to your doctor, pharmacist or nurse before you are given t... | {'Title': '3. how comirnaty is given', 'Section_Content': 'comirnaty is given after dilution as an injection of 0.3 ml into a muscle of your upper arm. you will receive 2 injections, given at least 21 days apart. after the first dose of comirnaty, you should receive a second dose of the same vaccine after 21 days to co... | {'Title': '4. possible side effects', 'Section_Content': 'like all vaccines, comirnaty can cause side effects, although not everybody gets them. very common side effects: may affect more than 1 in 10 people injection site: pain, swelling tiredness headache muscle pain joint pain chills, fever common side effects: may a... | {'Title': '5. how to store comirnaty', 'Section_Content': 'keep this medicine out of the sight and reach of children. the following information about storage, expiry and use and handling is intended for healthcare professionals. do not use this medicine after the expiry date which is stated on the carton and label afte... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what comirnaty contains the active substance is covid-19 mrna vaccine. after dilution, the vial contains 6 doses of 0.3 ml with 30 micrograms mrna each. the other ingredients are: − ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyld... |
D6C195BCFFB90ECB7E0A4CC0B9EA813E | https://www.ema.europa.eu/documents/product-information/rivastigmine-teva-epar-product-information_en.pdf | Rivastigmine Teva | ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1
Me
dic
ina
l p
rod
uc
t n
o l
on
ge
r a
uth
ori
se
d
1. NAME OF THE MEDICINAL PRODUCT
Rivastigmine Teva 1.5 mg hard capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivas... | {'Title': '1. what rivastigmine teva is and what it is used for', 'Section_Content': "the active substance of rivastigmine teva is rivastigmine rivastigmine belongs to a class of substances called cholinesterase inhibitors. rivastigmine teva is used for the treatment of memory disorders in patients with alzheimer's dis... | {'Title': '2. before you take rivastigmine teva', 'Section_Content': "do not take rivastigmine teva - if you are allergic (hypersensitive) to rivastigmine (the active substance in rivastigmine teva) or to any of the other ingredients of rivastigmine teva listed in section 6 of this leaflet - if this applies to you, tel... | {'Title': '3. how to take rivastigmine teva', 'Section_Content': 'always take rivastigmine teva exactly as your doctor has told you. you should check with your doctor or pharmacist if you are not sure. how to start treatment your doctor will tell you what dose of rivastigmine teva to take. treatment usually starts with... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines, rivastigmine teva can cause side effects, although not everybody gets them. you may have side effects more often when you start your medicine or when your dose is increased. usually, the side effects slowly go away as your body gets used to t... | {'Title': '5. how to store rivastigmine teva', 'Section_Content': 'keep out of the reach and sight of children. do not use rivastigmine teva after the expiry date that is stated on the carton. the expiry date refers to the last day of that month. this medicinal product does not require any special storage conditions me... | {'Title': '6. further information', 'Section_Content': 'what rivastigmine teva contains the active substance is rivastigmine rivastigmine teva 1.5 mg hard capsules contains 1.5 mg rivastigmine as rivastigmine hydrogen tartrate rivastigmine teva 3 mg hard capsules contains 3 mg rivastigmine as rivastigmine hydrogen tart... |
75C161A3455F36F9417F2F8FF16A74A4 | https://www.ema.europa.eu/documents/product-information/neurobloc-epar-product-information_en.pdf | NeuroBloc | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
NeuroBloc 5000 U/ml solution for injection.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 5000 U Botulinum Toxin Type B.
Each 0.5 ml vial contains... | {'Title': '1. what neurobloc is and what it is used for', 'Section_Content': "neurobloc injection works by reducing or stopping muscle contractions. it contains the active ingredient 'botulinum toxin type b'. neurobloc is used to treat an illness called cervical dystonia (torticollis). this is where you have contractio... | {'Title': '2. what you need to know before you use neurobloc', 'Section_Content': 'do not use neurobloc: - if you are allergic to botulinum toxin type b or any of the other ingredients of neurobloc (listed in section 6) - if you have other problems with your nerves or muscles, such as amyotrophic lateral sclerosis (lou... | {'Title': '3. how to use neurobloc', 'Section_Content': 'neurobloc will be given to you by a doctor with specialist experience in the treatment of cervical dystonia and in the use of botulinum toxins. how much will be given - your doctor will decide how much neurobloc to give you - the usual dose is 10,000 units, howev... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. they may happen days to weeks after you have had the injection. you may feel pain at the place where you had the injection, but this should wear off after a few minutes. ... | {'Title': '5. how to store neurobloc', 'Section_Content': '- keep this medicine out of the sight and reach of children - do not use this medicine after the expiry date which is stated on the carton and on the vial after exp - store in a refrigerator (2-8). do not freeze - keep the vial in the outer carton in order to p... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what neurobloc contains the active substance is botulinum toxin type b. one millilitre (ml) contains 5000 u. one vial of 0.5 ml contains 2500 u of botulinum toxin type b. one vial of 1 ml contains 5000 u of botulinum toxin type b. one vial o... |
4406F5E84C9A761C89602A0DE3C1F08E | https://www.ema.europa.eu/documents/product-information/exjade-epar-product-information_en.pdf | Exjade | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected ... | {'Title': '1. what exjade is and what it is used for', 'Section_Content': 'what exjade is exjade contains an active substance called deferasirox. it is an iron chelator which is a medicine used to remove the excess iron from the body (also called iron overload). it traps and removes excess iron which is then excreted m... | {'Title': '2. what you need to know before you take exjade', 'Section_Content': 'do not take exjade - if you are allergic to deferasirox or any of the other ingredients of this medicine (listed in section 6). if this applies to you, tell your doctor before taking exjade. if you think you may be allergic, ask your docto... | {'Title': '3. how to take exjade', 'Section_Content': 'treatment with exjade will be overseen by a doctor who is experienced in the treatment of iron overload caused by blood transfusions. always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. how much e... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. most of the side effects are mild to moderate and will generally disappear after a few days to a few weeks of treatment. some side effects could be serious and need immed... | {'Title': '5. how to store exjade', 'Section_Content': ' keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister and the carton after exp. the expiry date refers to the last day of that month. store in the original package in order to prot... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what exjade contains the active substance is deferasirox. each dispersible tablet of exjade 125 mg contains 125 mg deferasirox. each dispersible tablet of exjade 250 mg contains 250 mg deferasirox. each dispersible tablet of exjade 500 mg co... |
00D784D36A6F97276B4CACA1A67234D2 | https://www.ema.europa.eu/documents/product-information/clopidogrel-apotex-epar-product-information_en.pdf | Clopidogrel Apotex | ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Clopidogrel Apotex 75 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 75 mg of clopidogrel (as besilate).
