LEVAQUIN® (levofloxacin) Presentation to AIDAC October 20, 1999

12/1/99


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Table of Contents

LEVAQUIN® (levofloxacin) Presentation to AIDAC October 20, 1999

FDA Approval: December 20, 1996

Community Acquired Pneumonia

Following FDA Approval 1996

Regulatory History

Rationale for the sNDA Clinical Program

Organization of Presentation

Summary - Dr. Bush

Organization of Presentation

Summary - Dr. Corrado

Organization of Presentation

Other Advisors Present

New Labeling Claim Sought (See Highlighted Text Below)

Levofloxacin Microbiological Activity Against Penicillin-Resistant Streptococcus pneumoniae

Activity of Levofloxacin Against Penicillin-Resistant Streptococcus pneumoniae

Overview

Microbiological Attributes of Levofloxacin Against Streptococcus pneumoniae

Diversity of Killing Mechanisms for ?-lactams and Quinolones in Streptococcus pneumoniae

Preferential Inhibition of E. coli DNA Gyrase

Preferential Inhibition of S. pneumoniae Topoisomerase IV by Quinolones

NCCLS Interpretive Standards for Streptococcus pneumoniae

Unrelated Resistance Mechanisms of Clinical Importance in S. pneumoniae

Lower Frequency of Selection of S. pneumoniae Quinolone Resistance by Levofloxacin

Simulated in vitro Model of Streptococcus pneumoniae Infection

No in vitro Selection of Levofloxacin-Resistant Pneumococci at Low Peak:MIC and AUC:MIC Ratios

Less Rapid Selection of Quinolone-Resistant S. pneumoniae by Levofloxacin

Minimal Effect of Single Mutations on Levofloxacin MICs in Isogenic Strains of S. pneumoniae

Effect of Multiple Mutations in Topo IV and DNA Gyrase on Levofloxacin MICs in Pneumococcal Isolates

Levofloxacin MICs in S. pneumoniae Strains With Efflux Mechanisms Selected in vitro by Ciprofloxacin

Increasing Resistance of S. pneumoniae to Penicillin and Erythromycin in the US

Multi-Drug Resistance in Penicillin-Resistant Streptococcus pneumoniae

The TRUST Studies (Tracking Resistance in the United States Today)

In Vitro Activity of Levofloxacin Against United States S. pneumoniae Clinical Isolates

Levofloxacin Activity Against United States S. pneumoniae Clinical Isolates (TRUST Studies)

Low Levofloxacin Resistance Across Sites in the TRUST Studies in 1997-99

In Vitro Activity of Levofloxacin Against Canadian S. pneumoniae Clinical Isolates

Susceptibility of S. pneumoniae in Asia and Europe 1997-1998

Number of Quinolone Prescriptions in Japan From 1993-1998

Efficacy of Levofloxacin in Murine Models of Infection With S. pneumoniae

Representative Dose-effect Relationship for Levofloxacin Administered Every 6 H Against S. pneumoniae HIP 1293 in the Murine Thigh Model of Infection

Relationship Between 24-h AUC/MIC Ratio and the Number of S. pneumoniae (7 Strains) in the Thighs of Neutropenic Mice After 24-h Therapy With Levofloxacin

Levofloxacin AUC/MIC ᡌ Predicts Efficacy Against PRSP in Murine Thigh Model

Conclusions

Levofloxacin

Levofloxacin

Penicillin Resistant S. pneumoniae

Why Consider Levofloxacin?

Characteristics to Be Considered in Choosing an Antibacterial

Levofloxacin

Levofloxacin Achieves High Plasma Levels ?g/ml

Levofloxacin 500 mg P.O. (Lung Biopsy of Lobectomy)

Pharmacokinetics: Levofloxacin Is Highly Bioavailable After Oral Administration

Levofloxacin Is Highly Distributed Into Pulmonary Tissue/fluid Levels: ELF

Levofloxacin Is Highly Distributed Into Pulmonary Tissue/fluid Levels: Alveolar Macrophage

Levofloxacin Clinical Trials

Pharmacodynamic Ratios

Levofloxacin Has Optimal Pharmacodynamic Properties

Pharmacokinetic Summary

Levofloxacin

Scope of Clinical Trials

Risk Factors for PRSP Infection

Levofloxacin Intent-to-treat Community Acquired Pneumonia Trials

Levofloxacin Clinical Trials

Levofloxacin Clinical Trials

Levofloxacin Clinical Trials

Levofloxacin

Levofloxacin Clinical Trials

Cross-Resistance of Clinical PRSP Isolates

In Vitro Summary

Levofloxacin

Levofloxacin Clinical Trials

Levofloxacin Clinical Trials

Levofloxacin Clinical Trials

Cumulative Experience for Severely Ill Evaluable Subjects with Pneumococcal Pneumonia

Levofloxacin Clinical Trials

Levofloxacin Clinical Trials

Posttherapy Clinical Success by Levofloxacin MIC - Evaluable Levofloxacin Subjects

Clinical Summary

Clinical Data Summary

Levofloxacin

Levofloxacin Clinical Trials

Phase III Studies: Other AEs of Interest

Worldwide Postmarketing Experience

U.S. Postmarketing Experience (12/96-8/99): Reports of Interest

Safety Summary

Conclusion

The Clinician’s Perspective

The Challenge of the Clinician

Present Options

Conclusion

Conclusion

Conclusion

New Labeling Claim Sought (See Highlighted Text Below)

Author: Ortho-McNeil Pharmaceutical