CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 201277Orig1s000 PHARMACOLOGY REVIEW(S) Tertiary Pharmacology/Toxicology Review From: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and Toxicology, OND IO NDA: 201277 Agency receipt date: 5/14/2010 Drug: gadobutrol Applicant: Bayer Healthcare Pharmaceuticals Inc Indication: gadolinium-based contrast agent (GBCA) to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system Reviewing Division: Division of Medical Imaging Products Background: The pharm/tox reviewer and team leader concluded that the nonclinical data support approval of gadobutrol for the indication listed above. Chronic nonclinical studies were not required for this application because of the acute use of the agent. Pharmacologic class: The Established Pharmacologic Class text phrase proposed for the highlights section of labeling is "gadolinium-based contrast agent". This phrase is not currently listed in the FDA list of Established Pharmacologic Class text phrases. Another phrase, paramagnetic contrast agent, is currently listed. However, recently approved PLR labeling for several other agents containing gadolinium and used for imaging have used the term "gadolinium-based contrast agent". Therefore, this may be the most appropriate term to use for gadobutrol under this application. Conclusions: The studies that were conducted are adequately summarized in the primary review. The findings appear to be consistent to those seen previously with this class of compounds with kidney being the primary target tissue. There are no outstanding nonclinical safety issues. I agree with the division pharm/tox conclusion that this application can be approved from a pharm/tox perspective. I agree with the labeling changes proposed in the primary pharm/tox review with a minor possible additional change that I discussed with the division pharm/tox supervisor. Reference ID: 2910688 1 --------------------------------------------------------------------------------------------------------- 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 02/25/2011 Reference ID: 2910688 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: 201-277 Supporting document/s: Original-1 Applicant’s letter date: May 14, 2010 CDER stamp date: May 14, 2010 Product: Gadovist 1.0® (Gadobutrol) Indication: Diagnostic MRI to detect and visualize areas of the central nervous system Applicant: Bayer HealthCare Pharmaceuticals, Inc., P.O. Box 1000, Montville, NJ 07045-1000 Review Division: Division of Medical Imaging Products (HFD-160) Reviewer: Olayinka A. Dina, Ph.D. Supervisor/Team Leader: Adebayo Laniyonu, Ph.D. Division Director: Rafel Dwaine Rieves, M.D. Project Manager: James Moore, Pharm.D, M.A. Template Version: September 1, 2010 Disclaimer Except as specifically identified, all data and information discussed below and necessary for approval of NDA 201-277 are owned by Bayer HealthCare Pharmaceuticals, Inc. or are data for which Bayer HealthCare Pharmaceuticals, Inc. has obtained a written right of reference. Any information or data necessary for approval of NDA 201-277 that Bayer HealthCare 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 described in the drug’s approved labeling. Any data or information described or referenced below from a previously approved application that Bayer HealthCare Pharmaceuticals, Inc. does not own (or from FDA reviews or summaries of a previously approved application) is for descriptive purposes only and is not relied upon for approval of NDA 201-277. Reference ID: 2905832 1 NDA No. 201-277 Reviewer: Olayinka Dina, Ph.D. TABLE OF CONTENTS 1 EXECUTIVE SUMMARY ......................................................................................... 8 1.1 INTRODUCTION .................................................................................................... 8 1.2 BRIEF DISCUSSION OF NONCLINICAL FINDINGS...................................................... 8 2 DRUG INFORMATION .......................................................................................... 14 2.1 DRUG ............................................................................................................... 14 2.2 RELEVANT INDS, NDAS, AND DMFS .................................................................. 16 2.3 DRUG FORMULATION ......................................................................................... 16 2.4 COMMENTS ON NOVEL EXCIPIENTS..................................................................... 18 2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 18 3 STUDIES SUBMITTED.......................................................................................... 19 3.1 STUDIES REVIEWED........................................................................................... 19 3.2 STUDIES NOT REVIEWED ................................................................................... 22 3.3 PREVIOUS REVIEWS REFERENCED...................................................................... 25 4 PHARMACOLOGY................................................................................................ 25 4.1 BRIEF SUMMARY................................................................................................ 25 4.1 PRIMARY PHARMACOLOGY ................................................................................. 25 4.2 SECONDARY PHARMACOLOGY ............................................................................ 34 4.3 SAFETY PHARMACOLOGY................................................................................... 34 5 PHARMACOKINETICS/ADME/TOXICOKINETICS` ............................................. 61 5.1 PK/ADME........................................................................................................ 61 5.3 TOXICOKINETICS ............................................................................................... 90 6 GENERAL TOXICOLOGY..................................................................................... 90 6.1 SINGLE-DOSE TOXICITY ..................................................................................... 90 6.2 REPEAT-DOSE TOXICITY .................................................................................. 106 7 GENETIC TOXICOLOGY .................................................................................... 123 8 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 138 9.1 FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................. 138 9.2 EMBRYONIC FETAL DEVELOPMENT ................................................................... 145 9.3 PRENATAL AND POSTNATAL DEVELOPMENT ....................................................... 161 9 LOCAL TOLERANCE........................................................................................... 169 10 SPECIAL TOXICOLOGY ................................................................................. 175 10.1 NEPHROGENIC SYSTEMIC FIBROSIS (NSF)........................................................ 175 11 INTEGRATED SUMMARY AND SAFETY EVALUATION............................... 228 12 APPENDIX/ATTACHMENTS........................................................................... 231 Reference ID: 2905832 2 NDA No. 201-277 Reviewer: Olayinka Dina, Ph.D. Table of Tables Table 1: Composition of Gadobutrol formulation, SH L562BB ...................................... 17 Table 2: Composition of other gadobutrol formulations used in nonclinical studies ...... 17 -1 -1 Table 3: Relaxivity values r1 and r2 at 0.47 Tesla [sec *(mmol/l) ]............................... 27 -1 -1 Table 4: Relaxivity values r1 and r2 at 2.0 Tesla [sec *(mmol/l) ]................................. 27 -1 -1 Table 5: Relaxivity values r1 and r2 at 1.5 Tesla [sec *(mmol/l) ]................................. 27 Table 6: T1 Shortening of gadolinium chelates at 1.5Tesla ........................................... 27 Table 7: Liberation of histamine from mast cells by gadobutrol..................................... 36 Table 8: Irwin test - Effect of Gadobutrol and Magnevist............................................... 39 Table 9: Effects of Gadobutrol or Magnevist on maximal electroshock-induced convulsions in mice ....................................................................................................... 41 Table 10: Effect of pretreatment with gadobutrol or Magnevist on maximal electroshock- induced convulsions in mice.......................................................................................... 43 Table 11: Effect of GBCAs on hERG-mediated potassium current ............................... 50 Table 12: Study Design (Report A08428)...................................................................... 55 Table 13: Treatment groups in Report 21000................................................................ 57 Table 14: Summary of single-dose Pharmacokinetic