August 22, 1996

Dear Health Care Professional:

Wyeth-Ayerst Laboratories and Interneuron Pharmaceuticals, Inc. would like you to be aware that a section of the Redux prescribing information is being updated.

Based on the final report of the International Primary Pulmonary Hypertension Study (IPPHS), an epidemiologic study that looked at the relationship between anorexigens and a rare, serious, and life-threatening cardiopulmonary disorder, primary pulmonary hypertension (PPH), the companies and the U.S. Food and Drug Administration (FDA) have met to evaluate the data and discuss labeling revisions.

Based on a preliminary evaluation of the IPPHS data, provided by the investigators and reviewed prior to the approval of Redux, the risk of PPH in persons who have used anorexigens for 3 or more months was about 9 times higher than in non-users. PPH is estimated to occur in the general population at 1 to 2 cases per million adults per year, and the current labeling for Redux estimates the risk at 18 cases per million for persons using the drug longer than 3 months. In the final report, the risk was calculated to be about 23 times higher for patients using anorexigens for 3 or more months compared to non-users. The incidence of PPH for patients taking anorexigens, including Redux, is now estimated to be between 23 and 46 cases per million patients per year.

There are no new data in the IPPHS final report. The preliminary report differed from the final report because investigators reclassified and included 10 previously excluded cases: some where compounded mixtures of anorexigens were used, and some where information about anorexigens was incomplete.

Although the incidence of PPH for patients taking anorexigens remains small, PPH is a serious disorder with an estimated 4-year mortality rate of 45%. Therefore, it is very important that Redux not be prescribed for cosmetic weight loss. Redox is indicated for use only in those patients who have a body mass index (BMI) of at least 30 kg/m squared (which is approximately 30 percent over desirable weight) or a BMI of at least 27 kg/m squared (which is approximately 20 percent over desirable weight) in the presence of other risk factors (e.g., hypertension, diabetes or hyperlipidemia).

In order for the labeling of Redux to be consistent with the final IPPHS report and to allow you to counsel your patients with accurate information, we are working with FDA to revise product labeling appropriately. In the interim, this letter provides an overview of the IPPHS data to use as a reference in treating your obese patients.

As indicated in the current labeling, patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope, or lower extremity edema. These patients should be evaluated for the etiology of these symptoms and the possible presence of PPH.

Obesity is a serious medical problem in the United States. Redux, combined with a reduced-calorie diet, is indicated for the management of obesity, including weight loss and maintenance of that weight loss. In clinical trials, Redux helped produce a significant reduction in weight during the first 4 to 6 months, and that loss was maintained during the year-long therapy. The safety and effectiveness of Redux beyond one year have not been determined.

Contraindications, Warnings, and Side Effects

Redux (dexfenfluramine hydrochloride capsules) C-IV should not be used in patients hypersensitive to dexfenfluramine or related compounds; in patients with diagnosed pulmonary hypertension; or in patients taking (or within 14 days of discontinuing) monamine oxidase (MAO) inhibitors. Redux should not be administered to patients using other serotonergic drugs. Redux is not recommended for women who are pregnant or nursing or for pediatric patients. In animals receiving high doses of Redux for short periods of time resulting in brain concentrations approximately 10 times those seen in humans, neurochemical changes were observed. The dose and brain serotonin concentration of dexfenfluramine may affect reversibility. The relevance of these findings to humans is not known. The most commonly reported adverse effects are diarrhea, dry mouth, and somnolence. The adverse effects were generally mild and transient.

Additional Information

Enclosed for your information is the current product insert regarding Redux. We will forward to you the revised version once our discussions with the FDA are complete.

The medical community can further our understanding of adverse events by reporting all cases to Wyeth-Ayerst at 1-800-934-5556 or to the FDA MedWatchprogram by phone 1-800-FDA-1088, by fax at 1-800-FDA-0178 or modem 1-800-FDA-7737 or by mail:

MedWatch, HF-2
FDA
5600 Fishers Lane
Rockville, MD 20857

For information regarding Redux, please don't hesitate to contact your Wyeth-Ayerst sales representative or call the company's medical information line at 1-800-934-5556.

Sincerely,

Marc W. Deitch, M.D.
Senior Vice President, Medical Affairs and Medical Director

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