Manufacturers and FDA withdraw fenfluramine and dexfenfluramine over heart valve damage

Fenfluramine (Pondimin) and dexfenfluramine (Redux) were withdrawn from the U.S. market on September 15, 1997, in an announcement by their manufacturers and the Food and Drug Administration after reports linked the appetite suppressants to damaged heart valves and pulmonary hypertension ^[1]. Phentermine, the "phen" in the combination widely called fen-phen, was not withdrawn ^[1].

The action followed a July 8, 1997, FDA public health advisory and letters from the agency to 700,000 U.S. health care practitioners and institutions asking about similar patients ^[1]. Investigators at the Mayo Clinic and MeritCare Medical Center in Fargo, North Dakota, had reported 24 patients who took fenfluramine plus phentermine and had unusual valvular changes with regurgitation on both sides of the heart; eight also had pulmonary hypertension, and all 24 had symptoms and heart murmurs ^[2].

By September 30, 1997, the FDA had received 144 provider-initiated reports involving fenfluramine or dexfenfluramine, with or without phentermine, in connection with valvulopathy. Of the 132 reports with complete information, 113 (86%) met the case definition of aortic regurgitation of mild or greater severity and/or mitral regurgitation of moderate or greater severity ^[1]. Among those 113, 111 (98%) were women, the median age was 44 (range 22 to 68), the median duration of drug use was 9 months (range 1 to 39 months), and 87 (77%) had symptoms. Twenty-seven (24%) needed cardiac valve-replacement surgery, and three of those patients died after surgery ^[1].

Five independent echocardiographic surveys of people who had taken one of the drugs, alone or with phentermine, found valvular disease meeting the case definition in 30.0% to 38.3% of patients, an overall prevalence of 32.8% (95% confidence interval 27.7% to 38.9%) ^[1]. The report put the expected prevalence of regurgitation meeting the same definition in the general adult population at roughly 5% or less ^[1]. Prevalence rose with longer use: 22% for less than 3 months of exposure, 22% for 3 to 5 months, and 35% for 6 months or more ^[1]. A separate account reported that 86 of 271 patients who took fen-phen for 6 to 24 months had significant indications of valvular regurgitation, as did 6 of 20 patients who took dexfenfluramine, with or without phentermine ^[2]. The MMWR stated that whether these lesions generally resolve, progress or remain unchanged after the drug is stopped had not been determined ^[1].

Since 1995, about 14 million prescriptions had been written for either fenfluramine or dexfenfluramine, and the report estimated that 1.2 million to 4.7 million Americans had been exposed ^[1]. Court records put the number who took Pondimin between January 1995 and mid-September 1997 at about 4 million, and the number who took Redux between June 1996 and September 15, 1997 at 2 million ^[3]. None of the 113 case patients used phentermine alone ^[1]. Phentermine had been approved in 1959 only for single-drug, short-term use of "a few weeks"; fen-phen was a combination used far more widely and for longer periods than that label allowed ^[1].

Why it matters for patients

The government's interim guidance in November 1997 recommended that everyone exposed to fenfluramine or dexfenfluramine, for any length of time, have a medical history and cardiovascular examination, and that echocardiographic evaluation be performed for certain exposed patients ^[1]. The American Heart Association and American College of Cardiology said all exposed people should see a doctor and be examined, that those with cardiopulmonary problems should have an echocardiogram, and that all such patients should have one before invasive procedures for which 1997 guidelines recommend preventive antibiotics; the groups did not recommend echocardiograms for everyone who had taken the drugs ^[2].

The court that approved the national settlement said people who took these diet drugs for more than three or four months are at increased risk of asymptomatic valvular heart disease and that a screening echocardiogram is appropriate for them. It added that patients with FDA-positive levels of regurgitation need antibiotic prophylaxis and ongoing medical surveillance, and that serious regurgitation warrants compensation ^[3]. As of class notice, about 18,000 people who used Pondimin or Redux had filed lawsuits against American Home Products ^[3].

What happens next

American Home Products agreed in 1999 to pay as much as $3.75 billion, then described as the largest settlement involving a U.S. pharmaceutical firm ^[2]. The court approved the settlement on August 28, 2000 ^[3]; corrected accounts put the court-approved value at $4.75 billion, later valued at roughly $7.65 billion, while the frequently quoted $13 billion figure is a 2003 Forbes estimate of total Wyeth payouts on Pondimin and Redux claims, not a single judgment.

The program refunded drug costs, paid for medical screening and additional services, and paid cash to claimants with documented regurgitation, with up to $1.5 million for people who developed significant mitral regurgitation within 14 years of final approval ^[2]. Payments were scheduled over 15 years ^[2], and the court's order described a registry and roughly 20 years of medical monitoring ^[3].