Excipients with a known effect:
Each film-co... | {'Title': '1. what clopidogrel apotex is and what it is used for', 'Section_Content': "clopidogrel apotex contains clopidogrel and belongs to a group of medicines called antiplatelet medicinal products. platelets are very small structures in the blood which clump together during blood clotting. by preventing this clump... | {'Title': '2. what you need to know before you take clopidogrel apotex', 'Section_Content': "do not take clopidogrel apotex: if you are allergic (hypersensitive) to clopidogrel or any of the other ingredients of this medicine (listed in section 6). if you have a medical condition that is currently causing bleeding such... | {'Title': '3. how to take clopidogrel apotex', 'Section_Content': "always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the recommended dose, including for patients with a condition called 'atrial fibrillation' (an irregular heartbeat), i... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. contact your doctor immediately if you experience: - fever, signs of infection or extreme tiredness. these may be due to rare decrease of some blood cells. - signs of liv... | {'Title': '5 how to store clopidogrel apotex', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and on the blister, after exp. the expiry date refers to the last day of that month. refer to the storage conditions ... | {'Title': '6. contents of the pack and other information', 'Section_Content': "what clopidogrel apotex contains the active substance is clopidogrel. each tablet contains 75 mg of clopidogrel (as besilate). the other ingredients are (see section 2 'clopidogrel apotex contains lactose'): - tablet core: hydroxypropylcellu... |
04911FCEAF108BB5FFDE953E31D76C08 | https://www.ema.europa.eu/documents/product-information/trazec-epar-product-information_en.pdf | Trazec | Me
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ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Me
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1. NAME OF THE MEDICINAL PRODUCT
TRAZEC 60 mg film-coated tablets
2. QUALITATIVE A... | {'Title': '1. what trazec is and what it is used for', 'Section_Content': 'trazec is a medicine to lower blood sugar (glucose), which is taken by mouth (these medicines are also known as oral anti-diabetics). it is used by people with type 2 diabetes. (this kind of diabetes is also called non-insulin-dependent diabetes... | {'Title': '2. before you take trazec', 'Section_Content': 'follow all instructions given to you by your doctor and pharmacist carefully, even if they are different from what is in this leaflet. do not take trazec - if you are allergic (hypersensitive) to nateglinide or any of the other ingredients of trazec. - if you h... | {'Title': '3. how to take trazec', 'Section_Content': 'always take trazec exactly as your doctor has told you. you should check with your doctor or pharmacist if you are not sure. when to take trazec take trazec before the three main meals, usually: - 1 dose before breakfast - 1 dose before lunch - 1 dose before dinner... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, trazec can cause side effects, although not everybody gets them. the side effects caused by trazec are usually mild to moderate. the most common side effects are symptoms of low blood sugar (hypoglycaemia), which are usually mild. these inclu... | {'Title': '5. how to store trazec', 'Section_Content': 'keep out of the reach and sight of children. store in the original package. do not use trazec after the expiry date stated on the carton after exp. the expiry date refers to the last day of that month. do not use any trazec pack that is damaged or shows signs of t... | {'Title': '6. further information', 'Section_Content': 'what trazec contains - the active substance is nateglinide. - the other ingredients are lactose monohydrate; cellulose, microcrystalline; povidone; croscarmellose sodium; magnesium stearate and silica, colloidal anhydrous. - the tablet coating contains hypromellos... |
7DA87D77F9783DA205FA5997A6611135 | https://www.ema.europa.eu/documents/product-information/vantobra-epar-product-information_en.pdf | Vantobra | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Me
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1. NAME OF THE MEDICINAL PRODUCT
Vantobra 170 mg nebuliser solution
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each singl... | {'Title': '1. what vantobra is and what it is used for', 'Section_Content': 'what vantobra is vantobra contains an antibiotic medicine called tobramycin. it belongs to a class of antibiotic medicines called aminoglycosides. what vantobra is used for vantobra is used in patients with cystic fibrosis aged 6 years and old... | {'Title': '2. what you need to know before you use vantobra', 'Section_Content': 'do not use vantobra: if you are allergic (hypersensitive) to tobramycin, to any type of aminoglycoside antibiotics, or to any of the other ingredients of vantobra (listed in section 6). if this applies to you, tell your doctor before usin... | {'Title': '3. how to use vantobra', 'Section_Content': 'always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure. the recommended dose is two ampoules each day (one in the morning and one in the evening) for 28 days. the dose is the same for all persons aged 6 years and o... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. some side effects can be serious chest tightness with difficulty in breathing (rare, affecting up to 1 in 1,000 people) allergic reactions including hives and itching (ve... | {'Title': '5. how to store vantobra', 'Section_Content': "keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the ampoule or the pouch or carton after exp. the expiry date refers to the last day of that month. store in a refrigerator (2 - 8). if y... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what vantobra contains - the active substance is tobramycin. one ampoule contains 170 mg of tobramycin as a single dose. - the other ingredient(s) (excipient(s)) are: sodium chloride, calcium chloride, magnesium sulphate, water for injection... |
3F2DC70FD05CC06A9B2BB6AEA533A253 | https://www.ema.europa.eu/documents/product-information/bosulif-epar-product-information_en.pdf | Bosulif | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected ... | {'Title': '1. what bosulif is and what it is used for', 'Section_Content': None, 'Entity_Recognition': None} | {'Title': '2. what you need to know before you take bosulif', 'Section_Content': None, 'Entity_Recognition': None} | {'Title': '3. how to take bosulif', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. bosulif will only be prescribed to you by a doctor with experience in medicines to treat leukaemia. dose and method of administration the recom... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. you must immediately contact your doctor if you experience any of those serious side effects (see also section 2 "what you need to know before you take bosulif"): blood d... | {'Title': '5. how to store bosulif', 'Section_Content': '- keep this medicine out of the sight and reach of children. - do not use this medicine after the expiry date which is stated on the blister foil and carton after "exp". the expiry date refers to the last day of that month. - this medicine does not require any sp... | {'Title': '6. content of the pack and other information', 'Section_Content': 'what bosulif contains - the active substance is bosutinib. bosulif film-coated tablets come in different strengths. bosulif 100 mg: each film-coated tablet contains 100 mg bosutinib (as monohydrate). bosulif 400 mg: each film-coated tablet co... |
4102ED063BB0171B37B6BDF6463572DA | https://www.ema.europa.eu/documents/product-information/brilique-epar-product-information_en.pdf | Brilique | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Brilique 60 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 60 mg ticagrelor.
Brilique contains less than 1 mmol sodium (23 mg) per dose, i.e. is essentially ‘sodium-free’.
