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Pre-Approval Efficacy and Safety Data

Pre-Approval Efficacy and Safety Data. John Alexander M.D., M.P.H. Medical Team Leader Division of Anti-Infective & Ophthalmology Products, CDER/FDA. Overview. Efficacy Data Acute Exacerbation of Chronic Bronchitis (AECB) Acute Bacterial Sinusitis (ABS) Community-Acquired Pneumonia (CAP)

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Pre-Approval Efficacy and Safety Data

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  1. Pre-Approval Efficacy and Safety Data John Alexander M.D., M.P.H. Medical Team Leader Division of Anti-Infective & Ophthalmology Products, CDER/FDA

  2. Overview • Efficacy Data • Acute Exacerbation of Chronic Bronchitis(AECB) • Acute Bacterial Sinusitis (ABS) • Community-Acquired Pneumonia (CAP) • Multi-Drug Resistant Streptococcus pneumoniae (MDRSP) • Safety Data • Controlled Clinical Trials • Foreign Post-Marketing

  3. Acute Exacerbation of Chronic Bronchitis • Two Studies with the Original NDA • Study 3003 • Telithromycin 800 mg QD for 5 days • Amox/Clav 500mg/125mg TID for 10 days • Study 3007 • Telithromycin 800 mg QD for 5 days • Cefuroxime Axetil 500 mg BID for 10 days • One Study in the Resubmission • Study 3013 • Telithromycin 800 mg QD for 5 days • Clarithromycin 500 mg BID for 10 days

  4. Acute Exacerbation of Chronic Bronchitis

  5. Acute Exacerbation of Chronic Bronchitis • Pathogen Analyses in Briefing Package • Bacteriological Success for H. influenzae • Original NDA • Telithromycin 15/25 (60.0%) • Comparators 15/17 (88.2%) • Resubmission • Telithromycin 27/35 (77.1%) • Clarithromycin 30/36 (83.3%)

  6. Acute Bacterial Sinusitis • Three Studies with 1st Review Cycle • Study 3002 • Telithromycin for 5 or 10 days, uncontrolled • Study 3005 • Telithromycin for 5 days or 10 days • Amox/Clav 500mg/125mg TID for 10 days • Study 3011 • Telithromycin 800 mg QD for 5 days • Cefuroxime Axetil 250 mg BID for 10 days • No New ABS Studies in the Resubmission

  7. Acute Bacterial Sinusitis

  8. Acute Bacterial Sinusitis • Pathogen Analyses in Briefing Package • Comparable H. influenzae Cure Rates for Telithromycin and Cefuroxime (82-86%) • Outcomes for Penicillin- and Erythromycin-Resistant S. pneumoniae • No Specific Claim for ABS due to MDRSP

  9. Community-Acquired Pneumonia • Original NDA Studies • Study 3001 • Telithromycin 800 mg QD for 10 days • Amoxicillin 1g TID for 10 days • Study 3006 • Telithromycin 800 mg QD for 10 days • Clarithromycin 500 mg BID for 10 days • Study 3009 • Telithromycin 800 mg QD for 7-10 days • Trovafloxacin 200 mg QD for 7-10 days • Open-Label Studies 3000, 3009OL, 3010

  10. Community-Acquired Pneumonia

  11. Community-Acquired Pneumonia

  12. MDRSP in CAP • Two New CAP Studies in Resubmission • Study 4003 • Telithromycin for 5 days or 7 days • Clarithromycin 500 mg BID for 10 days • Study 3012 • Open-label, Telithromycin for 7 days • Resubmission Analyses Focused on Resistant Pathogens

  13. MDRSP in CAPTelithromycin Cure Rates: CAP due to MDRSP

  14. Pre-Approval Safety • Ketolide (Related to Macrolide Class) • Animal Toxicology Studies • Hepatic, Cardiac (QT Prolongation) • Clinical Pharmacology • CYP3A4 and CYP2D6 Substrate • Strong CYP3A4 Inhibitor • Phase 1 Studies • Liver Function Test Increases

