CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 203505Orig1s000 PHARMACOLOGY REVIEW(S) Comments on N203505 ospemifene From A. Jacobs, AD Date: January 15, 2013 1. I concur that there are no outstanding pharm/tox issues 2. I concur with the proposed pregnancy labeling. 3. I have conveyed some editorial suggestions to the reviewer and they will be addressed as appropriate. Reference ID: 3245227 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- ABIGAIL C JACOBS 01/15/2013 Reference ID: 3245227 DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION Application number: 203505 Supporting document/s: eCTD Applicant’s letter date: April 25, 2012 CDER stamp date: April 25, 2012 Product: Ospemifene Indication: Vulvar and Vaginal Atrophy in Postmenopausal Women Applicant: Shionogi, Inc. Review Division: Division of Reproductive and Urologic Products Reviewer: Jeffrey Bray, Ph.D. Expert Reviewer/Team Leader: Alex Jordan, Ph.D. Division Director: Hylton Joffe, M.D. Project Manager: George Lyght Disclaimer Except as specifically identified, all data and information discussed below and necessary for approval of NDA 203505 are owned by Shionogi, Inc., or are data for which Shionogi, Inc., has obtained a written right of reference. Any information or data necessary for approval of NDA 203505 that Shionogi, Inc., does not own or have a written right to reference constitutes one of the following: (1) published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or information described or referenced below from reviews or publicly available summaries of a previously approved application is for descriptive purposes only and is not relied upon for approval of NDA 203505. 1 Reference ID: 3245246 NDA # 203505 Reviewer: Jeffrey Bray, PhD TABLE OF CONTENTS 1 EXECUTIVE SUMMARY ......................................................................................... 8 1.1 INTRODUCTION .................................................................................................... 8 1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 8 1.3 RECOMMENDATIONS .......................................................................................... 10 2 DRUG INFORMATION .......................................................................................... 12 2.1 DRUG ............................................................................................................... 12 2.2 RELEVANT IND/S, NDA/S, AND DMF/S ............................................................... 13 2.3 DRUG FORMULATION ......................................................................................... 13 2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 13 2.6 PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 16 3 STUDIES SUBMITTED.......................................................................................... 17 3.1 STUDIES REVIEWED........................................................................................... 17 3.2 STUDIES NOT REVIEWED ................................................................................... 18 3.3 PREVIOUS REVIEWS REFERENCED...................................................................... 19 4 PHARMACOLOGY................................................................................................ 19 4.1 PRIMARY PHARMACOLOGY ................................................................................. 19 4.3 SAFETY PHARMACOLOGY................................................................................... 19 5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 24 5.1 PK/ADME........................................................................................................ 24 5.2 TOXICOKINETICS ............................................................................................... 37 6 GENERAL TOXICOLOGY..................................................................................... 38 6.1 SINGLE-DOSE TOXICITY ..................................................................................... 38 6.2 REPEAT-DOSE TOXICITY .................................................................................... 39 7 GENETIC TOXICOLOGY ...................................................................................... 65 7.1 IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES)....................... 65 7.2 IN VITRO ASSAYS IN MAMMALIAN CELLS.............................................................. 67 7.3 IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY).................. 69 7.4 OTHER GENETIC TOXICITY STUDIES.................................................................... 70 8 CARCINOGENICITY ............................................................................................. 71 9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 109 9.1 FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................. 109 9.2 EMBRYONIC FETAL DEVELOPMENT ................................................................... 109 9.3 PRENATAL AND POSTNATAL DEVELOPMENT ....................................................... 114 10 SPECIAL TOXICOLOGY STUDIES................................................................. 125 11 INTEGRATED SUMMARY AND SAFETY EVALUATION............................... 128 2 Reference ID: 3245246 NDA # 203505 Reviewer: Jeffrey Bray, PhD 12 APPENDIX/ATTACHMENTS........................................................................... 139 3 Reference ID: 3245246 NDA # 203505 Reviewer: Jeffrey Bray, PhD Table of Tables Table 1 List of Impurities .............................................................................................. 14 Table 2 Potential Impurities in Ospemifene (FC-1271a) Drug Substance.................... 15 Table 3 Batches Used for Toxicological and Clinical Studies; Analysis Results and the Uses of Batches ............................................................................................................ 16 Table 4 Summary of Supportive Stability Results in HDPE Bottles and Blisters .......... 16 Table 5 Inhibition of Ospemifene Oxidations to M4 and M5 Metabolites in Human Liver Microsomes using CYP Enzyme Selective Inhibitors .................................................... 26 Table 6 Formation of 4’-hydroxy ospemifene with CYP Specific Inhibitors.................. 27 Table 7 Comparison of M1 and M2 Metabolite Exposure to the Parent Ospemifene... 29 Table 8 CYP-associated Activities in vitro in Liver Microsomes from Female Rats...... 30 Table 9 CYP-associated Activities in vitro in Liver Microsomes from Female Cynomolgus Monkeys................................................................................................... 30 Table 10 Inhibition of CYP Enzymes by Ospemifene................................................... 31 Table 11 Inhibition of CYP Enzymes by 4-hydroxy ospemifene ................................... 32 Table 12 Inhibitory potency of 4’-hydroxy ospemifene (HM-136) towards CYP activities in the incubations with a pool of human liver microsomes............................................. 33 Table 13 Animals Replaced During First 4 Weeks of Treatment.................................. 73 Table 14 Male Mice Sacrificed Early during 2-Year Oral Ospemifene Carcinogenicity Study Due to Urogenital Swelling.................................................................................. 74 Table 15 Disposition of Female Mice during a 2-Year Oral Ospemifene Carcinogenicity Study............................................................................................................................. 75 Table 16 Mean Body Weight Gain (g) for Female Mice during a 2-Year Oral Ospemifene Carcinogenicity Study ............................................................................... 77 Table 17 Type and Incidence of Protruding Organs in Male Mice Sacrificed Before Week 13 and After Dosing Cessation Week 14 ............................................................ 78 Table 18 Selected Macroscopic Findings of Note in Female Mice at Necropsy during a 2-Year Oral Ospemifene Carcinogenicity Study (n=51 total/group)............................... 78 Table 19 Selected Neoplastic Findings of Note in Female Mice at Necropsy during a 2- Year Oral Ospemifene Carcinogenicity Study (n=51/group) ......................................... 80 Table 20 Adrenal and Ovary Neoplastic Findings in Female Mice at Necropsy during a 2-Year Oral Ospemifene Carcinogenicity Study............................................................ 81 Table 21 List of Statistically Significant Increasing Dose-Response Neoplasms with P- Values and % Incidence (Combined Fatal+Non-fatal) from a 2-Year Oral Ospemifene Carcinogenicity Study.................................................................................................... 82 Table