# Presentation: 844928

## Viagra (sildenafil citrate): Extensive Clinical and Post-Marketing Experience

- Michael Sweeney, MD
- Senior Medical Director
- Pfizer Inc

## Erectile Dysfunction (ED) and Cardiovascular (CV) Disease

- ED is primarily a vascular condition
- Major risk factors for ED and CV disease are virtually identical
- Age
- Hypertension
- Diabetes
- Hypercholesterolemia
- Smoking, obesity, sedentary lifestyle, etc.
- Profile of typical ED patient
- age generally over 50
- multiple risk factors and/or CV disease
- multiple concomitant medications

## Cardiovascular Events in the ED Population 

- Approximately 400,000 sudden cardiac deaths occur in the United States (US) per year (~ 1 per minute)
- Overwhelming majority of these patients have coronary artery disease
- Baseline rate of myocardial infarction (MI) in average 50 year old US male is 1-2% per year
- Men with ED have about twice the baseline risk of MI
- Risk of MI is doubled within 2 hours after sexual intercourse in men with or without CV disease
**	****Therefore, CV events are expected to occur in the ED population**

## The Viagra Experience

- Viagra approved by FDA March 1998
- Currently approved in 120 countries
- In 5 years:
- Over 20 million patients worldwide
- Over 1 billion doses taken
- Viagra has been in clinical research for >10 years
- More than 13,000 patients in clinical studies with greater than 13,000 patient-years of observation
- More than 26,000 patients followed in a post-marketing surveillance study in UK
- ~ 200 independent clinical publications (> 10,000 patients)

## Post-Marketing Data

- Over 20 million patients treated worldwide
- Many have cardiovascular (CV) risk factors
- No reports of Torsade de Pointes (TdP)
- Two cases reporting “QT prolongation” temporally related to concomitant medications known to prolong QT interval

## Post-Marketing Data: Case reports

- One consumer report of QTc prolongation temporally associated with the introduction of cisapride
- No clinical events reported
- Patient had taken Viagra for 2 years prior to cisapride without adverse effects
- One healthcare professional report of QT prolongation in temporal association with sotalol
- 77 y.o. male with multiple CV risk factors
- 3 weeks after last dose of Viagra

## Post-Marketing Data:Case Analysis

- Although there are limitations in interpreting spontaneous adverse event reports, the primary purpose is to identify signals
- An analysis has recently been published concluding: “...reports of death in men prescribed sildenafil that were submitted to the FDA led us to conclude that there did not appear to be an increase in deaths due to MI above expected numbers.”
- Wysowski, DK et al. Comparisons of Reported and Expected Deaths in Sildenafil (Viagra) Users. *Am J Cardiol* 2002: 89;1331-1334

## Post-Marketing Data

- Prescription Event Monitoring (PEM) study completed in “real world” clinical practice in UK
- 26,000 men prescribed Viagra for ED
- 42,000 patient-years of observation
- No cases of TdP or prolonged QTc reported
- Rate of CV events, including MI and sudden death, were consistent with rates that national statistics would predict, even allowing for underreporting

## Clinical Trial Data

- Over 100 completed clinical trials
- More than 13,000 patients treated with Viagra
- More than 6,000 patients with placebo
- The rate of MI and CV adverse events were comparable to placebo
- The number of sudden death cases was well within the expected rate of sudden death from epidemiological data in an age-adjusted general population

## Relevance of Study 10929 to Viagra

- Sildenafil has absolute oral bioavailability of 40%
- The most potent CYP 3A4 inhibitors increase Cmax less than 4-fold
- 400mg sildenafil (4 X maximum recommended dose) leads to peak plasma levels that exceed those encountered in normal clinical practice
- Mean change of QTc of less than 10msec after 400mg of sildenafil (study 10929) consistent with no preclinical signal and no reports of TdP

## Viagra Experience: Summary

- No cases of TdP reported post-marketing in over 20 million patients worldwide
- No clinically relevant change in QT/QTc observed in clinical studies
- Incidence of CV events similar to placebo in studies of 13,000 patients
- 	**Viagra has extensive clinical and real world experience – with no clinically relevant effect on cardiac repolarization**

## Viagra Experience: Summary

- Viagra has a wide margin of safety
- relatively high bioavailability and short half-life
- CYP 3A4 inhibitors do not compromise its safety
- Safety and efficacy profiles may not be applicable across compounds with different PK and structural characteristics
- Viagra is the only PDE5i with extensive “real world” data in millions of patients to confirm a lack of any pro- arrhythmic effects
**	****Viagra has a demonstrated safety and efficacy profile through 5 years post FDA approval**

## Viagra Experience: Final thoughts 

- Very positive benefit:risk ratio for ED patients with or without CV disease
- Now being used extensively in heart failure, heart transplant, and other serious cardiac patients
- Encouraging efficacy data in adult and pediatric pulmonary hypertension with no new safety signals
- 	**Viagra has improved the lives of many men with ED and their partners**