CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 202439Orig1s000 PHARMACOLOGY REVIEW(S) DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION Application number: 202439 Supporting document/s: Electronic Document Room (EDR) for NDAs 202439 and 22406 Applicant’s letter dates: 01/04/11, 02/18/11, 05/16/11, 05/21/11 CDER stamp dates: 01/05/11, 02/18/11, 05/16/11, 05/23/11 Product: Rivaroxaban (Bay 59-7939) Indication: Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Applicant: Janssen Pharmaceuticals Inc Review Division: Division of Cardiovascular and Renal Products Reviewer: Patricia P. Harlow, Ph.D. Supervisor/Team Leader: Thomas Papoian, Ph.D., D.A.B.T. Division Director: Norman Stockbridge, M.D., Ph.D. Project Manager: Alison Blaus Template Version: September 1, 2010 Disclaimer Except as specifically identified, all data and information discussed below and necessary for approval of NDA 202439 are owned by Ortho McNeil Janssen Pharmaceuticals Inc or are data for which Janssen Pharmaceuticals Inc has obtained a written right of reference. Any information or data necessary for approval of NDA 202439 that Janssen Pharmaceuticals 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 202439. 1 Reference ID: 2981795 NDA 202439 Patricia Harlow, Ph.D. TABLE OF CONTENTS 1 EXECUTIVE SUMMARY ......................................................................................... 7 1.1 INTRODUCTION .................................................................................................... 7 1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 7 1.3 RECOMMENDATIONS .......................................................................................... 11 2 DRUG INFORMATION .......................................................................................... 13 2.1 DRUG ............................................................................................................... 13 2.2 RELEVANT INDS, NDAS, BLAS AND DMFS......................................................... 13 2.3 DRUG FORMULATION ......................................................................................... 14 2.4 COMMENTS ON NOVEL EXCIPIENTS..................................................................... 14 2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 14 2.6 PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 15 2.7 REGULATORY BACKGROUND .............................................................................. 16 3 STUDIES SUBMITTED.......................................................................................... 17 3.1 STUDIES REVIEWED........................................................................................... 17 3.2 STUDIES NOT REVIEWED ................................................................................... 17 3.3 PREVIOUS REVIEWS REFERENCED...................................................................... 17 4 PHARMACOLOGY................................................................................................ 18 4.1 PRIMARY PHARMACOLOGY ................................................................................. 18 4.2 SECONDARY PHARMACOLOGY ............................................................................ 24 4.3 SAFETY PHARMACOLOGY................................................................................... 25 4.4 PHARMACODYNAMIC DRUG INTERACTIONS: .......................................................... 28 5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 34 5.1 PK/ADME........................................................................................................ 34 5.2 TOXICOKINETICS ............................................................................................... 42 6 GENERAL TOXICOLOGY..................................................................................... 43 6.1 SINGLE-DOSE TOXICITY ..................................................................................... 43 6.2 REPEAT-DOSE TOXICITY .................................................................................... 43 7 GENETIC TOXICOLOGY ...................................................................................... 52 7.1 IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES)....................... 53 7.2 IN VITRO ASSAYS IN MAMMALIAN CELLS.............................................................. 60 7.3 IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY).................. 63 8 CARCINOGENICITY ............................................................................................. 63 9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 71 9.1 FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................... 74 9.2 EMBRYONIC FETAL DEVELOPMENT ..................................................................... 74 9.3 PRENATAL AND POSTNATAL DEVELOPMENT ......................................................... 77 2 Reference ID: 2981795 NDA 202439 Patricia Harlow, Ph.D. 10 SPECIAL TOXICOLOGY STUDIES................................................................... 79 11 INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 95 12 APPENDIX/ATTACHMENTS........................................................................... 100 3 Reference ID: 2981795 NDA 202439 Patricia Harlow, Ph.D. Table of Tables Table 1: List of Nonclinical Study Reports Submitted to NDA 202,439 ......................... 17 Table 2: Previous Reviews Referenced ........................................................................ 17 Table 3: Reviewer’s Summary - PH-32009, PH-35082 ................................................. 19 Table 4: Reviewer's Summary - In vitro Effects in Different Species - PH-32009.......... 20 Table 5: Reviewer’s Summary – Rivaroxaban Specificity ............................................. 21 Table 6: Reviewer’s Summary – Pharmacology Studies............................................... 21 Table 7: Reviewer’s Summary – Relevant Results from R-8462, R-8463..................... 24 Table 8: Reviewer’s Summary – R8466 Study Results................................................. 27 Table 9: Reviewer’s Summary of Antithrombotic Activity and Bleeding in Rats ............ 28 Table 10: Reviewer’s Summary of Pharmacodynamic Interactions .............................. 29 Table 11: Reviewer’s Summary – Bleeding Times (BT) in R-8472 ............................... 30 Table 12: Sponsor's Summary - Bleeding Times in PH-34870...................................... 31 Table 13: Sponsor's Summary - Bleeding Times - PH34871 ........................................ 32 Table 14: Sponsor's Summary - Bleeding Times - PH35374 ........................................ 33 Table 15: Reviewer's Summary - Exposure in PH-33051 and PH-34379 ..................... 34 Table 16: Reviewer's Summary of Protein Binding - PH-32966; PH-33395 .................. 35 Table 17: Reviewer's Summary - Distribution in Long-Evans and Wistar Rats ............. 36 Table 18: Maternal and Fetal Rivaroxaban Radioactivity Levels - PH34872................. 37 Table 19: Reviewer's Summary - Rivaroxaban Metabolites in Plasma ......................... 39 Table 20: Reviewer's Summary of In Vitro Metabolism in Various Species .................. 39 Table 21: Reviewer's Summary of Inhibitor of Rivaroxaban Metabolism....................... 41 Table 22: Reviewer's Summary of In Vitro Transport Studies ....................................... 41 Table 23: Reviewer's Summary of Pivotal Toxicology Studies...................................... 43 Table 24: Reviewer's Summary of Chronic Toxicology Studies .................................... 44 Table 25: Safety Margins Based on Chronic Toxicology Studies .................................. 45 Table 26: PH 36161: Sponsor's Body Weight Graphs, Reviewer's Tabular Summary.. 48 Table 27: Sponsor's Summaries of Food and Water Intake – Study ............................. 48 Table 28: Reviewer's Summary of Mitochondrial Enzyme Activites - PH-36161........... 51 Table 29: Genetic Toxicology Study Reports for BAY 59-7939..................................... 52 Table 30: Reviewer’s Summary – Genetic Toxicology Studies Using Micronized Rivaroxaban .................................................................................................................. 52 Table 31: Reviewer's Summary – Ames Assays - Study PH-34016.............................. 55 Table 32: Reviewer's Summary - Prior Historical Control Data – Study PH-34016 ....... 56 Table 33: Reviewer's Summary – Ames Assays – Study PH-33561............................. 58 Table 34: Reviewer's Summary Prior Historical Control Data – Study PH-33561 ......... 59 Table 35: Reviewer's Modification of Sponsor's Tables – Study PH34198 ................... 62 Table 36: Reviewer's Modification of Sponsor's 2004