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Alpivab, INN-Peramivir 22 February 2018 EMA/CHMP/148367/2018 Committee for Medicinal Products for Human Use (CHMP) Assessment report Alpivab International non-proprietary name: peramivir Procedure No. EMEA/H/C/004299/0000 authorised Note longer Assessment report as adopted by the CHMP with allno information of a commercially confidential nature deleted. Product Medicinal 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2018. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 6 1.1. Submission of the dossier ...................................................................................... 6 1.2. Steps taken for the assessment of the product ......................................................... 7 2. Scientific discussion ................................................................................ 8 2.1. Problem statement ............................................................................................... 8 2.1.1. Disease or condition ........................................................................................... 8 2.1.2. Epidemiology and risk factors, screening tools/prevention ...................................... 8 2.1.3. Aetiology and pathogenesis ................................................................................ 9 2.1.4. Clinical presentation, diagnosis and stage/prognosis .............................................. 9 2.1.5. Management ..................................................................................................... 9 2.2. Quality aspects .................................................................................................. 10 2.2.1. Introduction .................................................................................................... 10 2.2.2. Active Substance ............................................................................................. 10 2.2.3. Finished Medicinal Product ................................................................................ 14 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 17 2.2.5. Conclusions on the chemical, pharmaceutical and biologicalauthorised aspects ...................... 18 2.2.6. Recommendations for future quality development................................................ 18 2.3. Non-clinical aspects ............................................................................................ 18 2.3.1. Introduction ....................................................................................................longer 18 2.3.2. Pharmacology ................................................................................................. 19 2.3.3. Pharmacokinetics.............................................................................................no 21 2.3.4. Toxicology ...................................................................................................... 22 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 24 2.3.6. Discussion on non-clinical aspects...................................................................... 25 2.3.7. Conclusion on the non-clinicalProduct aspects ................................................................ 26 2.4. Clinical aspects .................................................................................................. 26 2.4.1. Introduction .................................................................................................... 26 2.4.2. Pharmacokinetics............................................................................................. 29 2.4.3. PharmacodynamicsMedicinal .......................................................................................... 42 2.4.4. Discussion on clinical pharmacology ................................................................... 47 2.4.5. Conclusions on clinical pharmacology ................................................................. 50 2.5. Clinical efficacy .................................................................................................. 50 2.5.1. Dose response studies - Main study ................................................................... 51 2.5.2. Discussion on clinical efficacy ............................................................................ 79 2.5.3. Conclusions on the clinical efficacy ..................................................................... 82 2.6. Clinical safety .................................................................................................... 83 2.6.1. Discussion on clinical safety .............................................................................. 98 2.6.2. Conclusions on the clinical safety ....................................................................... 99 2.7. Risk Management Plan ........................................................................................ 99 2.8. Pharmacovigilance ............................................................................................ 101 2.9. New Active Substance ....................................................................................... 101 Assessment report EMA/CHMP/148367/2018 Page 2/108 2.10. Product information ........................................................................................ 101 2.10.1. User consultation ......................................................................................... 101 2.10.2. Additional monitoring ................................................................................... 102 3. Benefit-Risk Balance............................................................................ 102 3.1. Therapeutic Context ......................................................................................... 102 3.1.1. Disease or condition ....................................................................................... 102 3.1.2. Available therapies and unmet medical need ..................................................... 102 3.1.3. Main clinical studies ....................................................................................... 103 3.2. Favourable effects ............................................................................................ 103 3.3. Uncertainties and limitations about favourable effects ........................................... 103 3.4. Unfavourable effects ......................................................................................... 104 3.5. Uncertainties and limitations about unfavourable effects ....................................... 105 3.6. Effects Table .................................................................................................... 105 3.7. Benefit-risk assessment and discussion ............................................................... 106 3.7.1. Importance of favourable and unfavourable effects ............................................ 106 3.7.2. Balance of benefits and risks ........................................................................... 107 3.7.3. Additional considerations on the benefit-risk balance ......................................... 107 3.8. Conclusions ..................................................................................................... 107 4. Recommendations ...............................................................................authorised 107 longer no Product Medicinal Assessment report EMA/CHMP/148367/2018 Page 3/108 List of abbreviations AS Active substance CHMP Committee for Medicinal Products for Human use CFU Colony Forming Units GC Gas Chromatography HDPE High Density Polyethylene HPLC High performance liquid chromatography ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IPC In-process control ICP AES Inductively coupled plasma atomic emission spectroscopy IR Infrared KF Karl Fischer titration mil thousandth of an inch NLT Not less than NMR Nuclear Magnetic Resonance NMT Not more than Ph. Eur. European Pharmacopoeia PIL Patient Information Leaflet RRT Relative retentionauthorised time SEM Scanning Electron Microscopy SM Starting material SmPC Summary of Product Characteristics TGA Thermo-Gravimetric Analysis WFI Waterlonger for injection XR(P)D X Rayno (Powder) Diffraction ADR Adverse drug reaction AE Adverse event ALT Alanine aminotransferase AP Product Alkaline phosphatase ARDS Acute respiratory distress syndrome AST Aspartate aminotransferase AUC Area under the time concentration curve BID Twice daily BMI Body mass index CDC Medicinal Centers for Disease Control and Prevention CFB Change from baseline CI Confidence interval CL Clearance CLcr Creatinine clearance Cmax Maximum concentration CSR Clinical study report CK / CPK Creatine phosphokinase COPD Chronic obstructive pulmonary disease CYP Cytochrome ECDC European Centre for Disease Prevention and Control Emax Maximum effect ET50 Time above IC50 that resulted in 50% of maximum possible effect Assessment report EMA/CHMP/148367/2018 Page 4/108 GCP Good Clinical Practice GI Gastrointestinal h Hour(s) HA Haemagglutinin IL Interleukin IM Intramuscular ISE Integrated summary of efficacy ISS Integrated summary of safety ITTI Intent-to-Treat-Infected
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