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Application Type NDA Submission Number 50-679 Reviewer Name CLINICAL REVIEW Application Type NDA Submission Number 50-679 Reviewer Name Peter Kim, MD, MS Review Completion Date 1/20/09, revised 4/6/09 Established Name Cefepime Trade Name Maxipime Therapeutic Class Cephalosporin (4th generation) Applicant Bristol-Myers Squibb (BMS) Formulation Parenteral Dosing Regimen Variable (from 500 mg q12h to 2 gm q8h) Indications Pneumonia, Empiric Therapy for Febrile Neutropenic Patients, Uncomplicated and Complicated Urinary Tract Infections (including pyelonephritis), Uncomplicated Skin and Skin Structure Infections, Complicated Intra-abdominal Infections Intended Population Patients aged > 2 months 1 Table of Contents 1 EXECUTIVE SUMMARY .....................................................................................................................................3 1.1 RECOMMENDATION ON REGULATORY ACTION ...................................................................................................3 1.2 RECOMMENDATION ON POSTMARKETING ACTIONS ............................................................................................3 1.2.1 Risk Management Activity.........................................................................................................................3 1.2.2 Post marketing requirements......................................................................................................................4 1.2.3 Other Phase 4 Requests..............................................................................................................................4 1.3 SUMMARY OF CLINICAL FINDINGS......................................................................................................................4 1.3.1 Brief Overview of Clinical Issue................................................................................................................4 1.3.2 Efficacy ......................................................................................................................................................4 1.3.3 Safety .........................................................................................................................................................5 2 INTRODUCTION AND BACKGROUND............................................................................................................6 2.1 REGULATORY ACTIVITY (ABRIDGED VERSION)..................................................................................................6 2.2 OTHER RELEVANT BACKGROUND INFORMATION .............................................................................................14 3 DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY ..........................................................26 3.1 REVIEW STRATEGY ...........................................................................................................................................26 3.2 THE YAHAV ET AL. PAPER.................................................................................................................................29 3.3 CHARACTERIZATION OF THE BMS DATA REPOSITORY FOR CEFEPIME CLINICAL TRIALS ...................................33 4 INTEGRATED REVIEW OF SAFETY..............................................................................................................42 4.1 METHODS AND FINDINGS ..................................................................................................................................42 4.1.1 Deaths ......................................................................................................................................................50 4.111 Collaborative Work with Ana Szarfman, M.D., Ph.D...........................................................................140 4.112 Highlights from the analysis performed by Yu-te Wu, Ph.D. (Statistical reviewer, Quantitative Safety and Pharmacoepidemiology group) .................................................................................................................186 5 ADDITIONAL CLINICAL ISSUES..................................................................................................................220 5.1 SANZ ET AL. (2002).........................................................................................................................................220 5.2 CURRENT CEFEPIME SUSCEPTIBILITY .............................................................................................................225 5.3 MEDICAL OFFICER DISCUSSION ......................................................................................................................226 6 OVERALL ASSESSMENT ................................................................................................................................230 6.1 CONCLUSIONS .................................................................................................................................................230 6.2 RECOMMENDATION ON REGULATORY ACTION ...............................................................................................230 6.3 RECOMMENDATION ON POSTMARKETING ACTIONS ........................................................................................230 6.3.1 Risk Management Activity.....................................................................................................................230 6.3.2 Post marketing requirements..................................................................................................................231 6.3.3 Other Phase 4 Requests..........................................................................................................................231 6.4 LABELING REVIEW..........................................................................................................................................231 6.5 COMMENTS TO APPLICANT .............................................................................................................................232 7 APPENDICES......................................................................................................................................................233 7.1 REGULATORY ACTIVITY (UNABRIDGED VERSION WITH M.O. COMMENTS) ....................................................233 7.2 HIGHLIGHTS FROM THE ORIGINAL MO REVIEW OF BMS’S FIRST CEFEPIME NDA (COMPLETED IN 1994) .....254 7.3 ADDITIONAL INFORMATION FROM THE 1997 JOINT CLINICAL AND STATISTICAL REVIEW OF CEFEPIME AS EMPIRIC MONOTHERAPY FOR FEBRILE NEUTROPENIA ..........................................................................................256 7.4 CEFEPIME CLINICAL TRIALS INCLUDED IN THE META-ANALYSIS BY YU-TE WU, PH.D....................................302 7.5 LINE-BY-LINE LABELING REVIEW ..................................................................................................................305 7.6 CLINICAL REVIEW OF BMS’ SUBMISSION ENTITLED, “A META-ANALYSIS OF BMS RANDOMIZED CEFEPIME TRIALS”.................................................................................................................................................................306 8 REFERENCES ....................................................................................................................................................328 2 1 EXECUTIVE SUMMARY 1.1 Recommendation on Regulatory Action Due to its antibacterial activity against Gram-positive and Gram-negative pathogens, including Pseudomonas aeruginosa and Enterobacteriaceae; the lack of a clear, biologically plausible reason for the increased mortality observed in the meta-analysis by Yahav et al.1 [Lancet Infect Dis. 2007 May;7(5):338-48]; and the lack of a statistically significant mortality difference in the Agency’s meta-analysis (which included the studies in the Yahav meta-analysis plus additional studies not included in the Yahav analysis), the M.O. currently recommends that cefepime remain on the market and maintain all approved indications. The M.O. notes that only adequately powered and well-controlled prospective trials may definitively answer the question as to whether or not the use of cefepime is associated with increased mortality. However, given the practical limitations of executing such trials using a mortality endpoint, and in particular, additional trials to study cefepime as empiric monotherapy in febrile neutropenic patients, the following additional risk management activities will be recommended. 1.2 Recommendation on Postmarketing Actions 1.2.1 RISK MANAGEMENT ACTIVITY The M.O. recommends that the following risk management activities move forward. 1. The Agency, through the Office of Surveillance and Epidemiology (OSE), in conjunction with the Premier Healthcare Informatics database, is poised to perform a postmarketing analysis of mortality associated with the administration of cefepime versus comparable agents. 2. BMS, in conjunction with the (b) (4) Drug Utilization Database, is also poised to perform their own postmarketing analysis of mortality associated with the administration of cefepime versus comparable agents. 3. The following issue is currently under review. The Division may consider changing the dosing recommendations and/or mean inhibitory concentration (MIC) susceptibility breakpoints for P. aeruginosa and the Enterobacteriaceae. This inclusion of additional language in the “Microbiology” section of the U.S. label would improve consistency between the U.S. and EMEA product labels due to a change in bacterial resistance to cefepime (as well as other antibacterial agents). 4. The Division
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