For t... | {'Title': '1. what brilique is and what it is used for', 'Section_Content': "what brilique is brilique contains an active substance called ticagrelor. this belongs to a group of medicines called antiplatelet medicines. what brilique is used for brilique in combination with acetylsalicylic acid (another antiplatelet age... | {'Title': '2. what you need to know before you take brilique', 'Section_Content': "do not take brilique if: you are allergic to ticagrelor or any of the other ingredients of this medicine (listed in section 6). you are bleeding now. you have had a stroke caused by bleeding in the brain. you have severe liver disease. y... | {'Title': '3. how to take brilique', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. how much to take the usual dose is one tablet of 60 mg twice a day. continue taking brilique as long as your doctor tells you. take this medic... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. the following side effects may happen with this medicine: brilique affects blood clotting, so most side effects are related to bleeding. bleeding may occur in any part of... | {'Title': '5. how to store brilique', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister and carton after exp. the expiry date refers to the last day of that month. this medicine does not require any special storag... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what brilique contains the active substance is ticagrelor. each film-coated tablet contains 60 mg of ticagrelor. the other ingredients are: tablet core: mannitol (e421), calcium hydrogen phosphate dihydrate, sodium starch glycolate type a, h... |
4B4322A0A2CA4BE3D81A8A3BC62E2E3A | https://www.ema.europa.eu/documents/product-information/cosentyx-epar-product-information_en.pdf | Cosentyx | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Cosentyx 150 mg powder for solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial of powder contains 150 mg secukinumab. ... | {'Title': '1. what cosentyx is and what it is used for', 'Section_Content': 'cosentyx contains the active substance secukinumab. secukinumab is a monoclonal antibody which belongs to a group of medicines called interleukin (il) inhibitors. this medicine works by neutralising the activity of a protein called il-17a, whi... | {'Title': '2. what you need to know before you use cosentyx', 'Section_Content': 'do not use cosentyx: if you are allergic to secukinumab or any of the other ingredients of this medicine (listed in section 6). if you think you may be allergic, ask your doctor for advice before using cosentyx. if you have an active infe... | {'Title': '3. how to use cosentyx', 'Section_Content': "cosentyx is given via injection under your skin (known as a subcutaneous injection) by a healthcare professional. make sure you discuss with your doctor when you will have your injections and your follow-up appointments. how much cosentyx is given and for how long... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects stop using cosentyx and tell your doctor or seek medical help immediately if you get any of the following side effects: possible serious infection - ... | {'Title': '5. how to store cosentyx', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the outer box or vial after "exp". before reconstitution: store the vial in the refrigerator between 2 and 8. after reconstitution: the s... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what cosentyx contains - the active substance is secukinumab. each vial of powder for solution for injection contains 150 mg secukinumab. after reconstitution, 1 ml of solution contains 150 mg secukinumab. - the other ingredients are sucrose... |
5C61714547A198B17CE6A2C6D90A7556 | https://www.ema.europa.eu/documents/product-information/viraferonpeg-epar-product-information_en.pdf | ViraferonPeg | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
ViraferonPeg 50 micrograms powder and solvent for solution for injection
ViraferonPeg 80 micrograms powder and solvent for solution for injection
ViraferonPeg 100 micrograms powder and solvent for solution for injection
ViraferonP... | {'Title': '1. what viraferonpeg is and what it is used for', 'Section_Content': "the active substance in this medicine is a protein called peginterferon alfa-2b, which belongs to the class of medicines called interferons. interferons are made by your body's immune system to help fight infections and severe diseases. th... | {'Title': '2. what you need to know before you use viraferonpeg', 'Section_Content': 'do not use viraferonpeg you should tell your doctor before starting treatment if you, or the child you are caring for: - are allergic to peginterferon alfa-2b or any of the other ingredients of this medicine (listed in section 6). - a... | {'Title': '3. how to use viraferonpeg', 'Section_Content': 'always use this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. general information about taking this medicine your doctor has determined the correct dose of this medicine based on how much ... | {'Title': '4. possible side effects', 'Section_Content': None, 'Entity_Recognition': [{'Text': 'viraferonpeg', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, '... | {'Title': '5. how to store viraferonpeg', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton, after exp. store in a refrigerator (2c - 8c). use the reconstituted solution (solution you prepared by adding water for i... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what viraferonpeg contains - the active substance is peginterferon alfa-2b. viraferonpeg 50 micrograms powder and solvent for solution for injection each vial contains 50 micrograms of peginterferon alfa-2b measured on a protein basis. each ... |
06E4D87BCC7C4199F765DBFDFFA818C2 | https://www.ema.europa.eu/documents/product-information/iressa-epar-product-information_en.pdf | Iressa | ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
IRESSA 250 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 250 mg of gefitinib.
Excipients with known effect:
Each tablet contains 163.5 mg of lactose (as monohydrate).
Each tablet contains 3.8... | {'Title': '1. what iressa is and what it is used for', 'Section_Content': "iressa contains the active substance gefitinib which blocks a protein called 'epidermal growth factor receptor' (egfr). this protein is involved in the growth and spread of cancer cells. iressa is used to treat adults with non-small cell lung ca... | {'Title': '2. what you need to know before you take iressa', 'Section_Content': "do not take iressa if you are allergic to gefitinib or any of the other ingredients of this medicine (listed in section 6, 'what iressa contains'). if you are breast-feeding. warnings and precautions talk to your doctor or pharmacist befor... | {'Title': '3. how to take iressa', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. the recommended dose is one 250 mg tablet per day. take the tablet at about the same time each day. you can take the tablet with or without food... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines this medicine can cause side effects, although not everybody gets them. tell your doctor immediately if you notice any of the following side effects - you may need urgent medical treatment: allergic reaction (common), particularly if symptoms ... | {'Title': '5. how to store iressa', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton, blister and overwrap foil after exp. the expiry date refers to the last day of that month. store in the original package in ord... | {'Title': '6. contents of the pack and other information', 'Section_Content': "what iressa contains the active substance is gefitinib. each tablet contains 250 mg of gefitinib. the other ingredients (excipients) are lactose monohydrate, microcrystalline cellulose (e460), croscarmellose sodium, povidone (k29-32) (e1201)... |
8EE3C9FA484FF1EE8B88FB996A647522 | https://www.ema.europa.eu/documents/product-information/inomax-epar-product-information_en.pdf | INOmax | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
INOmax 400 ppm mol/mol medicinal gas, compressed
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Nitric oxide (NO) 400 ppm mol/mol.
A 2 litre gas cylinder filled at 15... | {'Title': '1. what inomax is and what it is used for', 'Section_Content': "inomax contains nitric oxide, a gas used for the treatment of newborn babies with lung failure associated with high blood pressure in the lungs, a condition known as hypoxic respiratory failure. when inhaled, this gas mixture can improve the flo... | {'Title': '2. what you need to know before you begin a treatment with inomax', 'Section_Content': "do not use inomax - if you (as the patient) or your child (as the patient) are allergic (hypersensitive) to nitric oxide or any other ingredients of inomax. (see section 6 'further information' where the full list of ingr... | {'Title': '3. how inomax is given', 'Section_Content': "your doctor will decide the correct dose of inomax and will administer inomax to you or your child's lungs through a system designed for delivering this gas. this delivery system will ensure that the correct amount of nitric oxide is delivered by diluting inomax w... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the doctor will examine you or your child closely for all side effects. side effects that are very commonly seen (affects more than 1 user in 10) in association with inom... | {'Title': '5. how to store inomax', 'Section_Content': 'keep this medicine out of the sight and reach of children do not use this medicine after the expiry date which is stated on the label after exp. the expiry date refers to the last day of that month. inomax therapy should only be used and handled by hospital person... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what inomax contains the active substance in inomax is nitric oxide 400 ppm mol/mol. a 2 litre gas cylinder filled at 155 bar absolute brings 307 litres of gas under pressure of 1 bar at 15oc. a 10 litre gas cylinder filled at 155 bar absolu... |
9E4E860B31FF2ADF0758575A786C18FA | https://www.ema.europa.eu/documents/product-information/otezla-epar-product-information_en.pdf | Otezla | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Otezla 10 mg film-coated tablets
Otezla 20 mg film-coated tablets
