Assessment report Zoely International Non proprietary Name: nomegestrol/estradiol Procedure No. EMEA/H/C/001213 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 Table of contents 1. Background information on the procedure .............................................. 5 1.1. Submission of the dossier.................................................................................... 5 Information on Paediatric requirements ....................................................................... 5 Scientific Advice ....................................................................................................... 5 Licensing status ....................................................................................................... 5 1.2. Steps taken for the assessment of the product ....................................................... 6 2. Scientific discussion ................................................................................ 7 2.1. Introduction ...................................................................................................... 7 2.2. Quality aspects .................................................................................................. 7 2.2.1. Introduction ................................................................................................... 7 2.2.2. Active Substance............................................................................................. 8 Manufacture ............................................................................................................ 8 Specification ............................................................................................................ 8 Stability .................................................................................................................. 8 Active Substance ...................................................................................................... 8 Manufacture ............................................................................................................ 9 2.2.3. Finished Medicinal Product ................................................................................ 9 Pharmaceutical Development ..................................................................................... 9 Adventitious agents ................................................................................................ 10 Manufacture of the product ...................................................................................... 10 Product specification ............................................................................................... 11 Stability of the product............................................................................................ 11 2.2.4. Discussion on chemical, pharmaceutical and biological aspects............................. 12 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ..................... 12 2.3. Non-clinical aspects .......................................................................................... 12 2.3.1. Introduction ................................................................................................. 12 2.3.2. Pharmacology ............................................................................................... 12 Primary pharmacodynamic studies ............................................................................ 12 Primary pharmacodynamics in vitro .......................................................... 12 Primary pharmacodynamics in vivo ........................................................... 12 Secondary pharmacodynamic studies ........................................................................ 13 Safety pharmacology programme ............................................................................. 13 Pharmacodynamic drug interactions .......................................................................... 13 2.3.3. Pharmacokinetics .......................................................................................... 13 Pharmacokinetic drug interactions ............................................................ 14 2.3.4. Toxicology.................................................................................................... 14 Single dose toxicity................................................................................................. 14 Repeat dose toxicity................................................................................................ 15 Genotoxicity .......................................................................................................... 15 Carcinogenicity....................................................................................................... 15 Reproduction Toxicity.............................................................................................. 15 Toxicokinetic data................................................................................................... 16 Page 2/52 Local Tolerance ...................................................................................................... 16 Other toxicity studies .............................................................................................. 16 2.3.5. Ecotoxicity/environmental risk assessment........................................................ 16 2.4. Clinical aspects ................................................................................................ 19 2.4.1. Introduction ................................................................................................. 19 GCP...................................................................................................................... 19 2.4.2. Pharmacokinetics .......................................................................................... 19 Absorption............................................................................................................. 22 Distribution............................................................................................................ 23 Elimination ............................................................................................................ 23 Dose proportionality and time dependencies............................................................... 24 Special populations ................................................................................................. 24 Pharmacokinetic interaction studies........................................................................... 26 2.4.3. Pharmacodynamics........................................................................................ 26 Mechanism of action ............................................................................................... 26 Primary and Secondary pharmacology ....................................................................... 27 2.4.4. Discussion on clinical pharmacology ................................................................. 27 2.4.5. Conclusions on clinical pharmacology ............................................................... 28 2.5. Clinical efficacy ................................................................................................ 28 2.5.1. Dose response study(ies) ............................................................................... 30 2.5.2. Main study(ies) ............................................................................................. 30 Methods ................................................................................................................ 35 Study Participants .................................................................................................. 35 Treatments............................................................................................................ 35 Objectives ............................................................................................................. 35 Outcomes/endpoints ............................................................................................... 35 Sample size ........................................................................................................... 36 Randomisation ....................................................................................................... 36 Blinding (masking).................................................................................................. 36 Statistical methods ................................................................................................. 37 Results.................................................................................................................. 37 Recruitment........................................................................................................... 37 Conduct of the study............................................................................................... 37 Baseline data ......................................................................................................... 37 Numbers analysed .................................................................................................. 37 Outcomes and estimation .......................................................................................