The drug combination fenfluramine/phentermine, usually called fen-phen, was an anti-obesity treatment in the early 1990s that utilized two anorectics. Fenfluramine was marketed by American Home Products (later known as Wyeth) as Pondimin, but was shown to cause potentially fatal pulmonary hypertension and heart valve problems, which eventually led to its withdrawal in 1997 and legal damages of over $13 billion. Phentermine was not shown to have harmful effects.
Fenfluramine acts as a serotonin releasing agent, phentermine as primarily a norepinephrine releasing agent. Phentermine also induces the release of serotonin and dopamine, although to a far lesser extent than it induces the release of norepinephrine.
History
Fenfluramine as a single drug was first introduced in the 1970s, but was not popular because it only temporarily reduced weight. A 1984 study found a weight loss of 7.5 kg on average in 24 weeks, as compared to 4.4 kg under placebo. It sold modestly until the 1990s, when it was combined with phentermine and heavily marketed.
Testing on children in New York City
The State Psychiatric Institute, associated with Columbia University, the Research Foundation of the City University of New York, and Mount Sinai Medical Center tested fenfluramine intravenously on more than 100 Black and Hispanic boys between the ages of 6 and 10, with delinquent older brothers, to test the theory that delinquent behavior could be predicted by serotonin levels. These studies were conducted before the drug was pulled from the market in September 1997. In 1998, CNN reported that these organizations were under "evaluation" by the Office for Protection from Research Risks, an arm of the National Institutes of Health. An article in Nature reports that these tests were published as a study in Archives of General Psychiatry in 1997 and that "The New York trial, funded largely by the Lowenstein Foundation, with some support from the National Institute of Mental Health, was halted in 1995, two years before the drug was withdrawn." In 199 the New York Times reported that the Mount Sinai School of Medicine and the Research Foundation of the City University of New York were officially faulted by Federal research-ethics officials for conducting these tests. The article reports that the yearlong investigation found no misconduct by New York State Psychiatric Institute for these tests. This article reports the number of children involved in the study as 150, and states that none were harmed.
Harm and litigation
A similar drug, aminorex, had caused severe lung damage and "provided reason to worry that similar drugs ... could increase the risk of a rare but often fatal lung disease, pulmonary hypertension." In 1994, Wyeth official Fred Wilson expressed concerns about fenfluramine's labeling containing only four cases of pulmonary hypertension when a total of 41 had been observed, but no action was taken until 1996. In 1995, Wyeth introduced dexfenfluramine (the dextro isomer, marketed as Redux), which it hoped would cause fewer adverse effects. However, the medical officer of the Food and Drug Administration (FDA), Leo Lutwak, insisted upon a black box warning of pulmonary hypertension risks. After Lutwak refused to approve the drug, the FDA management had James Milton Bilstad, FDA Senior Drug Evaluator, sign it and approved the drug with no black box warning for marketing in 1996. European regulators required a major warning of pulmonary hypertension risks.
In 1996, a 30-year-old woman developed heart problems after a month of using fenfluramine/phentermine; when she died in February 1997, the Boston Herald devoted a front-page article to her. In August 1997 a paper in the New England Journal of Medicine (NEJM) from the Mayo Clinic discussed clinical findings in 24 people who had taken fen-phen. The authors noted that their findings suggested a possible correlation between mitral valve dysfunction and the use of these anorectic agents. The FDA alerted medical practitioners that it had received nine additional reports of the same type, and requested all health care professionals to report any such cases to the agency’s MedWatch program, or to their respective pharmaceutical manufacturers. The FDA subsequently received over a hundred additional reports of valvular heart disease in people taking fen-phen, fenfluramine alone or dexfenfluramine alone. The FDA requested that the manufacturers of fenfluramine and dexfenfluramine stress the potential risk to the heart in the drugs' labeling and in package inserts. The FDA continued to receive reports in 1997 of valvular heart disease in people who had taken these drugs. This disease typically involves the aortic and mitral valves.