At the present time, no cases of heart valve disease meeting FDA's case definition have been reported with phentermine alone. Analysis of the data points to an association of heart valve disease with fenfluramine and dexfenfluramine.

The type of valve disease that FDA believes may be associated with fenfluramine and dexfenfluramine is an extremely unusual type of drug reaction. Because valve disease is not usually associated with drug use, it is not normally screened for in human clinical testing of drugs. Since valvular heart disease is not screened for in clinical trials, it would usually not be detected unless patients developed symptoms. No cases were detected in 500 patients followed for one year in a clinical trial of dexfenfluramine.

Furthermore, asymptomatic heart valve disease (heart valve disease without symptoms) would not likely be detected in patients taking the drugs as part of a weight loss program. The number of patients who have been reported to have symptoms of heart valve disease associated with recent exposure to the drugs has been very small, compared to the number of recent prescriptions, although there may be a delay in the development of symptoms. And even in symptomatic patients, the link between the symptoms and drug use may not be obvious because such a reaction is not common. These factors may explain why this problem was not discovered earlier. During the last few years, there has been a marked increase in amount and duration of use of fenfluramine, as it became widely prescribed as part of the fen-phen regimen.. In 1992, articles were published about study results suggesting that the combined use of phentermine and fenfluramine would result in significant weight loss when used over an extended period of time.

The results of these studies were not reviewed by FDA, and the conclusion about long-term use of the combination of drugs has not received FDA approval. The increased magnitude and duration of use probably led to an increase in the number of cases of symptomatic heart valve disease, which may have contributed to the recent recognition of this association.

With respect to dexfenfluramine (Redux), which was approved on April 29, 1996, the labeling states that safety has not been shown for longer than one year of use. This reflects the length of the study upon which dexfenfluramine was approved. It was a one-year European study of 1,000 subjects, half of whom were treated with dexfenfluramine. The study population was 80 percent women with an average age of 41. Heart disease was not noted in the study. A follow-up study directed toward uncovering heart disease after termination of the study was not performed because there was no reason to believe at that time that the heart was affected.

In addition, dexfenfluramine had been marketed in Europe for over a decade without detection of an association between dexfenfluramine and heart valve problems. FDA is currently trying to obtain such follow-up.

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