Otezla 30 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Otezla 10 mg film-coated ... | {'Title': '1. what otezla is and what it is used for', 'Section_Content': "what otezla is otezla contains the active substance 'apremilast'. this belongs to a group of medicines called phosphodiesterase 4 inhibitors, which help to reduce inflammation. what otezla is used for otezla is used to treat adults with the foll... | {'Title': '2. what you need to know before you take otezla', 'Section_Content': "do not take otezla: if you are allergic to apremilast or any of the other ingredients of this medicine (listed in section 6). if you are pregnant or think you may be pregnant. warnings and precautions talk to your doctor or pharmacist befo... | {'Title': '3. how to take otezla', 'Section_Content': "always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. how much to take when you first start taking otezla, you will receive a 'treatment initiation pack' which contains all the doses as listed in th... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects depression and suicidal thoughts tell your doctor straight away about any changes in behaviour or mood, feelings of depression, thoughts of suicide o... | {'Title': '5. how to store otezla', 'Section_Content': ' keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister or on the wallet or on the carton after exp. the expiry date refers to the last day of that month. do not store above 30. do n... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what otezla contains the active substance is apremilast. otezla 10 mg film-coated tablets: each film-coated tablet contains 10 mg of apremilast. otezla 20 mg film-coated tablets: each film-coated tablet contains 20 mg of apremilast. otezla 3... |
36D957BB334DB6054C51CE128D9E6B08 | https://www.ema.europa.eu/documents/product-information/equidacent-epar-product-information_en.pdf | Equidacent | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See s... | {'Title': '1. what equidacent is and what it is used for', 'Section_Content': 'equidacent contains the active substance bevacizumab, which is a humanised monoclonal antibody (a type of protein that is normally made by the immune system to help defend the body from infection and cancer). bevacizumab binds selectively to... | {'Title': '2. what you need to know before you use equidacent', 'Section_Content': "do not use equidacent if: you are allergic (hypersensitive) to bevacizumab or to any of the other ingredients of this medicine (listed in section 6). you are allergic (hypersensitive) to chinese hamster ovary (cho) cell products or to o... | {'Title': '3. how to use equidacent', 'Section_Content': 'dosage and frequency of administration the dose of equidacent needed depends on your body weight and the kind of cancer to be treated. the recommended dose is 5 mg, 7.5 mg, 10 mg or 15 mg per kilogram of your body weight. your doctor will prescribe a dose of equ... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. if you get any side effects talk to your doctor, pharmacist or nurse. this includes any possible side effects not listed in this leaflet. the side effects listed below we... | {'Title': '5. how to store equidacent', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the outer carton and on the vial label after the abbreviation exp. the expiry date refers to the last day of that month. store in a ref... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what equidacent contains the active substance is bevacizumab. each ml of concentrate contains 25 mg of bevacizumab, corresponding to 1.4 to 16.5 mg/ml when diluted as recommended. each 4 ml vial contains 100 mg of bevacizumab, corresponding ... |
6713FC7614B0655EA9786EAEFC31C1C6 | https://www.ema.europa.eu/documents/product-information/iclusig-epar-product-information_en.pdf | Iclusig | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See sect... | {'Title': '1. what iclusig is and what it is used for', 'Section_Content': 'iclusig is used to treat adults with the following leukaemia types who are no longer benefiting from treatment with other medicines, or have a certain genetic difference known as a t315i mutation: chronic myeloid leukaemia (cml): a blood cancer... | {'Title': '2. what you need to know before you take iclusig', 'Section_Content': "do not take iclusig if you are allergic to ponatinib or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor or pharmacist before taking iclusig if you have: a liver or pancreas... | {'Title': '3. how to take iclusig', 'Section_Content': "always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. iclusig therapy should be prescribed by a doctor experienced in leukaemia treatment. iclusig is available as: a 45 mg film-coated... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. patients aged 65 and over are more likely to be affected by side effects. seek medical attention immediately if you experience any of the following serious side effects. ... | {'Title': '5. how to store iclusig', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the bottle label and carton after exp. the expiry date refers to the last day of that month. store in the original container in order to p... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what iclusig contains the active substance is ponatinib. each 15 mg film-coated tablet contains 15 mg ponatinib (as ponatinib hydrochloride). each 30 mg film-coated tablet contains 30 mg ponatinib (as ponatinib hydrochloride). each 45 mg fil... |
FA65F69B53B33366EDF59BA3A1938917 | https://www.ema.europa.eu/documents/product-information/maviret-epar-product-information_en.pdf | Maviret | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See sectio... | {'Title': '1. what maviret is and what it is used for', 'Section_Content': "maviret is an antiviral medicine used to treat adults and adolescents (12 to less than 18 years old) with long-term ('chronic') hepatitis c (an infectious disease that affects the liver, caused by the hepatitis c virus). it contains the active ... | {'Title': '2. what you need to know before you take maviret', 'Section_Content': "do not take maviret if: you are allergic to glecaprevir, pibrentasvir or any of the other ingredients of this medicine (listed in section 6 of this leaflet). you have severe liver problems other than from hepatitis c. you are taking the f... | {'Title': '3. how to take maviret', 'Section_Content': 'always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. your doctor will tell you how long you need to take maviret for. how much to take the recommended dose for adults and adolescents... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor or pharmacist if you notice any of the following side effects: very common: may affect more than 1 in 10 people feeling very tired (fatigue) headache com... | {'Title': '5. how to store maviret', 'Section_Content': "keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and blister after 'exp'. this medicine does not require any special storage. do not throw away any medicines via wastewater or ... | {'Title': '6. contents of the pack and other information', 'Section_Content': "what maviret contains the active substances are glecaprevir and pibrentasvir. each tablet contains 100 mg of glecaprevir and 40 mg of pibrentasvir. the other ingredients are: − tablet core: copovidone (type k 28), vitamin e polyethylene glyc... |
6ADFC0A7644EC15EE22DE3F3603EA17D | https://www.ema.europa.eu/documents/product-information/desloratadine-actavis-epar-product-information_en.pdf | Desloratadine Actavis | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Desloratadine Actavis 5 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 mg desloratadine.
For the full list of excipien... | {'Title': '1. what desloratadine actavis is and what it is used for', 'Section_Content': 'what desloratadine actavis is desloratadine actavis contains desloratadine which is an antihistamine. how desloratadine actavis works desloratadine actavis is an antiallergy medicine that does not make you drowsy. it helps control... | {'Title': '2. what you need to know before you take desloratadine actavis', 'Section_Content': 'do not take desloratadine actavis: if you are allergic to desloratadine, or any of the other ingredients of this medicine (listed in section 6) or to loratadine. warnings and precautions talk to your doctor, pharmacist or nu... | {'Title': '3. how to take desloratadine actavis', 'Section_Content': 'always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. adults and adolescents 12 years of age and over the recommended dose is one tablet once a day with water, with or w... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. during the marketing of desloratadine, cases of severe allergic reactions (difficulty in breathing, wheezing, itching, hives and swelling) have been reported very rarely.... | {'Title': '5. how to store desloratadine actavis', 'Section_Content': "keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton, bottle label and blister after 'exp'. the expiry date refers to the last day of that month. blisters: this medic... | {'Title': '6. contents of the pack and other information', 'Section_Content': "what desloratadine actavis contains - the active substance is desloratadine. each film-coated tablet (tablet) contains 5 mg desloratadine. - the other ingredients are: tablet core: microcrystalline cellulose, starch (pregelatinised), mannito... |
63D135067B8CEA205B852322BF670E5D | https://www.ema.europa.eu/documents/product-information/atectura-breezhaler-epar-product-information_en.pdf | Atectura Breezhaler | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Atectura Breezhaler 125 micrograms/62.5 micrograms inhalation powder, hard capsules
