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Center for Drug Evaluation and Research Application CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 22-512 PHARMACOLOGY REVIEW(S) Tertiary Pharmacology Review By: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and Toxicology OND IO NDA: 22-307 Submission date: 4/19/2010 Drug: Pradaxa™ (Dabigatran etexilate mesylate) Sponsor: Boehringer Ingelheim Pharma GmbH & Co. KG Indication: Prevention of stroke and systemic embolism in patients with atrial fibrillation Reviewing Division: Division of Cardiovascular and Renal Products Comments: The pharm/tox reviewer and supervisor found the nonclinical information submitted for dabigatran to be sufficient to support the proposed use. The reviewer proposes pregnancy category C for the labeling. Dabigatran induced some reproductive toxicity in rats manifest as a decreased number of implantations, decreased number of viable fetuses, increase in the resorption rate, increase in post-implantation loss, and an increase in the number of dead offspring when given at doses of 70 mg/kg (about 2.6 to 3 times the MRHD of 300 mg/day on a mg/m2 basis). Dabigatran also induced some fetal structural variations but did not induce fetal malformations in rats or rabbits. Dabigatran was evaluated for carcinogenicity in 2-year rat and mouse studies. The Executive Carcinogenicity Assessment Committee concluded that these studies were adequate and there were no drug-related tumors in either study. Conclusions: I concur with the Division pharm/tox conclusion that the nonclinical data support approval of this NDA. No additional nonclinical studies are recommended at this time. The proposed Established Pharmacologic Class for dabigatran is "direct thrombin inhibitor". This is appropriate because it is consistent with other moieties of this class. I agree with the division recommendations on labeling. --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- PAUL C BROWN 10/14/2010 Reference ID: 2850171 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: 22-512 Supporting document/s: EDR Applicant’s letter date: 4/19/10 (Initial 9/17/09) CDER stamp date: 4/19/10 (Initial 9/17/09) Product: Pradaxa™ (Dabigatran etexilate mesylate) Indication: Prevention of stroke and systemic embolism in patients with atrial fibrillation Applicant: Boehringer Ingelheim Pharma GmbH & Co. KG Review Division: Division of Cardiovascular and Renal Products Reviewer: Patricia P. Harlow, Ph.D. Supervisor/Team Leader: Albert DeFelice, Ph.D. Division Director: Norman Stockbridge, M.D., Ph.D. Project Manager: Alison Blaus Template Version: December 7, 2009 Disclaimer Except as specifically identified, all data and information discussed below and necessary for approval of NDA 22-512 are owned by Boehringer Ingelheim Pharma GmbH & Co. KG or are data for which Boehringer Ingelheim Pharma GmbH & Co. KG has obtained a written right of reference. Any information or data necessary for approval of NDA 22-512 that Boehringer Ingelheim Pharma GmbH & Co. KG 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 described in the drug’s approved labeling. Any data or information described or referenced below from FDA reviews or publicly available summaries of a previously approved application is for descriptive purposes only and is not relied upon for approval of NDA 22-512. 1 NDA 22-512 Patricia Harlow, Ph.D. TABLE OF CONTENTS 1 EXECUTIVE SUMMARY ......................................................................................... 9 1.1 RECOMMENDATIONS ............................................................................................ 9 1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS .................................................... 11 2 DRUG INFORMATION .......................................................................................... 18 3 STUDIES SUBMITTED.......................................................................................... 23 4 PHARMACOLOGY................................................................................................ 32 4.1 PRIMARY PHARMACOLOGY ................................................................................. 32 4.2 SECONDARY PHARMACOLOGY ............................................................................ 42 4.3 SAFETY PHARMACOLOGY................................................................................... 43 5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 51 5.1 PK/ADME........................................................................................................ 51 5.2 TOXICOKINETICS ............................................................................................... 72 6 GENERAL TOXICOLOGY..................................................................................... 74 6.1 SINGLE-DOSE TOXICITY ..................................................................................... 74 6.2 REPEAT-DOSE TOXICITY .................................................................................... 74 6.2.1 REPEAT-DOSE TOXICITY IN RODENTS.............................................................. 76 6.2.2 REPEAT-DOSE TOXICITY IN NONRODENTS ....................................................... 94 7 GENETIC TOXICOLOGY .................................................................................... 122 8 CARCINOGENICITY ........................................................................................... 171 9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 204 9.1 FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................. 204 9.2 EMBRYONIC FETAL DEVELOPMENT ................................................................... 223 9.3 PRENATAL AND POSTNATAL DEVELOPMENT....................................................... 245 10 SPECIAL TOXICOLOGY STUDIES................................................................. 265 11 INTEGRATED SUMMARY AND SAFETY EVALUATION............................... 269 12 APPENDIX/ATTACHMENTS........................................................................... 277 2 NDA 22-512 Patricia Harlow, Ph.D. Table of Tables Table 1: Reviewer's Summary of Specified Impurities .................................................. 22 Table 2: Sponsor's Summary of Selectivity for Thrombin - Study U00-1351................. 34 Table 3: From Sponsor's Tables – Study U00-1457 – Coagulation Assays .................. 35 Table 4: Reviewer’s Summary - Activity of Forms of Dabigatran .................................. 36 Table 5: Sponsor's Summaries – Rabbit Venous Thrombosis – Study U06-1567......... 40 Table 6: Sponsor's Summary - Study U02-1700 ........................................................... 41 Table 7: Sponsor's Tables - Study U00-1588................................................................ 42 Table 8: From (b) (4) Study 8810448.......................................................................... 43 Table 9: From Sponsor's Body Temperature Tables – Study U05-1533 ....................... 45 Table 10: Modification of Sponsor's Tables – Study U06-1056..................................... 47 Table 11: Reviewer's Summary of Ranges of Individual Values – Study U06-1056...... 48 Table 12: Sponsor’s Summary Tables – Study U09-1332-02 ....................................... 51 Table 13: Sponsor's PK Overview Tables - Rats and Rabbits....................................... 52 Table 14: Sponsor's PK Overview Tables - Monkeys and Mice .................................... 52 Table 15: Sponsor's Summary – Study U05-2159 ........................................................ 53 Table 16: Sponsor’s Tables – Overview of Metabolites in Plasma................................ 57 Table 17: Sponsor's Overview of Metabolites in Urine and Feces ................................ 58 Table 18: Sponsor’s Summary - Protein Binding – Studies U00-1294 and U06-1211 .. 59 Table 19: Sponsor's Tables – Punched Samples – Study U00-1096 ............................ 60 Table 20: Sponsor's Tables – Radioluminography - Study U00-1096 ........................... 61 Table 21: Sponsor's Tables – Placental Transfer - Study U02-1372............................. 62 Table 22: Reviewer's Summary - Study U99-1767........................................................ 67 Table 23: Reviewer's Modification of Sponsor Tables - Study U99-1134...................... 67 Table 24: Reviewer's Summary - Study U05-1339........................................................ 68 Table 25: Reviewer’s Summary – Enzyme Kinetics – Study U07-1421 ........................ 68 Table 26: Sponsor's Tables – Study U99-1092............................................................. 71 Table 27: Sponsor’s Overview of Excretion in Animals ................................................. 71 Table 28: Sponsor's Tables – Study U06-1452............................................................. 72 Table 29: Reviewer's Summary of TK from Multiple Toxicology Studies......................
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