  15. Safety Data in Phase 3 Trials

  16. Visual Adverse Effects • Recognized in Phase 3 Study Results • Ketek/Comp: 1.1%/0.28% • Females>Males, Younger Age (<40) • CYP3A4 Inhibitor 1.9%/0.4% • First or Second Dose (65%) • Mechanistic Studies (Dose-Response) • Appendix D of Briefing Document

  17. Cardiac Adverse Effects • QT Prolongation • On-therapy increase in QTc • QTc (Bazett’s) – 1.5 msec Increase • QTc (Fridericia’s) – 3.8 msec Increase • Careful Review of Cardiac Adverse Events in Phase 3 Trials • Additional Phase 1 Study of QTc • Elderly, Renal Impairment, CYP3A4 Inhibitor

  18. Hepatic Adverse Effects • LFT Increases in Phase 3 Trials • Appendix B of Briefing Document • Serious Hepatic AE • 76 y/o Female with CAP • 50 y/o Finnish Man with CAP • Led to Design of Study 3014

  19. Foreign Post-Marketing • Approximately 3.7M Exposures Ex-US as of January 2003 • France, Germany, Italy, Spain, Mexico, Brazil • Other EU, Latin American, International • Total 2345 Reports in 932 Patients • Focus on Visual, Hepatic, Myasthenia Gravis • Appendix C of Briefing Package

  20. Foreign Post-Marketing • Visual AE – 415 AE in 315 Patients • 33.8% of All Patients in Post-Marketing • Serious Visual AE: 101 Reports in 66 Patients • Counts F>M, Age (<40, 40-55, >55) • Severe Visual Effects – ADL • Most (>75%) Recovered • Limited Information in Passive Reports

  21. Foreign Post-Marketing • Hepatic AE - 90 Reports in 43 Patients • 24 Female: 16 Male • Patterns of Liver Injury • Most Unclear (24/43) • Cholestatic (12) and Cytolytic (5) • Limited Data for Causality • 1 Death – Multiple Confounding Factors • Hep. A, Q Fever, High-Dose Acetaminophen

  22. Foreign Post-Marketing • Exacerbations of Myasthenia Gravis • 13 Patients – Likely Cases • 6 Patients – Probable Cases • Sx: Varied from Ptosis/Weakness to Respiratory Failure

  23. US Approval • Approved on April 1, 2004 (400 mg Tabs) • Indications for mild to moderate CAP (including MDRSP), ABS and AECB • Warnings: QT Effects, Myasthenia Gravis Exacerbation, and C. difficile Colitis • Precautions: Hepatic Dysfunction, Visual AE (Driving Precautions), Drug Interactions

  24. US Post-Marketing • Continued Monitoring • 300 mg Tablets for Patients with Severe Renal Impairment • Labeling Supplement – Appendix E • Precautions: Syncope Usually with Vagal Syndrome (Driving) • 56 Reports in Syncope/LOC Preferred Terms as of July 1, 2004 • Reduced to 11 Cases after Review

  25. Back-Up Slides Return to meeting agenda.

  26. QT Prolongation Study (1063) • Elderly Patients with Renal Impairment • A: Ketoconazole 400 mg QD alone • B: Ketoconazole + Telithromcyin 800 mg QD • C: Ketoconazole + Clarithromycin 500 mg BID • 1.6 Fold Increase in Cmax of Telithromycin • 2.7 Fold Increase in AUC of Telithromycin • Change in QTc(N) from Day -1 to Day 5 • A: -4.5 msec • B: 6.5 msec • C: 11.7 msec

  27. Acute Sinusitis

  28. Return: Return to meeting agenda. Anti-Infective Drugs Advisory Committee in Joint Session with the Drug Safety and Risk Management Advisory Committee. December 14 & 15, 2006

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