Atectura Breezhaler 125 micrograms/127.5 micrograms inhalation powder... | {'Title': '1. what atectura breezhaler is and what it is used for', 'Section_Content': 'what atectura breezhaler is and how it works atectura breezhaler contains two active substances called indacaterol and mometasone furoate. indacaterol belongs to a group of medicines called bronchodilators. it relaxes the muscles of... | {'Title': '2. what you need to know before you use atectura breezhaler', 'Section_Content': "follow all the doctor's instructions carefully. do not use atectura breezhaler - if you are allergic to indacaterol, mometasone furoate or any of the other ingredients of this medicine (listed in section 6). if you think you ma... | {'Title': '3. how to use atectura breezhaler', 'Section_Content': 'always use this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. how much atectura breezhaler to inhale there are three different strengths of atectura breezhaler capsules. your doctor... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. some side effects could be serious stop using atectura breezhaler and get medical help immediately if you have any of the following: common: may affect up to 1 in every 1... | {'Title': '5. how to store atectura breezhaler', 'Section_Content': None, 'Entity_Recognition': None} | {'Title': '6. contents of the pack and other information instructions for use of atectura breezhaler inhaler', 'Section_Content': 'what atectura breezhaler contains - the active substances are indacaterol (as acetate) and mometasone furoate. atectura breezhaler 125 micrograms/62.5 micrograms each capsule contains 173 m... |
4C6F014617258C188FB3CAA03399D036 | https://www.ema.europa.eu/documents/product-information/blincyto-epar-product-information_en.pdf | Blincyto | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected ad... | {'Title': '1. what blincyto is and what it is used for', 'Section_Content': 'the active ingredient in blincyto is blinatumomab. this belongs to a group of medicines called antineoplastic agents which target cancer cells. blincyto is used to treat adults with acute lymphoblastic leukaemia. acute lymphoblastic leukaemia ... | {'Title': '2. what you need to know before you use blincyto', 'Section_Content': "do not use blincyto: - if you are allergic to blinatumomab or any of the other ingredients of this medicine (listed in section 6). - if you are breast-feeding. warnings and precautions talk to your doctor, pharmacist or nurse before using... | {'Title': '3. how to use blincyto', 'Section_Content': 'always use this medicine exactly as your doctor, pharmacist or nurse have told you. check with your doctor, pharmacist or nurse if you are not sure. how blincyto is given blincyto will be given to you through a vein (intravenous) continuously for 4 weeks using an ... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. some of these side effects may be serious. tell your doctor immediately if you get any of the following or combination of the following side effects: chills, shivering, f... | {'Title': '5. how to store blincyto', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label and carton after exp. the expiry date refers to the last day of that month. unopened vials: - store and transport refrigerated ... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what blincyto contains - the active substance is blinatumomab. each vial of powder contains 38.5 micrograms of blinatumomab. reconstitution with water for injections results in a final blinatumomab concentration of 12.5 micrograms/ml. - the ... |
FCFCCD0CE6929608B66C7313BC4E0B2A | https://www.ema.europa.eu/documents/product-information/imatinib-actavis-epar-product-information_en.pdf | Imatinib Actavis | ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1
1. NAME OF THE MEDICINAL PRODUCT
Imatinib Actavis 50 mg hard capsules
Imatinib Actavis 100 mg hard capsules
Imatinib Actavis 400 mg hard capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Imatinib Actavis 50 mg hard capsules
Each hard capsule contai... | {'Title': '1. what imatinib actavis is and what it is used for', 'Section_Content': 'imatinib actavis is a medicine containing an active substance called imatinib. this medicine works by inhibiting the growth of abnormal cells in the diseases listed below. these include some types of cancer. imatinib actavis is a treat... | {'Title': '2. what you need to know before you take imatinib actavis', 'Section_Content': "imatinib actavis will only be prescribed to you by a doctor with experience in medicines to treat blood cancers or solid tumours. follow all your doctor's instructions carefully, even if they differ from the general information c... | {'Title': '3. how to take imatinib actavis', 'Section_Content': "your doctor has prescribed imatinib actavis because you suffer from a serious condition. imatinib actavis can help you to fight this condition. however, always take this medicine exactly as your doctor or pharmacist has told you. it is important that you ... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. they are usually mild to moderate. some side effects may be serious. tell your doctor straight away if you get any of the following: very common (may affect more than 1 i... | {'Title': '5. how to store imatinib actavis', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and blister after exp. the expiry date refers to the last day of that month. do not store above 25. store in the origi... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what imatinib actavis contains - the active substance is imatinib (as mesilate). each capsule contains 50 mg imatinib (as mesilate). - the other ingredients are: capsule content: cellulose microcrystalline, copovidone, crospovidone, sodium s... |
1DA298606E59612D832FFC82E504F91D | https://www.ema.europa.eu/documents/product-information/anagrelide-mylan-epar-product-information_en.pdf | Anagrelide Mylan | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Anagrelide Mylan 0.5 mg hard capsules
Anagrelide Mylan 1 mg hard capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Anagrelide M... | {'Title': '1. what anagrelide mylan is and what it is used for', 'Section_Content': 'anagrelide mylan contains the active substance, anagrelide. anagrelide is a medicine which interferes with the development of platelets. it reduces the number of platelets produced by the bone marrow, which results in a decrease in the... | {'Title': '2. what you need to know before you take anagrelide mylan', 'Section_Content': 'do not take anagrelide mylan if you are allergic to anagrelide or any of the other ingredients of this medicine (listed in section 6). an allergic reaction may be recognised as a rash, itching, swollen face or lips, or shortness ... | {'Title': '3. how to take anagrelide mylan', 'Section_Content': 'always take anagrelide mylan exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. the amount of anagrelide that people take can be different, and this depends on your condition. your doctor will prescribe the best... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. if you are worried, speak to your doctor. serious side effects uncommon: heart failure (signs include shortness of breath, chest pain, swelling of the legs due to fluid b... | {'Title': '5. how to store anagrelide mylan', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and bottle label after exp. the expiry date refers to the last day of that month. store in the original package in ord... | {'Title': '6. contents of the pack and other information', 'Section_Content': "what anagrelide mylan contains the active substance is anagrelide. each capsule contains anagrelide hydrochloride monohydrate equivalent to 0.5 mg anagrelide. the other ingredients are lactose, croscarmellose sodium, povidone, microcrystalli... |
1B231D72EFCF1289444C70AA9FE3F436 | https://www.ema.europa.eu/documents/product-information/zoely-epar-product-information_en.pdf | Zoely | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
1. NAM... | {'Title': '1. what zoely is and what it is used for', 'Section_Content': "zoely is a contraceptive pill that is used to prevent pregnancy. all 24 white film-coated tablets are active tablets that contain a small amount of two different female hormones. these are nomegestrol acetate (a progestogen) and estradiol (an oes... | {'Title': '2. what you need to know before you use zoely', 'Section_Content': None, 'Entity_Recognition': [{'Text': 'zoely', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 7, 'BeginOffset': 78, 'EndOffset': 89, 'Score': 0.4390912652015686, 'Text': 'blood clots', 'Category': 'MEDICAL_CONDITION', 'Type... | {'Title': '3. how to use zoely', 'Section_Content': None, 'Entity_Recognition': [{'Text': 'zoely', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'the tablets the zoely blister', 'Type': 'TREATMENT', 'BeginOffset': 21, 'EndOffset': 50}, {'Text': '28', 'Type': 'NUMBER', 'BeginOffset': 60, 'EndOffset... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. if you get any side effect, particularly if severe or persistent, or have any change to your health that you think may be due to zoely, please talk to your doctor. an inc... | {'Title': '5. how to store zoely', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the blister and carton after exp. the expiry date refers to the last day of that month. this medicine does not require any special storage c... | {'Title': '6. contents of the pack and other information', 'Section_Content': "what zoely contains - the active substances are: nomegestrol acetate and estradiol white active film-coated tablets: each tablet contains 2.5 mg nomegestrol acetate and 1.5 mg estradiol (as hemihydrate). yellow placebo film-coated tablets: t... |
C89FAB3627FDCF11CEF85ABB09623E6A | https://www.ema.europa.eu/documents/product-information/eklira-genuair-epar-product-information_en.pdf | Eklira Genuair | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
1. NAME O... | {'Title': '1. what eklira genuair is and what it is used for', 'Section_Content': 'what eklira genuair is the active ingredient of eklira genuair is aclidinium bromide, which belongs to a group of medicines called bronchodilators. bronchodilators relax airways and help keep bronchioles open. eklira genuair is a dry pow... | {'Title': '2. what you need to know before you use eklira genuair', 'Section_Content': 'do not use eklira genuair - if you are allergic to aclidinium bromide or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor, pharmacist or nurse before using eklira genu... | {'Title': '3. how to use eklira genuair', 'Section_Content': 'always use this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the recommended dose is one inhalation twice a day in the morning and evening. the effects of eklira genuair last for 12 hou... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. allergic reactions may rarely occur (may affect up to 1 in 1,000 people). stop using the medicine and contact your doctor immediately if you develop swelling of your face... | {'Title': '5. how to store eklira genuair', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the inhaler label and carton after "exp". the expiry date refers to the last day of that month. keep the inhaler inside the pouch u... | {'Title': '6. contents of the pack and other information instructions for use', 'Section_Content': 'what eklira genuair contains - the active substance is aclidinium bromide. each delivered dose contains 375 micrograms aclidinium bromide equivalent to 322 micrograms of aclidinium. - the other ingredient is lactose mono... |
