18 May 2017 EMA/CHMP/353055/2017 Committee for Medicinal Products for Human Use (CHMP) Assessment report Reagila International non-proprietary name: cariprazine Procedure No. EMEA/H/C/002770/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 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, 2017. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure ......................................................................... 8 1.1. Submission of the dossier .................................................................................................... 8 1.2. Steps taken for the assessment of the product ....................................................................... 8 2. Scientific discussion ......................................................................................................... 10 2.1. Problem statement ........................................................................................................... 10 2.1.1. Disease or condition ....................................................................................................... 10 2.1.2. Epidemiology ................................................................................................................ 10 2.1.3. Biologic features ............................................................................................................ 10 2.1.4. Clinical presentation ....................................................................................................... 10 2.1.5. Management ................................................................................................................. 10 2.2. About the product ............................................................................................................ 11 2.3. Quality aspects ................................................................................................................ 11 2.3.1. Introduction .................................................................................................................. 11 2.3.2. Active Substance ........................................................................................................... 11 2.3.3. Finished Medicinal Product .............................................................................................. 13 2.3.4. Discussion on chemical, pharmaceutical and biological aspects ............................................ 15 2.3.5. Conclusions on the chemical, pharmaceutical and biological aspects ..................................... 15 2.3.6. Recommendation(s) for future quality development ........................................................... 15 2.4. Non-clinical aspects .......................................................................................................... 15 2.4.1. Introduction .................................................................................................................. 15 2.4.2. Pharmacology ............................................................................................................... 16 2.4.3. Pharmacokinetics ........................................................................................................... 18 2.4.4. Toxicology .................................................................................................................... 20 2.4.5. Ecotoxicity/environmental risk assessment ....................................................................... 26 2.4.6. Discussion on non-clinical aspects .................................................................................... 27 2.4.7. Conclusion on the non-clinical aspects .............................................................................. 31 2.5. Clinical aspects ................................................................................................................ 31 2.5.1. Introduction .................................................................................................................. 31 2.5.2. Pharmacokinetics ........................................................................................................... 37 2.5.3. Pharmacodynamics ........................................................................................................ 42 2.5.4. Discussion on clinical pharmacology ................................................................................. 44 2.5.5. Conclusions on clinical pharmacology ............................................................................... 45 2.6. Clinical efficacy ................................................................................................................ 46 2.6.1. Dose response study ...................................................................................................... 46 2.6.2. Main studies .................................................................................................................. 46 2.6.3. Discussion on clinical efficacy ......................................................................................... 108 2.6.4. Conclusions on the clinical efficacy .................................................................................. 115 2.7. Clinical safety ................................................................................................................. 115 2.7.1. Discussion on clinical safety ........................................................................................... 143 2.7.2. Conclusions on the clinical safety .................................................................................... 146 2.8. Risk Management Plan ..................................................................................................... 146 2.9. Pharmacovigilance ........................................................................................................... 149 Assessment report EMA/CHMP/353055/2017 Page 2/162 2.10. New Active Substance .................................................................................................... 149 2.11. Product information ....................................................................................................... 149 2.11.1. User consultation ........................................................................................................ 149 2.11.2. Quick Response (QR) code ........................................................................................... 150 2.11.3. Additional monitoring .................................................................................................. 150 3. Benefit-Risk Balance ...................................................................................................... 150 3.1. Therapeutic Context ........................................................................................................ 150 3.1.1. Disease or condition ...................................................................................................... 150 3.1.2. Available therapies and unmet medical need .................................................................... 150 3.1.3. Main clinical studies ...................................................................................................... 150 3.2. Favourable effects ........................................................................................................... 151 3.3. Uncertainties and limitations about favourable effects .......................................................... 152 3.4. Unfavourable effects ........................................................................................................ 153 3.5. Uncertainties and limitations about unfavourable effects ...................................................... 154 3.6. Benefit-risk assessment and discussion .............................................................................. 159 3.6.1. Importance of favourable and unfavourable effects ........................................................... 159 3.6.2. Balance of benefits and risks .......................................................................................... 161 4. Recommendations.......................................................................................................... 161 Assessment report EMA/CHMP/353055/2017 Page 3/162 List of abbreviations List of abbreviations ADO adverse event associated with drop out (premature study discontinuation) AE adverse event AIMS Abnormal Involuntary Movement Scale ALP alkaline phosphatase ALT alanine aminotransferase (same as serum glutamic-pyruvic transaminase [SGPT]) AST aspartate aminotransferase (same as serum glutamic-oxaloacetic transaminase [SGOT]) AUC area under the concentration-time curve BARS Barnes Akathisia Rating Scale BCVA best-corrected visual acuity BD bipolar depression BMI body mass index BP blood pressure bpm beats per minute BUN blood urea nitrogen CDR cognitive drug research system attention battery CFB change from baseline CI confidence interval CGI-S Clinical Global Impressions–Severity CGI–I Clinical Global Impressions –Intensity CQA Critical Quality Attribute Cmax maximum concentration CNS central nerve system CPK creatine phosphokinase CK-MB creatine kinase MB isoenzyme C-SSRS Columbia–Suicide