Drovelis, INN-Drospirenone/Estetrol

25 March 2021 EMA/212533/2021 Committee for Medicinal Products for Human Use (CHMP) Assessment report Drovelis International non-proprietary name: drospirenone / estetrol Procedure No. EMEA/H/C/005336/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union Table of contents 1. Background information on the procedure ......................................................................... 7 1.1. Submission of the dossier .................................................................................................... 7 1.2. Steps taken for the assessment of the product ....................................................................... 8 1.3. Steps taken for the re-examination procedure ........................... Error! Bookmark not defined. 2. Scientific discussion ......................................................................................................... 10 2.1. Problem statement ........................................................................................................... 10 2.1.1. Disease or condition ....................................................................................................... 10 2.1.2. Epidemiology ................................................................................................................ 10 2.1.3. Management ................................................................................................................. 10 2.2. Quality aspects ................................................................................................................ 12 2.2.1. Introduction .................................................................................................................. 12 2.2.2. Active Substance ................................................................. Error! Bookmark not defined. 2.2.3. Finished Medicinal Product .................................................... Error! Bookmark not defined. 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .. Error! Bookmark not defined. 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspectsError! Bookmark not defined. 2.2.6. Recommendation(s) for future quality development ................. Error! Bookmark not defined. 2.3. Non-clinical aspects .......................................................................................................... 21 2.3.1. Introduction .................................................................................................................. 21 2.3.2. Pharmacology ............................................................................................................... 22 2.3.3. Pharmacokinetics........................................................................................................... 25 2.3.4. Toxicology .................................................................................................................... 27 2.3.5. Ecotoxicity/environmental risk assessment ....................................................................... 37 2.3.6. Discussion on non-clinical aspects.................................................................................... 41 2.3.7. Conclusion on the non-clinical aspects .............................................................................. 41 2.4. Clinical aspects ................................................................................................................ 45 2.4.1. Introduction .................................................................................................................. 45 2.4.2. Pharmacokinetics........................................................................................................... 50 2.4.3. Pharmacodynamics ........................................................................................................ 58 2.4.4. Discussion on clinical pharmacology ................................................................................. 84 2.4.5. Conclusions on clinical pharmacology ............................................................................... 88 2.5. Clinical efficacy ................................................................................................................ 88 2.5.1. Dose response study(ies) ............................................................................................... 89 2.5.2. Main study(ies) ............................................................................................................. 90 2.5.3. Discussion on clinical efficacy ......................................................................................... 128 2.5.4. Conclusions on the clinical efficacy .................................................................................. 136 2.6. Clinical safety ................................................................................................................. 136 2.6.1. Discussion on clinical safety ........................................................................................... 158 2.6.2. Conclusions on the clinical safety .................................................................................... 158 2.7. Risk Management Plan ..................................................................................................... 161 Assessment report EMA/212533/2021 Page 2/175 2.8. Pharmacovigilance ........................................................................................................... 163 2.9. New Active Substance ...................................................................................................... 164 2.10. Product information ....................................................................................................... 165 2.10.1. User consultation ........................................................................................................ 165 2.10.2. Additional monitoring .................................................................................................. 165 3. Benefit-Risk Balance ...................................................................................................... 166 3.1. Therapeutic Context ........................................................................................................ 166 3.1.1. Disease or condition ...................................................................................................... 166 3.1.2. Available therapies and unmet medical need .................................................................... 166 3.1.3. Main clinical studies ...................................................................................................... 167 3.2. Favourable effects ........................................................................................................... 167 3.3. Uncertainties and limitations about favourable effects .......................................................... 168 3.4. Unfavourable effects ........................................................................................................ 169 3.5. Uncertainties and limitations about unfavourable effects ...................................................... 171 3.6. Effects Table ................................................................................................................... 171 3.7. Benefit-risk assessment and discussion .............................................................................. 172 3.7.1. Importance of favourable and unfavourable effects ........................................................... 172 3.7.2. Balance of benefits and risks .......................................................................................... 173 3.7.3. Additional considerations on the benefit-risk balance ........................................................ 173 3.8. Conclusions .................................................................................................................... 173 4. Recommendations ......................................................................................................... 174 Assessment report EMA/212533/2021 Page 3/175 List of abbreviations ADR adverse drug reaction ALT alanine aminotransferase APC activated protein C APTT activated partial thromboplastin time ASMF Active substance master file ATC anatomic therapeutic class ATR Attenuated total reflectance AUC area under the curve BCRP breast cancer resistance protein BMI body mass index CEP Certificate of Suitability CHC combined hormonal contraceptive CHMP Committee for Medicinal Products for Human Use CI confidence interval Cmax maximum plasma concentration COC combined oral contraceptive COSY Correlated Spectroscopy CQA Critical quality attribute CRP C-reactive protein CV coefficient of variation CWB continued withdrawal bleeding CYP cytochrome P450 DHT dihydrotestosterone DNG dienogest DRSP drospirenone DSC Differential scanning calorimetry DSG desogestrel E1 estrone E2 estradiol E2V estradiol valerate E3 estriol E4 estetrol (monohydrate) EE ethinylestradiol EMA European Medicines Agency ER estrogen receptor EWB early withdrawal bleeding F1+2 prothrombin fragments 1+2 Assessment report EMA/212533/2021 Page 4/175 FCT film coated tablet FDA Food and Drug Administration

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