528B762D4619412DFD587388A74F39C1 | https://www.ema.europa.eu/documents/product-information/refixia-epar-product-information_en.pdf | Refixia | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See sectio... | {'Title': '1. what refixia is and what it is used for', 'Section_Content': 'what refixia is refixia contains the active substance nonacog beta pegol and is a long-acting recombinant coagulation factor ix product. factor ix is a protein naturally found in the blood that helps to stop bleeding. what refixia is used for r... | {'Title': '2. what you need to know before you use refixia', 'Section_Content': 'do not use refixia: if you are allergic to the active substance or any of the other ingredients of this medicine (listed in section 6). if you are allergic to hamster proteins. if you are not sure if either of the above applies to you, tal... | {'Title': '3. how to use refixia', 'Section_Content': 'treatment with refixia will be started by a doctor who is experienced in the care of patients with haemophilia b. always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure about how to use refixia. your doctor will cal... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. allergic reactions are possible with this medicine. if sudden and severe allergic reactions (e.g. anaphylactic reactions) occur, the injection must be stopped immediately... | {'Title': '5. how to store refixia', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use refixia after the expiry date which is stated after "exp" on the carton and on the vial and the pre-filled syringe labels. the expiry date refers to the last day of that month. store in a refri... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what refixia contains 34 the active substance is nonacog beta pegol (pegylated human coagulation factor ix (rdna)). each vial of refixia contains nominally 500 iu, 1000 iu or 2000 iu nonacog beta pegol corresponding to approximately 125 iu/m... |
24F22F9DA3FA2ED775EDC64E4696201A | https://www.ema.europa.eu/documents/product-information/pelmeg-epar-product-information_en.pdf | Pelmeg | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse
reaction... | {'Title': '1. what pelmeg is and what it is used for', 'Section_Content': 'pelmeg contains the active substance pegfilgrastim. pegfilgrastim is a protein produced by biotechnology in bacteria called e. coli. it belongs to a group of proteins called cytokines, and is very similar to a natural protein (granulocyte-colony... | {'Title': '2. what you need to know before you use pelmeg', 'Section_Content': 'do not use pelmeg if you are allergic to pegfilgrastim, filgrastim, e. coli derived proteins, or any of the other ingredients of this medicine. warnings and precautions talk to your doctor, pharmacist or nurse before using pelmeg: if you ex... | {'Title': '3. how to use pelmeg', 'Section_Content': 'pelmeg is for use in adults aged 18 and over. always use pelmeg exactly as your doctor has told you. you should check with your doctor or pharmacist if you are unsure. the usual dose is one 6 mg subcutaneous injection (injection under your skin) using a pre-filled s... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. please tell your doctor immediately if you have any of the following or combination of the following side effects: swelling or puffiness, which may be associated with pas... | {'Title': '5. how to store pelmeg', 'Section_Content': None, 'Entity_Recognition': None} | {'Title': '6. contents of the pack and other information', 'Section_Content': None, 'Entity_Recognition': None} |
399E88688D80CED2B7C61AD85C3A1E0C | https://www.ema.europa.eu/documents/product-information/idflu-epar-product-information_en.pdf | IDflu | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Me
dic
ina
l p
rod
uc
t n
o l
on
ge
r a
uth
ori
se
d
2
1. NAME OF THE MEDICINAL PRODUCT
IDflu 15 microgram/strain suspension for injection
Influenza vaccine (split virion, inactivated)
2. QUALITATI... | {'Title': '1. what idflu is and what it is used for', 'Section_Content': "idflu is a vaccine.this vaccine is recommended to help to protect you against flu. the vaccine may be administered to individuals of 60 years of age and over, especially in those who run an increased risk of associated complications. when an inje... | {'Title': '2. what you need to know before you use idflu', 'Section_Content': 'do not use idflu: - if you are allergic to: the active substances, any of the other ingredients of this vaccine (listed in section 6), any component that may be present in very small amounts such as eggs (ovalbumin, chicken proteins), neomyc... | {'Title': '3. how to use idflu', 'Section_Content': 'always use this vaccine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the recommended dose is 0.1 ml for individuals 60 years of age and over. idflu is administered to you by your doctor or nurse. idflu i... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this vaccine can cause side effects, although not everybody gets them. you should see your doctor immediately if you experience symptoms of angioedema, such as: swollen face, tongue or pharynx difficulty to swallow hives and difficulties to b... | {'Title': '5. how to store idflu', 'Section_Content': None, 'Entity_Recognition': None} | {'Title': '6. contents of the pack and other information', 'Section_Content': "what idflu contains the active substances are influenza virus (inactivated split) of the following strains*: a/california/7/2009 (h1n1)pdm09 - like strain (a/california/7/2009, nymc x-179a) ...................................................... |
E6A99A8422B8B26B49739D643ED1FAA0 | https://www.ema.europa.eu/documents/product-information/revolade-epar-product-information_en.pdf | Revolade | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Revolade 12.5 mg film-coated tablets
Revolade 25 mg film-coated tablets
Revolade 50 mg film-coated tablets
Revolade 75 mg film-coated tablets
... | {'Title': '1. what revolade is and what it is used for', 'Section_Content': 'revolade contains eltrombopag, which belongs to a group of medicines called thrombopoietin receptor agonists. it is used to help increase the number of platelets in your blood. platelets are blood cells that help to reduce or prevent bleeding.... | {'Title': '2. what you need to know before you take revolade', 'Section_Content': "do not take revolade if you are allergic to eltrombopag or any of the other ingredients of this medicine (listed in section 6 under 'what revolade contains'). check with your doctor if you think this applies to you. warnings and precauti... | {'Title': '3. how to take revolade', 'Section_Content': "always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. do not change the dose or schedule for taking revolade unless your doctor or pharmacist advises you to. while you are taking revolade, you wil... | {'Title': '4. possible side effects', 'Section_Content': None, 'Entity_Recognition': [{'Text': 'revolade', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndO... | {'Title': '5. how to store revolade', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and the blister. this medicine does not require any special storage conditions. do not throw away any medicines via wastewater... | {'Title': '6. contents of the pack and other information', 'Section_Content': "what revolade contains the active substance in revolade is eltrombopag. 12.5 mg film-coated tablets each film-coated tablet contains eltrombopag olamine equivalent to 12.5 mg eltrombopag. 25 mg film-coated tablets each film-coated tablet con... |
D88405464CAD9C406AE56D99F2ACED75 | https://www.ema.europa.eu/documents/product-information/kovaltry-epar-product-information_en.pdf | Kovaltry | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Kovaltry 250 IU powder and solvent for solution for injection
Kovaltry 500 IU powder and solvent for solution for injection
Kovaltry 1000 IU powder and solvent for solution... | {'Title': '1. what kovaltry is and what it is used for', 'Section_Content': 'kovaltry contains the active substance human recombinant coagulation factor viii, also called octocog alfa. kovaltry is prepared by recombinant technology without addition of any human- or animal derived components in the manufacturing process... | {'Title': '2. what you need to know before you use kovaltry', 'Section_Content': "do not use kovaltry if you are allergic to octocog alfa or to any of the other ingredients of this medicine (listed in section 6). allergic to mouse or hamster proteins. warnings and precautions talk to your doctor or pharmacist if you ha... | {'Title': '3. how to use kovaltry', 'Section_Content': 'treatment with kovaltry will be started by a doctor who is experienced in the care of patients with haemophilia a. always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure. the number of factor viii units is expresse... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the most serious side effects are allergic reactions which may be severe allergic reaction. stop injecting kovaltry immediately and speak to your doctor at once if such r... | {'Title': '5. how to store kovaltry', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on labels and cartons. the expiry date refers to the last day of that month. store in a refrigerator (2 8 ). do not freeze. store this medic... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what kovaltry contains the active substance is octocog alfa (human coagulation factor viii). each vial of kovaltry contains nominally 250, 500, 1000, 2000 or 3000 iu octocog alfa. the other ingredients are sucrose, histidine, glycine (e 640)... |
4845D3160FDE0A0270C5AFDDFC80E5BE | https://www.ema.europa.eu/documents/product-information/ammonaps-epar-product-information_en.pdf | Ammonaps | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
AMMONAPS 500 mg tablets.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 500 mg sodium phenylbutyrate.
