Fenfluramine and dexfenfluramine withdrawn from the US market

Federal regulators and the manufacturers announced on September 15, 1997, that fenfluramine (Pondimin) and dexfenfluramine (Redux) were being withdrawn from the US market after data linked the appetite suppressants to heart-valve disease ^[1]. Phentermine, the other half of the "fen-phen" combination, was not withdrawn ^[1].

The signal surfaced publicly on July 8, 1997, when 24 cases of valvular heart disease were reported in women treated with fenfluramine and phentermine ^[1]. Valve lesions appeared on both sides of the heart, but a left-sided valve was affected in every case, and the tissue changes resembled those seen in carcinoid-induced valve disease, a serotonin-related syndrome ^[1]. Eight of those 24 patients also had pulmonary hypertension ^[2]. The FDA issued a public health advisory the same day and sent letters to 700,000 US health-care practitioners and institutions asking for similar reports ^[1].

What the data showed

By September 30, 1997, the FDA had received 144 spontaneous reports of valve problems tied to fenfluramine or dexfenfluramine, with or without phentermine ^[1]. Of the 132 reports with complete information, 113 (86%) met the agency's case definition of aortic regurgitation of mild or greater severity and/or mitral regurgitation of moderate or greater severity ^[1]. Of those 113 cases, 111 (98%) were in women, the median age was 44 (range 22 to 68), and the median duration of drug use was 9 months (range 1 to 39 months) ^[1]. Two percent had used fenfluramine alone, 14% dexfenfluramine alone, 79% fenfluramine plus phentermine, and 5% all three; none had used phentermine alone ^[1]. Twenty-seven patients (24%) needed valve-replacement surgery, and three of them died after surgery ^[1].

The decisive evidence came from five unpublished echocardiogram surveys of people taking the drugs who had no obvious heart symptoms. Across those surveys, 32.8% met the case definition (range 30.0% to 38.3%; 95% confidence interval 27.7%–38.9%) ^[1]. Preliminary population studies put the expected background rate at 5% or less ^[1]. Only 17% of those meeting the case definition had an audible murmur, which is why history and physical exam alone were judged insufficient to find the problem ^[1].

Exposure was enormous. About 14 million prescriptions for fenfluramine or dexfenfluramine had been written since 1995, implying an estimated 1.2 million to 4.7 million people exposed ^[1]. Court records put it at roughly 4 million people taking Pondimin from January 1995 to mid-September 1997 and 2 million taking Redux from June 1996 through September 15, 1997 ^[3].

Why it matters for patients

The fen-phen episode is the reference point many patients and clinicians still use when weighing weight-loss drugs. It shows how a widely used combination can be built on off-label prescribing: phentermine was approved in 1959 for short-term use of "a few weeks," fenfluramine in 1973 for short-term single-drug use, and dexfenfluramine in 1996 for longer-term use in markedly obese people, with safety beyond one year not established in trials ^[1].

It also shows what happens after a withdrawal. Federal health agencies told everyone exposed to the drugs, for any length of time, to have a medical history and cardiovascular exam, and recommended echocardiograms for defined groups, plus antibiotic prophylaxis before certain invasive procedures for those with valve lesions ^[1]. Key questions were left open at the time, including whether lesions resolve, progress or stay the same after stopping ^[1]. Roughly 18,000 people had sued American Home Products by the time class notice issued, and one Texas woman won $23.5 million in 1999 ^[2][3].

What happens next

November 14, 1997: HHS published interim public health recommendations for exposed patients ^[1]. 1999: American Home Products proposed a national class settlement reported at up to $3.75 billion, with a $1 billion fund for refunds, screening and services and a second fund starting at $650 million ^[2]. August 28, 2000: the federal court in the Eastern District of Pennsylvania approved the class settlement ^[3].

Correction: a previous version of this article cited the $3.75 billion figure for the approved settlement. That was the 1999 proposal ^[2]; the amount approved in 2000 was higher, and the widely quoted $13 billion figure refers to total later payouts, not a single judgment. The specific approved and final totals are not documented in the sources cited here.