13 December 2012 EMA/91055/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report Adasuve International non-proprietary name: loxapine Procedure No. EMEA/H/C/002400 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2013. Reproduction is authorised provided the source is acknowledged. Contents 1. Background information on the procedure .............................................. 8 1.1. Submission of the dossier .................................................................................... 8 Information on Paediatric requirements ....................................................................... 8 Information relating to orphan market exclusivity .......................................................... 8 Scientific Advice ....................................................................................................... 8 Licensing status ....................................................................................................... 8 1.2. Steps taken for the assessment of the product ....................................................... 9 2. Scientific discussion .............................................................................. 10 2.1. Introduction .................................................................................................... 10 2.2. Quality aspects ................................................................................................ 11 2.2.1. Introduction ................................................................................................. 11 2.2.2. Active Substance ........................................................................................... 11 Manufacture .......................................................................................................... 11 Specification .......................................................................................................... 12 Stability ................................................................................................................ 12 Comparability exercise for Active Substance ............................................................... 12 2.2.3. Finished Medicinal Product .............................................................................. 12 Pharmaceutical Development ................................................................................... 12 Adventitious agents ................................................................................................ 13 Manufacture of the product ...................................................................................... 14 Product specification ............................................................................................... 14 Stability of the product ............................................................................................ 14 Comparability Exercise for Finished Medicinal Drug Product .......................................... 15 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. Recommendation(s) for future quality development ............................................ 15 2.3. Non-clinical aspects .......................................................................................... 15 2.3.1. Introduction ................................................................................................. 15 2.3.2. Pharmacology ............................................................................................... 15 2.3.3. Pharmacokinetics .......................................................................................... 20 2.3.4. Toxicology .................................................................................................... 21 2.3.5. Ecotoxicity/environmental risk assessment ........................................................ 23 2.3.6. Discussion on non-clinical aspects .................................................................... 23 2.3.7. Conclusion on the non-clinical aspects .............................................................. 25 2.4. Clinical aspects ................................................................................................ 25 2.4.1. Introduction ................................................................................................. 25 GCP ...................................................................................................................... 25 2.4.2. Pharmacokinetics .......................................................................................... 25 2.4.3. Pharmacodynamics ........................................................................................ 27 2.4.4. Discussion on clinical pharmacology ................................................................. 28 2.4.5. Conclusions on clinical pharmacology ............................................................... 29 2.5. Clinical efficacy ................................................................................................ 29 2.5.1. Dose response study ...................................................................................... 30 Adasuve Assessment report Page 2/91 2.5.2. Main studies ................................................................................................. 32 Study Participants .................................................................................................. 34 Treatments ............................................................................................................ 34 Outcomes/endpoints ............................................................................................... 35 Sample size ........................................................................................................... 35 Randomisation ....................................................................................................... 35 Blinding (masking) .................................................................................................. 35 Statistical methods ANCOVA/ANOVA ......................................................................... 35 Participant flow ...................................................................................................... 36 Recruitment ........................................................................................................... 37 Conduct of the study ............................................................................................... 37 Baseline data ......................................................................................................... 37 Figure 7 ................................................................................................................ 39 Number analysed ................................................................................................... 41 Outcomes and estimation ........................................................................................ 42 Summary of main study(ies) .................................................................................... 50 2.5.3. Ancillary analyses .......................................................................................... 55 2.5.4. Analysis performed across trials (pooled analyses and meta-analysis) ................... 58 2.5.5. Clinical studies in special populations ............................................................... 58 2.5.6. Supportive studies ......................................................................................... 58 2.5.7. Discussion on clinical efficacy .......................................................................... 65 Design and conduct of clinical studies ........................................................................ 65 Efficacy data and additional analyses. ........................................................................ 67 2.5.8. Conclusions on the clinical efficacy ................................................................... 69 2.6. Clinical safety .................................................................................................. 69 2.6.1. Patient exposure ........................................................................................... 70 2.6.2. Adverse events ............................................................................................. 70 2.6.3. Serious adverse event/deaths/other significant events ........................................ 72 2.6.4. Laboratory findings ........................................................................................ 72 2.6.5. Safety in special populations ........................................................................... 72 2.6.6. Safety related to drug-drug interactions and other interactions ............................ 73 2.6.7. Discontinuation due to adverse events .............................................................. 74 2.6.8. Post marketing experience .............................................................................. 74 2.6.9. Discussion on clinical safety ...........................................................................