Each AMMONAPS tablet contains 62 mg of sodium. ... | {'Title': '1. what ammonaps is and what it is used for', 'Section_Content': 'ammonaps is prescribed to patients with urea cycle disorders. patients with these rare disorders have a deficiency of certain liver enzymes and are therefore unable to eliminate nitrogen waste. nitrogen is a building block of proteins, because... | {'Title': '2. what you need to know before you take ammonaps', 'Section_Content': 'do not take ammonaps - if you are pregnant. - if you are breast-feeding. - if you are allergic to sodium phenylbutyrate or any of the other ingredients of this medicine (listed in section 6). warnings and precautions talk to your doctor ... | {'Title': '3. how to take ammonaps', 'Section_Content': 'always take this medicine exactly as your doctor has told you. check with your doctor or pharmacist if you are not sure. dosage the daily dose of ammonaps will be calculated from your protein tolerance, diet and body weight or body surface. you will need regular ... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the frequency of possible side effects is listed below. very common: affects more than 1 user in 10 common: affects 1 to 10 users in 100 uncommon: affects 1 to 10 users i... | {'Title': '5. how to store ammonaps', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the carton and the bottle label after "exp". the expiry date refers to the last day of that month. do not store above 30. do not throw aw... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what ammonaps contains - the active substance is sodium phenylbutyrate. each tablet of ammonaps contains 500 mg of sodium phenylbutyrate. - the other ingredients are microcrystalline cellulose, magnesium stearate and colloidal anhydrous sili... |
04034542AB28557EFC1CC133B66770F7 | https://www.ema.europa.eu/documents/product-information/apealea-epar-product-information_en.pdf | Apealea | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Apealea 60 mg powder for solution for infusion.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial of powder contains 60 mg of paclitaxel.
After reconstitution, each... | {'Title': '1. what apealea is and what it is used for', 'Section_Content': "apealea is a cancer medicine containing the active substance paclitaxel, which belongs to a group of medicines called taxanes. paclitaxel affects or stops growth of rapidly dividing cells, such as tumour cells. apealea is used to treat the foll... | {'Title': '2. what you need to know before you are given apealea', 'Section_Content': 'do not use apealea if you: are allergic to paclitaxel or any of the other ingredients of this medicine (listed in section 6) are breast-feeding have a count of white blood cells called neutrophils below 1.5 × 109/l before start of th... | {'Title': '3. how apealea is given', 'Section_Content': 'apealea is given to you by a doctor or nurse by a slow drip (infusion) into a vein. this will take about one hour. the dose is based on your body surface area (worked out from your height and weight) and blood test results. the usual dose is 250 mg/m2 body surfac... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. tell your doctor or nurse immediately if you have any of the following: very common (may affect more than 1 in 10 people): − nerve disorder in arms and legs which causes ... | {'Title': '5. how to store apealea', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the vial label and carton after exp. the expiry date refers to the last day of that month. unopened vials: store in a refrigerator (2 8 ).... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what apealea contains the active substance is paclitaxel. one vial contains 60 mg of paclitaxel. after preparation, each millilitre of solution contains 1 mg of paclitaxel (micellar). the other ingredients are: − n-(all-trans-retinoyl)-l-cys... |
5CB1F30065ADFE84951D65E10F9A2CCF | https://www.ema.europa.eu/documents/product-information/pylobactell-epar-product-information_en.pdf | Pylobactell | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Pylobactell, 100 mg, Soluble Tablet
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Active substance Quantity per tablet
13C-urea 100 m... | {'Title': '1. what pylobactell is and what it is used for', 'Section_Content': 'pylobactell is a breath test for determining the presence of the bacterium, helicobacter pylori (h. pylori) in the gut (stomach and adjacent bowel) which may be the reason for your stomach (gastric) condition. your doctor has recommended th... | {'Title': '2. what you need to know before you use pylobactell', 'Section_Content': 'do not use pylobactell if you: - are allergic to 13c-urea or to any of the other ingredients of this medicine (listed in section 6). - suffer from any medical condition that you think may affect, or be affected by, the test. warnings a... | {'Title': '3. how to use pylobactell', 'Section_Content': "always use this medicine exactly as your doctor, pharmacist or nurse has told you. check with your doctor, pharmacist or nurse if you are not sure. the test will take about 45 minutes. a supply of drinking water will be needed. it is recommended that the breath... | {'Title': '4. possible side effects', 'Section_Content': 'no side effects to pylobactell have been reported. 13c and urea are harmless naturally occurring substances which are found in your body. reporting of side effects if you get any side effects, talk to your doctor, pharmacist or nurse. this includes any possible ... | {'Title': '5. how to store pylobactell', 'Section_Content': 'keep out of the sight and reach of children. do not store the kit above 25. the tablet must be taken when dissolved. do not use pylobactell after the expiry date which is stated on the carton after exp. the expiry date refers to the last day of that month.', ... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what the pylobactell tablet contains - the active substance is 13c-urea. each tablet contains 100 mg of 13c-urea - the other ingredients are povidone (e1201), microcrystalline cellulose (e460i), colloidal anhydrous silica and sodium benzoate... |
A1DFAB9F4613067C3DFA5916453A4CC7 | https://www.ema.europa.eu/documents/product-information/novoeight-epar-product-information_en.pdf | NovoEight | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
NovoEight 250 IU powder and solvent for solution for injection
NovoEight 500 IU powder and solvent for solution for injection
NovoEight 1000 IU powder and solvent for solution ... | {'Title': '1. what novoeight is and what it is used for', 'Section_Content': "novoeight contains the active substance turoctocog alfa, human coagulation factor viii. factor viii is a protein naturally found in the blood that helps it to clot. novoeight is used to treat and prevent bleeding episodes in patients with hae... | {'Title': '2. what you need to know before you use novoeight', 'Section_Content': 'do not use novoeight: if you are allergic to the active substance or to any of the other ingredients of this medicine (listed in section 6) if you are allergic to hamster proteins. do not use novoeight if either of the above applies to y... | {'Title': '3. how to use novoeight', 'Section_Content': "treatment with novoeight will be started by a doctor who is experienced in the care of patients with haemophilia a. always use this medicine exactly as your doctor has told you. check with your doctor if you are not sure. your doctor will calculate your dose for ... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. the following side effects may occur with this medicine. if severe, sudden allergic reactions (anaphylactic reactions) occur (very rare), the injection must be stopped im... | {'Title': '5. how to store novoeight', 'Section_Content': "keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date, which is stated after 'exp' on the carton and on the vial and the pre-filled syringe labels. the expiry date refers to the last day of that month. store i... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what novoeight contains the active substance is turoctocog alfa (human coagulation factor viii (rdna)). each vial of novoeight contains nominally 250, 500, 1000, 1500, 2000 or 3000 iu turoctocog alfa. the other ingredients are l-histidine, s... |
