20 November 2014 EMA/78875/2015 Committee for Medicinal Products for Human Use (CHMP) Assessment report Senshio International non-proprietary name: ospemifene Procedure No. EMEA/H/C/002780/0000 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, 2015. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Manufacturers ...................................................................................................... 8 1.3. Steps taken for the assessment of the product ......................................................... 8 2. Scientific discussion ................................................................................ 9 2.1. Introduction......................................................................................................... 9 2.2. Quality aspects .................................................................................................. 11 2.2.1. Introduction .................................................................................................... 11 2.2.2. Active Substance ............................................................................................. 11 2.2.3. Finished Medicinal Product ................................................................................ 13 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 15 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 16 2.2.6. Recommendation(s) for future quality development ............................................. 16 2.3. Non-clinical aspects ............................................................................................ 16 2.3.1. Introduction .................................................................................................... 16 2.3.2. Pharmacology ................................................................................................. 16 2.3.3. Pharmacokinetics............................................................................................. 20 2.3.4. Toxicology ...................................................................................................... 24 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 27 2.3.6. Discussion on non-clinical aspects...................................................................... 30 2.3.7. Conclusion on the non-clinical aspects ................................................................ 30 2.4. Clinical aspects .................................................................................................. 31 2.4.1. Introduction .................................................................................................... 31 Pharmacokinetics ...................................................................................................... 35 Pharmacodynamics ................................................................................................... 40 2.4.2. Discussion on clinical pharmacology ................................................................... 45 2.4.3. Conclusions on clinical pharmacology ................................................................. 50 2.5. Clinical efficacy .................................................................................................. 50 2.5.1. Dose response studies...................................................................................... 51 2.5.2. Main studies ................................................................................................... 53 2.5.3. Supportive studies ........................................................................................... 60 2.5.4. Clinical studies in special populations ................................................................. 63 2.5.5. Analysis performed across trials (pooled analyses AND meta-analysis) ................... 64 2.5.6. Discussion on clinical efficacy ............................................................................ 65 2.5.7. Conclusions on the clinical efficacy ..................................................................... 73 2.6. Clinical safety .................................................................................................... 73 2.6.1. Discussion on clinical safety .............................................................................. 90 2.6.2. Conclusions on the clinical safety ....................................................................... 92 2.7. Pharmacovigilance .............................................................................................. 93 2.8. Risk Management Plan ........................................................................................ 93 2.9. User consultation ............................................................................................. 103 Assessment report EMA/78875/2015 Page 2/116 3. Benefit-Risk Balance............................................................................ 104 Benefits ................................................................................................................. 104 Beneficial effects ..................................................................................................... 104 Uncertainty in the knowledge about the beneficial effects ............................................ 105 Risks ..................................................................................................................... 106 Unfavourable effects ............................................................................................... 106 Uncertainty in the knowledge about the unfavourable effects ....................................... 107 Benefit-risk balance ................................................................................................ 108 Importance of favourable and unfavourable effects ..................................................... 108 Benefit-risk balance ................................................................................................ 109 Discussion on the benefit-risk balance ....................................................................... 110 4. Recommendations ............................................................................... 112 Assessment report EMA/78875/2015 Page 3/116 List of abbreviations ADR Adverse drug reaction AE Adverse event ALT Alanine aminotransferase ANCOVA Analysis of covariance ANOVA Analysis of variance ASC-H Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion ASC-US Atypical squamous cells of undetermined significance ASMF Active substance master file ASM Active substance manufacturer AST Aspartate aminotransferase ATE Arterial thromboembolism AUC Area under the curve BCRP Breast Cancer Resistance Protein BLQ Below the limit of quantification BMI Body mass index BrdU 5-bromo-2-deoxyuridine BSE Bovine Spongiform Encephalopathy BSEP Bile Salt Export Pump Cmax Maximum plasma concentration CI Confidence interval CMH Cochran-Mantel-Haenszel CMR Carcinogenic, Mutagenic, Reproductive toxicity CNS Central nervous system CVA Cardiovascular attack CYP Cytochrome P450 DBPC Double Blind Placebo Controlled DMBA Dimethylbenzoanthrasene DNA Deoxyribonucleic Acid DT Degradation time DVT Deep Vein Thrombosis ED50 50% effective dose ER Estrogen receptor F Female Assessment report EMA/78875/2015 Page 4/116 FDA Food and Drug Administration FSFI Female Sexual Function Index FSH Follicle Stimulating Hormone GLP Good laboratory practice hERG Human ether-a-go-go-related gene HI Hepatic impairment HPLC high performance liquid chromatography HRT Hormone replacement therapy HSIL High-grade squamous intraepithelial lesion IC50 50% inhibitory concentration ICH International conference on harmonisation IV Intravenous Ki Binding affinity of the inhibitor LH Luteinising Hormone LOD Limit of detection; Loss on drying LPS Lipopolysaccharide LOQ Limit of quantification MBS Most bothersome symptom NAS New active substance NEC New chemical entity NMRI Nuclear magnetic resonance imaging NMT Not more than NOAEL No observed adverse effect level NOEL No observed effect level OECD Organisation for Economic Co-operation and Development OATP Organic Anion-Transporting Polypeptide OVX Ovariectomised PASS Post-authorisation safety study Pap Papanicolaou PBT Persistence - Bioaccumulation - Toxicity PE Pulmonary embolism PK/PD Pharmacokinetic / pharmacodynamics PO Oral RH Relative humidity RI Renal impairment SAP Statistical Analysis plan SC Subcutaneous Assessment report EMA/78875/2015 Page 5/116 SD Standard deviation SE Standard error SERM Selective Estrogen Receptor Modulator SHBG Serum sex hormone-binding globulin SOC System organ class Tmax Time of maximum plasma concentration TEAE Treatment-emergent adverse event THF Tetrahydrofuran TTC Threshold of Toxicological Concern TSE Transmissible Spongiform Encephalopathies UDI-6 Urinary distress inventory-6 UGT Uridine'5 diphospho-glucuronosyl transferase