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Varuby, INN-Rolapitant 23 February 2017 EMA/239011/2017 Committee for Medicinal Products for Human Use (CHMP) Assessment report Varuby authorised International non-proprietary name: rolapitant Procedure No. EMEA/H/C/004196/0000 longer no Note Assessment report as adopted by the CHMP with all 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 5520 Send a question via our website www.ema.europa.eu/contact An agency of the European Union 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 ................................................................................ 9 2.1. Problem statement ............................................................................................... 9 2.1.1. Disease or condition .......................................................................................... 9 2.1.2. Epidemiology and risk factors ............................................................................. 9 2.1.3. Biologic features, aetiology and pathogenesis ..................................................... 10 2.1.4. Clinical presentation, diagnosis. ........................................................................ 10 2.1.5. Management ................................................................................................... 11 2.2. Quality aspects .................................................................................................. 13 2.2.1. Introduction....................................................................................................authorised 13 2.2.2. Active Substance ............................................................................................. 13 2.2.3. Finished Medicinal Product ................................................................................ 15 2.2.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 17 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 17 2.2.6. Recommendations for future quality developmentlonger ............................................... 18 2.3. Non-clinical aspects ............................................................................................ 18 2.3.1. Introduction....................................................................................................no 18 2.3.2. Pharmacology ................................................................................................. 18 2.3.3. Pharmacokinetics ............................................................................................ 22 2.3.4. Toxicology ...................................................................................................... 26 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 41 2.3.6. Discussion on non-clinical aspects ..................................................................... 42 2.3.7. Conclusion on the non-clinical aspects ............................................................... 44 2.4. Clinical aspects ..................................................................................................product 44 2.4.1. Introduction.................................................................................................... 44 2.4.2. Pharmacokinetics ............................................................................................ 45 2.4.3. Pharmacodynamics .......................................................................................... 51 2.4.4. Discussion on clinical pharmacology ................................................................... 52 2.4.5. Conclusions on clinical pharmacology ................................................................. 56 2.5. Clinical efficacy .................................................................................................. 56 2.5.1. DoseMedicinal response study(ies) ................................................................................. 56 2.5.2. Main studies ................................................................................................... 61 2.5.3. Discussion on clinical efficacy ............................................................................ 95 2.5.4. Conclusions on the clinical efficacy .................................................................... 99 2.6. Clinical safety .................................................................................................... 99 2.6.1. Discussion on clinical safety ............................................................................ 112 2.6.2. Conclusions on the clinical safety .................................................................... 114 Assessment report EMA/239011/2017 Page 2/126 2.7. Risk Management Plan ...................................................................................... 114 Summary of safety concerns ................................................................................ 114 2.8. Pharmacovigilance ........................................................................................... 119 2.9. New Active Substance ...................................................................................... 119 2.10. Product information ........................................................................................ 119 2.10.1. User consultation ......................................................................................... 119 2.10.2. Additional monitoring ................................................................................... 119 3. Benefit-Risk Balance ........................................................................... 119 3.1. Therapeutic Context ......................................................................................... 119 3.1.1. Disease or condition ...................................................................................... 119 3.1.2. Available therapies and unmet medical need ..................................................... 120 3.1.3. Main clinical studies ....................................................................................... 120 3.2. Favourable effects ............................................................................................ 121 3.3. Uncertainties and limitations about favourable effects ........................................... 121 3.4. Unfavourable effects ......................................................................................... 122 3.5. Uncertainties and limitations about unfavourable effects .......................................authorised 122 3.6. Effects Table .................................................................................................... 123 3.7. Benefit-risk assessment and discussion ............................................................... 124 3.7.1. Importance of favourable and unfavourable effects ............................................ 124 3.7.2. Balance of benefits and risks .......................................................................... 125 3.7.3. Additional considerations on the benefit-risk balancelonger ......................................... 125 3.8. Conclusions ..................................................................................................... 125 4. Recommendations ...............................................................................no 126 product Medicinal Assessment report EMA/239011/2017 Page 3/126 List of abbreviations 5-HT Serotonin ADME Absorption, distribution, metabolism, excretion AE Adverse event ALP Alkaline phosphatase ALT Alanine aminotransferase ANC Absolute neutrophil count ANCOVA Analysis of covariance AST Aspartate aminotransferase AUC Area under the concentration x time curve BA Bioavailability BCRP Breast cancer resistance protein BCS Biopharmaceutics Classification System BE Bioequivalence CEC Concomitant emetogenic chemotherapy authorised CHMP Committee for Medicinal Products for Human use CI Confidence interval CIC Chronic idiopathic cough ? CINV Chemotherapy-induced nausea and vomiting Cmax Maximum concentration CMH Cochran-Mantel-Haenszel longer CPP Critical process parameter CR Complete response no CSR Clinical study report CTCAE Common Terminology Criteria for Adverse Events CYP Cytochrome P450 DDI Drug-drug interaction DSC Differential Scanning Calorimetry EC European Commission ECG Electrocardiogramproduct EU European Union FLIE Functional Living Index-Emesis FT-IR Fourrier Transform Infrared Spectroscopy GC Gas Chromatography GCP Good Clinical Practice GMP Good Manufacturing Practice HEC Highly emetogenic chemotherapy HPLC MedicinalHigh performance liquid chromatography HRMS High resolution mass spectrometry ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IPC In-process control IR Infrared IV Intravenous Assessment report EMA/239011/2017 Page 4/126 Kb Equilibrium dissociation constant KF Karl Fischer titration Ki Inhibition constant LDPE Low density polyethylene LOD Loss on drying MEC Moderately emetogenic chemotherapy MedDRA Medical Dictionary
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