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Public Assessment Report 23 October 2014 EMA/CHMP/383987/2014 Committee for Medicinal Products for Human Use (CHMP) Assessment report Duavive International non-proprietary name: ESTROGENS CONJUGATED / BAZEDOXIFENE Procedure No. EMEA/H/C/002314/0000 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 5520 Send a question via our website www.ema.europa.eu/contact An agency of the European Union Table of contents 1. Background information on the procedure......................................................... 10 1.1. Submission of the dossier ................................................................................... 10 1.2. Manufacturers ................................................................................................... 11 1.3. Steps taken for the assessment of the product ...................................................... 12 2. Scientific discussion .............................................................................. 12 2.1. Introduction ...................................................................................................... 12 2.2. Quality aspects .................................................................................................. 14 2.2.1. Introduction.................................................................................................... 14 2.2.2. Active Substance ............................................................................................. 15 2.2.3. Finished Medicinal Product ................................................................................ 21 2.2.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 24 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 24 2.2.6. Recommendations for future quality development ............................................... 24 2.3. Non-clinical aspects ............................................................................................ 26 2.3.1. Introduction.................................................................................................... 26 2.3.2. Pharmacology ................................................................................................. 26 2.3.3. Pharmacokinetics ............................................................................................ 29 2.3.4. Toxicology ...................................................................................................... 29 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 33 2.3.6. Discussion on non-clinical aspects ..................................................................... 35 2.3.7. Conclusion on the non-clinical aspects ............................................................... 37 2.4. Clinical aspects .................................................................................................. 38 2.4.1. Introduction.................................................................................................... 38 2.4.2. Pharmacokinetics ............................................................................................ 44 2.4.3. Pharmacodynamics .......................................................................................... 48 2.4.4. Discussion on clinical pharmacology ................................................................... 49 2.4.5. Conclusions on clinical pharmacology ................................................................. 51 2.5. Clinical efficacy .................................................................................................. 52 2.5.1. Dose response study........................................................................................ 53 2.5.2. Main studies ................................................................................................... 56 2.5.3. Discussion on clinical efficacy .......................................................................... 100 2.5.4. Conclusions on the clinical efficacy .................................................................. 104 2.6. Clinical safety .................................................................................................. 106 2.6.1. Discussion on clinical safety ............................................................................ 123 2.6.2. Conclusions on the clinical safety .................................................................... 126 2.7. Pharmacovigilance ........................................................................................... 127 2.8. Risk Management Plan ...................................................................................... 128 Assessment report EMA/CHMP/383987/2014 Page 2/153 2.9. Product information .......................................................................................... 134 2.9.1. User consultation .......................................................................................... 140 3. Benefit-Risk Balance ........................................................................... 140 4. Recommendations ............................................................................... 149 Assessment report EMA/CHMP/383987/2014 Page 3/153 List of abbreviations AC Adjudication Committee ADR adverse drug reaction AE adverse event ALT alanine aminotransferase ANCOVA Analysis of covariance ANOVA Analysis of variance API Active pharmaceutical ingredient ASM Active Substance Manufacturer ASMF Active Substance Manufacturer File ASEX Arizona sexual experience AST aspartate aminotransferase AUC Area under the concentration-time curve BI-RADS Breast Imaging and Reporting Data System BMC Bone mineral content BMD Bone mineral density BMI Body mass index BR Brazil BSA body surface area BTM Bone turnover marker BUN blood urea nitrogen BZA Bazedoxifene BZA/CE Bazedoxifene/conjugated estrogens CAS Chemical Abstracts Service CE Conjugated estrogens CEDL Conjugated Estrogens Desiccation with Lactose cp centipoise CHD coronary heart disease CHF congestive heart failure CHMP Committee for Medicinal Products for Human Use CI Confidence interval CL/F Apparent oral clearance CMH Cochran-Mantel-Haenszel CHMP Committee for Proprietary Medicinal Products for Human Use Assessment report EMA/CHMP/383987/2014 Page 4/153 CO Clinical Overview COSTART Coding Symbols for a Thesaurus of Adverse Reaction Terms CRF case report form CRO Contract Research Organisation CSR Clinical study report CTx C-telopeptide CVA Cerebrovascular accident CVE cerebrovascular event CVEAC Cerebrovascular Event Adjudication Committee CYP Cytochrome P450 DB Double blind DSC differential scanning calorimetry DP Drug product DS Drug substance DVT deep vein thrombosis DXA Dual-energy x-ray absorptiometry ECG Electrocardiogram EE Efficacy evaluable EMA European Medicines Agency EMAS European Menopause and Andropause Society ESI electrospray ionisation ET Estrogen therapy EU European Union FDA Food and Drug Administration FSFV First subject first visit FSH Follicle stimulating hormone FT Fourier transform FPM finished product manufacturer GC Gas Chromatography GC-MS Gas Chromatography coupled to mass spectrometry GCP Good Clinical Practice GL Global GMP Good manufacturing practice Hct hematocrit HDL high-density lipoprotein Assessment report EMA/CHMP/383987/2014 Page 5/153 HOPE Women’s Health Osteoporosis Progestin Estrogen Study HPLC high pressure liquid chromatography HPMC Hydroxypropyl methylcellulose HRT Hormone replacement therapy HT Hormone therapy ICH International Conference on Harmonisation IEC Independent Ethics Committee INR international normalized ratio INT Interaction IR Infrared IRB Institutional Review Board ISAP Integrated Statistical Analysis Plan ISE Integrated Summary of Effectiveness ISS Integrated Summary of Safety JP Japanese Pharmacopoeia JPE Japanese Pharmaceutical Excipient KF Karl Fischer LDL low-density lipoprotein LDPE low-density polyethylen LOCF Last observation carried forward LOD limit of detection LOQ limit of quantitation LS Lumbar spine LSLV Last subject last visit MAA Marketing Authorisation Application MBS Most bothersome symptom MedDRA Medical Dictionary for Regulatory Activities MENQOL Menopause-Specific Quality of Life MI Myocardial infarction MITT Modified intent-to-treat MOS Medical Outcomes Study MPA Medroxyprogesterone acetate MRA Mutual Recognition Agreement MRI magnetic resonance imaging MS mass spectrometry Assessment report EMA/CHMP/383987/2014 Page 6/153 MS-TSQ Menopause Symptoms – Treatment Satisfaction Questionnaire MW molecular weight NA Not applicable NCI National Cancer Institute NDA New Drug Application NMT Not More Than OC Observed cases OOS out of specifcation OP osteoporosis OSS Osteoporosis substudy OSSI osteoporosis prevention I Substudy OSSII osteoporosis prevention II and metabolic substudy P1NP Procollagen type 1 N-propeptide PAI-1 plasminogen activator inhibitor 1 PAP Papanicolaou PBO Placebo PCI potentially clinically important PCUD Preserved Condensed Urine, Desiccated PE Pulmonary embolus Ph.Eur. European Pharmacopoeia PI Product information PKWP Pharmacokinetics working party PMU Pregnant Mare’s Urine PNP Premarin new process PP Per protocol RLX Raloxifene QOL Quality of life QTc corrected QT interval QTcB Bazett's corrected QT interval QTcF Fridericia corrected QT interval QTcN Population corrected QT interval
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