1 Presented at the May 29, 2003 meeting of the Cardiovascular and Renal Drugs Advisory Committee by Donna Griebel, M.D. Venkat Jarugula, Ph.D. Leslie Kenna,

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1 Presented at the May 29, 2003 meeting of the Cardiovascular and Renal Drugs Advisory Committee by Donna Griebel, M.D. Venkat Jarugula, Ph.D. Leslie Kenna, Ph.D.

2 Review Team Clinical –George Benson, MD –Marcea Whitaker, MD Office of Drug Safety –Debra Boxwell, Pharm D –Paula Gish, R. Ph. –Evelyn Farinas, R.Ph. –Sally Singer, R. Ph. –Melissa Truffa, R. Ph. –Ron Wassel, Pharm D Mark Avigan, MD Clinical Pharmacology –Ameeta Parekh, Ph.D. –Venkat Jarugula, Ph.D. –Leslie Kenna, Ph.D –DJ Chatterjee, Ph.D. –He Sun, Ph. D. Biostatistics –Mike Welch, Ph.D –Mahboob Sobhan, Ph.D –Sue Jane Wang, Ph.D

3 Mean QTc change vs Placebo Dose related QTc increase for alfuzosin QTc increase higher with Bazett and Fridericia QT effect lowest with Holter monitor method -Time-course effect on QT not captured with Holter monitor method

4 Outliers (# of subjects)

5 Concentration-QT relationship (Individual correction)

6 5 mg Vard mg TID Erythromycin 10 mg Vard mg TID Indinavir 5 mg Vard mg QD Ketoconazole 5 mg Vard mg BID Ritonavir Increase in Vardenafil Exposure Due to Drug Interaction 2.5 mg, 5 mg, 10 mg, 20 mg Vardenafil Proposed single doses 10 mg, 80 mg Vardenafil QT Study Vardenafil Drug-Drug Interaction Potential

7 Vardenafil - Ritonavir Drug Interaction Vardenafil Plasma Concentration (ng/mL) Time (hr) Vard 5 mg + RIT 600 mg BID Vard 80 mg Vard 5 mg C MAX 86 ng/mL; t 1/2 4 hr; AUC ng*hr/mL C MAX 2 ng/mL; t 1/2 3 hr; AUC ng*hr/mL C MAX 30 ng/mL; t 1/2 26 hr; AUC ng*hr/mL

8 ____ = Trend for pooled data____ = Trend for individual data QTcF (msec) Vardenafil Plasma Concentration (ng/mL) Exposure-Response: By Subject

9 ALPHA 1 - ADRENERGIC RECEPTOR BLOCKERS Over 110 million prescriptions since 1998

10 Class Effects: PHOSPHODIESTERASE TYPE V INHIBITORS Viagra®/sildenafil citrate (58 million prescriptions up to 12/21/02 in US) 1

11 Moxifloxacin Post-Marketing Experience 19 million patients exposed 15 cases of Torsade reported 9 U.S. 6 Foreign Risk Factors –Female = 11 –Age > 70 = 9 –History of cardiac disease, electrolyte = 8 –Concomitant drugs = 5