A1B5CA77B539E285D47E3A64125A95D2 | https://www.ema.europa.eu/documents/product-information/lartruvo-epar-product-information_en.pdf | Lartruvo | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Me
dic
ina
l p
rod
uc
t n
o l
on
ge
r a
uth
ori
se
d
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professional... | {'Title': '1. what lartruvo is and what it is used for', 'Section_Content': 'lartruvo contains the active substance olaratumab, which belongs to a group of medicines called monoclonal antibodies. olaratumab recognises and attaches specifically to a protein known as platelet-derived growth factor receptor-α (pdgfr-α). p... | {'Title': '2. what you need to know before you are given lartruvo', 'Section_Content': 'you must not be given lartruvo - if you are allergic to olaratumab or any of the other ingredients of this medicine (listed in section 6). warnings and precautions you should tell your doctor about any of the following: - if you are... | {'Title': '3. how you are given lartruvo', 'Section_Content': "a doctor experienced in the use of anti-cancer medicines will supervise your lartruvo therapy. premedication you will be given medicines to reduce the risk of an infusion-related reaction before you receive lartruvo. dose and administration the recommended ... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. your doctor will discuss these with you and will explain the risks and benefits of your treatment. the following side effects have been reported: infusion reactions lartr... | {'Title': '5. how to store lartruvo', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the outer carton and vial label after exp. the expiry date refers to the last day of that month. store in a refrigerator (2 8 ). do not f... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what lartruvo contains - the active substance is olaratumab. each millilitre of the concentrate for solution for infusion contains 10 mg of olaratumab. each 19 ml vial contains 190 mg of olaratumab. each 50 ml vial contains 500 mg of olaratu... |
84076FDAE8517FC06F70D93160D601E0 | https://www.ema.europa.eu/documents/product-information/solymbic-epar-product-information_en.pdf | Solymbic | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Me
dic
ina
l p
rod
uc
t n
o l
on
ge
r a
uth
ori
se
d
2
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information... | {'Title': '1. what solymbic is and what it is used for', 'Section_Content': None, 'Entity_Recognition': [{'Text': 'solymbic', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'solymbic', 'Type': 'TREATMENT', 'BeginOffset': 0, 'EndOffset': 8}, {'Text': 'the active substance adalimumab', 'Type': 'TREAT... | {'Title': '2. what you need to know before you use solymbic', 'Section_Content': 'do not use solymbic: - if you are allergic to adalimumab or any of the other ingredients of this medicine (listed in section 6). - if you have a severe infection, including active tuberculosis (see "warnings and precautions"). it is impor... | {'Title': '3. how to use solymbic', 'Section_Content': "always use this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. adults with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or axial spondyloarthritis without radiographic evid... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. most side effects are mild to moderate. however, some may be serious and require treatment. side effects may occur at least up to 4 months after the last solymbic injecti... | {'Title': '5. how to store solymbic', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the label and carton after exp. the expiry date refers to the last day of that month. store in a refrigerator (2c 8c). do not freeze. sto... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what solymbic contains - the active substance is adalimumab. each pre-filled syringe contains 20 mg of adalimumab in 0.4 ml of solution or 40 mg of adalimumab in 0.8 ml of solution. - the other ingredients are glacial acetic acid, sucrose, p... |
CD78CA4FC3E4B0ECA814EEE4FA81E8D3 | https://www.ema.europa.eu/documents/product-information/clopidogrel-teva-pharma-epar-product-information_en.pdf | Clopidogrel Teva Pharma | ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1
Me
dic
ina
l p
ro
du
ct
no
lo
ng
er
au
th
or
ise
d
1. NAME OF THE MEDICINAL PRODUCT
Clopidogrel Teva Pharma 75 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 75 mg of clopidogrel (as hydro... | {'Title': '1. what clopidogrel teva pharma is and what it is used for', 'Section_Content': "clopidogrel teva pharma contains clopidogrel and belongs to a group of medicines called antiplatelet medicinal products. platelets are very small structures in the blood, which clump together during blood clotting. by preventing... | {'Title': '2. what you need to know before you take clopidogrel teva pharma', 'Section_Content': "do not take clopidogrel teva pharma if you are allergic to clopidogrel or any of the other ingredients of this medicine (listed in section 6). if you have a medical condition that is currently causing bleeding such as a st... | {'Title': '3. how to take clopidogrel teva pharma', 'Section_Content': "always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the recommended dose, including for patients with a condition called 'atrial fibrillation' (an irregular heartbea... | {'Title': '4. possible side effects', 'Section_Content': "like all medicines, this medicine can cause side effects, although not everybody gets them. contact your doctor immediately if you experience: - fever, signs of infection or extreme tiredness. these may be due to rare decrease of some blood cells. - signs of liv... | {'Title': '5. how to store clopidogrel teva pharma', 'Section_Content': None, 'Entity_Recognition': None} | {'Title': '6. contents of the pack and other information', 'Section_Content': "what clopidogrel teva pharma contains the active substance is clopidogrel. each film-coated tablet contains 75 mg of clopidogrel (as hydrochloride). the other ingredients are (see section 2 'clopidogrel teva pharma contains hydrogenated cast... |
C9E8D7498E39356E239560CC21BAE76F | https://www.ema.europa.eu/documents/product-information/potactasol-epar-product-information_en.pdf | Potactasol | 1
ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
2
1. NAME OF THE MEDICINAL PRODUCT
Potactasol 1 mg powder for concentrate for solution for infusion
Potactasol 4 mg powder for concentrate for solution for infusion
2. QUALITATIVE AND QUANTITATIV... | {'Title': '1. what potactasol is and what it is used for', 'Section_Content': 'potactasol contains the active substance topotecan which helps to kill tumour cells. potactasol is used to treat: - ovarian cancer or small cell lung cancer that has come back after chemotherapy - advanced cervical cancer if surgery or radio... | {'Title': '2. what you need to know before you use potactasol', 'Section_Content': 'do not use potactasol - if you are allergic to topotecan or any of the other ingredients of this medicine (listed in section 6); - if you are breast-feeding.; - if your blood cell counts are too low. your doctor will tell you whether th... | {'Title': '3. how to use potactasol', 'Section_Content': 'your dose of potactasol will depend on: - the disease being treated, - your body surface area (m2), - the results of blood tests carried out before and during treatment, - how well you tolerate treatment. adults ovarian cancer and small cell lung cancer the usua... | {'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them. serious side effects you must tell your doctor immediately if you experience any of the following serious side effects. they may require hospitalisation and could even be... | {'Title': '5. how to store potactasol', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the vial and carton after exp. the expiry date refers to the last day of that month. keep the vial in the outer carton in order to prot... | {'Title': '6. contents of the pack and other information', 'Section_Content': 'what potactasol contains - the active substance is topotecan. each vial contains 1 mg or 4 mg topotecan (as hydrochloride). after reconstitution 1 ml concentrate contains 1 mg topotecan. - the other ingredients are: mannitol (e421), tartaric... |
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