By the time fenfluramine and its sister drug, dexfenfluramine were recalled, an estimated 6 million Americans and an estimated 77 million people worldwide had used one drug or the other. "Fen-phenomenal Tort Battle Brewing," published in the ABA Journal (January 1998). In 1996 alone, it is estimated that over 18 million prescriptions were written for fenfluramine and phentermine - the two drugs that comprise the "Fen-Phen." Connolly, et al. "Valvular Heart Disease Associated with Fenfluramine-Phentermine," New England Journal of Medicine 337: 581-8 (August 28, 1997). The litigation that has grown out of this recall is massive, especially as it relates to the pharmaceutical defendants, although increasing numbers of healthcare providers are also being sued. Eventually, the "recall could grow into one of the biggest medical-liability cases in history, perhaps exceeding the anticipated $2.4 billion from silicone breast implants." "Who's to Blame for Redux and Fenfluramine?" published in Time (December 29, 1997).
A) What is Fen-Phen?
"Fen-Phen" is the term given to the combined use of the drugs fenfluramine (a.k.a "fen") (or the use of dexfenfluramine, a.k.a. "Redux")) and phentermine (a.k.a. "phen"). Fenfluramine and dexfenfluramine were developed by a French company called Les Laboratories Servier ("LLS"). LLS sold the United States licensing rights of fenfluramine to A.H. Robin, which sold it under the trade name "Pondimin" (also "Ponderol"). Additionally, Wyeth-Ayerst Laboratories, a division of American Home Products, sold fenfluramine in the United States. LLS sold the United States licensing rights of dexfenfluramine to Interneuron Pharmaceuticals Inc., a Lexington, Massachusetts company. Interneuron, in turn, licensed Wyeth-Ayerst Laboratories to sell dexfenfluramine under the trade name "Redux."
Phentermine has been sold by various manufacturers/distributors (and under various trade names), including Smith-Kline Beecham Pharmaceuticals (Fastin), Gate Pharmaceuticals (Adipex), Goldline Laboratories (generic Fastin), ION Laboratories (Zantryl), Richwood Pharmaceuticals (Oby-Cap), Abana Pharmaceuticals (Obenix), and Medeva Pharmacology Inc. (Ionamin). Rheingold, "Fen-Phen/Redux Diet Drugs," reprinted in 15 Mealey's Litigation Reports: Drugs & Medical Devices 22 (August 1, 1997).
Fenfluramine and phentermine were sold separately but prescribed in combination. Phentermine was approved by the Food and Drug Administration ("FDA") in March 1959; fenfluramine in June 1973; and dexfenfluramine in April 1996. "Questions Arise About FDA's Previous Approval of Diet Drug," in Medical Industry Today (September 17, 1997).
B) The Itch that Fen-Phen Scratched
Most researchers estimate that as many as 35% of Americans are overweight by accepted standards. Additionally, as many as one in four women and one in six men can be classified as obese. Other estimates of the percentage of obese Americans vary, but usually fall within the range of 20% to 30%. O'Donnell, "Diets and Obesity Drug Treatment," Journal of Pharmacy Practice, Vol. IX, No. 5 (October 1996).
The treatment of obesity is a multibillion-dollar industry: Americans spend over $30 billion yearly in weight loss efforts. Oeser D., "Obesity Part I: Epidemiology, Etiology and Pathophysiology, and Nonpharmacotherapeutic Treatments," The Internet Journal of Academic Physician Assistants Vol. 1N2 (1997). Numerous treatments have been attempted for obesity, including the individual prescription use of phentermine, fenfluramine, or dexfenfluramine. Phentermine and fenfluramine were approved for short-term (a few weeks) obesity therapy. Dexfenfluramine was approved for long-term use in order to maintain weight loss, but was only to be prescribed for those who were diagnosed as obese. "Fen-Phen: A Primer on Diet Drug Litigation," 3 Andrews Diet Drugs Litigation Reporter 18 (December 1997).
C) How Do the Individual Components of Fen-Phen Work?
Fenfluramine (and similarly, dexfenfluramine) triggers the release of serotonin - one of the many natural chemicals stored in the nerves which facilitate a nerve cell's ability to send messages to another nerve cell - into the system. Drugs which enhance serotonin levels are thought to provide a feeling of fullness. One of the common side effects associated with fenfluramine is the feeling of lethargy and, at times, depression. As an appetite suppressant, phentermine works by releasing norepinephrine, similar to adrenalin, into the system. Norepinephrine acts as a stimulant and also leaves the user with the feeling of fullness.
Neither fenfluramine nor phentermine individually garnered large market shares as appetite suppressants, primarily because of their disappointing results in achieving weight loss by users.
