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Medicinal Product No Longer Authorised Assessment report INCIVO telaprevir Procedure No.: EMEA/H/C/002313/ Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Medicinal product no longer authorised 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8613 E-mail [email protected] Website www.ema.europaeu An agency of the European Union © European Medicines Agency, 2011. Reproduction is authorised provided the source is acknowledged. 21 July 2011 EMA/CHMP/475470/2011 Committee for Medicinal Products for Human Use (CHMP) CHMP assessment report INCIVO International non-proprietary name: telaprevir authorised Procedure No. EMEA/H/C/002313 longer no product Medicinal 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8613 E-mail [email protected] Website www.ema.europaeu An agency of the European Union CHMP assessment report Page 2/109 Product information Name of the medicinal product: INCIVO Applicant: Janssen-Cilag International N.V. Turnhoutseweg 30 BE-2340 Beerse Belgium Active substance: telaprevir International Nonproprietary Name/Common Name: telaprevir Pharmaco-therapeutic group Protease inhibitors authorised (ATC Code): (J05AE) INCIVO, in combination with peginterferon alfa and ribavirin, is indicated for the treatment of genotype Therapeutic indication(s): 1 chronic hepatitis C in adult patients with compensated liver disease (including cirrhosis): - who are treatment-naïve; - who have previously been treated with interferonlonger alfa (pegylated or non-pegylated) alone or in combination with ribavirin, including relapsers, partial responders and null responders (see sections 4.4 and 5.1). no Pharmaceutical form: Film-coated tablet Strength: 375 mg Route of administration: productOral use Packaging: bottle (HDPE) Package size: 168 (4 x 42) tablets Medicinal CHMP assessment report Page 3/109 Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier.................................................................................... 7 1.2. Manufacturers Manufacturer(s) responsible for batch release................................... 8 1.3. Steps taken for the assessment of the product ....................................................... 8 2. Scientific discussion ................................................................................ 9 2.1. Introduction ...................................................................................................... 9 2.2. Quality aspects ................................................................................................ 10 2.2.1. Introduction ................................................................................................. 10 2.2.2. Active substance ........................................................................................... 10 2.2.3. Finished medicinal product.............................................................................. 12 2.2.4. Discussion on chemical, pharmaceutical and biological aspects............................. 15 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ..................... 15 2.2.6. Recommendations for future quality development ..............................................authorised 15 2.3. Non-clinical aspects .......................................................................................... 16 2.3.1. Introduction ................................................................................................. 16 2.3.2. Pharmacology ............................................................................................... 16 2.3.3. Pharmacokinetics .......................................................................................... 18 2.3.4. Ecotoxicity/environmental risk assessment........................................................ 23 2.3.5. Discussion on non-clinical aspects....................................................................longer 25 2.3.6. Conclusion on the non-clinical aspects .............................................................. 26 2.4. Clinical aspects ................................................................................................ 26 2.4.1. Introduction .................................................................................................no 26 2.4.2. Pharmacodynamics........................................................................................ 34 2.4.3. Discussion on clinical pharmacology ................................................................. 34 2.4.4. Conclusions on clinical pharmacology ............................................................... 36 2.5. Clinical efficacy ................................................................................................ 36 2.5.1. Dose response studies ................................................................................... 42 2.5.2. Main studies ................................................................................................. 48 2.5.3. Discussion on clinicalproduct safety ............................................................................ 97 2.6. Pharmacovigilance............................................................................................ 99 3. Benefit-Risk Balance............................................................................ 104 4. Recommendations ............................................................................... 107 Medicinal CHMP assessment report Page 4/109 List of abbreviations AAG alpha 1-acid glycoprotein ADME absorption, distribution, metabolism, and excretion ADR adverse drug reaction AE adverse event ALT alanine aminotransferase AST aspartate aminotransferase AUC area under the plasma concentration-time curve BCS Biopharmaceutics Classification System BMI body mass index CHC chronic hepatitis C CI confidence interval CPA Child-Pugh A CPB Child-Pugh B CPC Child-Pugh C CrCl creatinine clearance CSR clinical study report CTP clinical trial protocol CYP cytochrome P450 DBP diastolic blood pressure authorised DDI drug-drug interaction ECG electrocardiogram DEP dermatology expert panel EPO erythropoietin eRVR extended rapid virologic response ESA erythropoiesis-stimulating agent ESI event of special interest EVR early virologic response longer FA full analysis FTC emtricitabine FU follow-up GGT gamma-glutamyl transferase no HAART highly-active antiretroviral therapy HCV hepatitis C virus HDL high-density lipoprotein HIV human immunodeficiency virus HSA human serum albumin IFN interferon LC-MS/MS liquid chromatography with tandem mass spectrometry LDH lactate dehydrogenase LDL l ow-density lipoprotein LLOQ lower limit of quantification MedDRA Medical Dictionaryproduct for Regulatory Activities NA not applicable NIH National Institutes of Health Pbo placebo Pbo/PR placebo, peginterferon alfa, and ribavirin Peg-IFN pegylated interferon Peg-IFN-alfa-2a peginterferon alfa-2a (Pegasys) Peg-IFN-alfa-2b peginterferon alfa-2b (PegIntron) P-gp P-glycoprotein PR pegylated interferon alfa and ribavirin PT prothrombin time PTT partial thromboplastin time Medicinalq8h every 8 hours q12h every 12 hours QTc QT interval corrected for heart rate QTcF QT interval corrected for heart rate according to Fridericia RBC r ed blood cell RBV ribavirin RVR rapid virologic response SAE serious adverse event CHMP assessment report Page 5/109 SAP statistical analysis plan SCS summary of clinical safety SD standard deviation SSC special search category SVR sustained virologic response TDF tenofovir disoproxil fumarate t.i.d. tris in die, three times per day TPGS d-alpha-tocopheryl polyethylene glycol-1000 succinate T/PR telaprevir, peginterferon alfa, and ribavirin V/F volume of distribution WBC white blood cell WT wild-type Definitions of Terms EVR (early virologic response) ≥2-log10 decrease in HCV RNA at Week 12 of treatment compared to baseline HCV RNA level RVR (rapid virologic response) Undetectable HCV RNA at Week 4 of treatment eRVR (extended RVR) Undetectable HCV RNA at Weeks 4 andauthorised 12 of treatment Prior treatment failure Subjects who previously received Peg-IFN/RBV, but who did not achieve SVR Prior relapser Subject who had undetectable HCV RNA at the end of prior treatment followed by detectable HCV RNA Prior nonresponders: Subjects who neverlonger had undetectable HCV RNA during prior treatment. This includes prior partial responders and prior null responders - Prior partial responder - Subject whono had ≥2-log10 decrease in HCV RNA at Week 12 of prior treatment compared to baseline HCV RNA level, but who never achieved undetectable HCV RNA levels during prior treatment - Prior null responder - Subject who had <2-log10 decrease in HCV RNA at Week 12 of prior treatment compared to baseline HCV RNA level during prior treatment and never achieved undetectable HCV RNA levels during prior treatment Relapse productUndetectable HCV RNA at the end of treatment followed by detectable HCV RNA during follow-up SVR (sustained virologic response) Undetectable HCV RNA 24 weeks after the last planned dose of treatment Viral breakthrough (Phase 3 studies) Undetectable HCV RNA followed by >100 IU/mL HCV RNA during treatment, or, for subjects who did not have undetectable HCV RNA, >1-log10 increase in HCV RNA over nadir during treatment On-treatment virologic failure: Discontinued due to meeting a virologic
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