D) The Birth of Fen-Phen
While the combination of fenfluramine and phentermine was probably in use prior to May 1992, it was the publication of a study by Michael Weintraub, MD (then at the University of Rochester School of Medicine, now a director of Drug Evaluation at the FDA) entitled "Longterm Weight Control Study" in the May 1992 issue of Clinical Pharmacology and Therapeutics that is recognized as the spark that started the wide spread use of Fen-Phen.
Dr. Weintraub tested the combined use of fenfluramine and phentermine in 121 subjects who started on a weight-reduction diet program. After six weeks, the subjects were divided into two groups, the control group and the Fen-Phen group. After seven months, the group receiving the Fen-Phen showed significant weight loss in 80% of subjects compared to the control group still using conventional weight-reduction measures. The average weight loss for the Fen-Phen group was three times as large as the control group. Dr. Weintraub continued the study and placed all participants on Fen-Phen. Significant weight loss was reported. When subjects were randomly selected to be given a placebo instead of the Fen-Phen, they regained weight. Some participants who showed little or no weight loss on the original dosage schedule started to lose weight at a higher dose. By the end of the study, Dr. Weintraub reported that 80% of the participants who had been on the Fen-Phen diet for four years had lost 16% of their total body weight (an average of 34 pounds each). Weintraub, et al., "Longterm Weight Control Study," published in Clinical Pharmacology and Therapeutics, 51(5): 586-646 (May 1992).
According to Dr. Weintraub, "the idea of giving the two drugs together was that each would balance out the adverse effects of the other. Fenfluramine was well-known to give those taking it a feeling of malaise, whereas phentermine alone often gave patients the jitters." "FDA Yanks Two Diet Drugs Used In Popular Fat-Busting Pill Combos," published in Biotechnology Newswatch (October 6, 1997). The attraction of Fen-Phen was that this combination had a positive effect on appetite control as well as on mood.
With the publication of Dr. Weintraub's study the combination of Fen-Phen quickly became one of the drug industry's hottest sellers. In 1996 alone, the sale of Redux and Pondimin (a trade name for fenfluramine) brought over $305 million in revenue. It is estimated that at the height of its usage, 200,000 prescriptions for Redux and Pondimin were being filled each week. "Early Warning: Heart-Valve Problem That Felled Diet Pill Had Arisen Previously," published in Wall Street Journal A1 (December 11, 1997).
E) The Recall of Fen-Phen
The downfall of the Fen-Phen craze began on July 8, 1997, when Doctor Heidi M. Connolly of the Mayo Clinic reported, in a speech, a "new clinical observation of a possible relationship between heart valve disease and the weight loss medications Phentermine and Fenfluramine, commonly known as Phen-Fen [sic]." Mayo Clinic Phen-Fen Press Conference Transcript (July 8, 1997). This culminated in the voluntary recall of fenfluramine and dexfenfluramine from the market just two months later, on September 15, 1997.
The Mayo Clinic study identified 24 previously healthy women with an average age of 43 who were treated with the Fen-Phen combination for approximately 12 months. According to the study, all developed the same unusual form of heart valve disease. Even though the findings of the study were to be published in the New England Journal of Medicine in August 1997, Dr. Connolly felt the need to report her findings earlier because of the "potential public health implications...." Id.
On the same day that Dr. Connolly delivered her speech, the FDA issued a news release alerting physicians to the reports of valvular heart disease in women treated with a combination of fenfluramine and phentermine. The FDA stated that "[t]hese are drugs that should be taken only by obese patients in conjunction with a weight loss regimen that includes a reduced-calorie diet and an exercise program, in accordance with approved labeling." "Health Advisory On Fenfluramine/Phentermine For Obesity," FDA Public Health Advisory (July 8, 1997). In addition to the women cited in the Mayo Clinic study, the FDA noted that it had received reports of 33 cases of unusual abnormalities in mitral, aortic, and tricuspid heart valves in women between the ages of 30 and 72 who had been taking fenfluramine and phentermine for one month to 28 months. The FDA pointed out, however, that there was no conclusive evidence of a cause-effect relationship between use of the drugs and the development of valvular disease.
On August 27, 1997, researchers from the National Institute of Mental Health published an article entitled "Brain Serotonin Neurotoxicity and Primary Pulmonary Hypertension From Fenfluramine and Dexfenfluramine" published in The Journal of the American Medical Association (August 27, 1997). The researchers stated that fenfluramine and dexfenfluramine "have been demonstrated to damage brain serotonin neurons in animal studies." They also pointed out that it "is not known if such damage occurs in humans or if there are clinical consequences." Id.
On August 28, 1997, the New England Journal of Medicine published Dr. Connolly's article entitled "Valvular Heart Disease Associated with Fenfluramine-Phentermine", New England Journal of Medicine 337: 581-588 (1997). In the article, Dr. Connolly postulated that "the combination of fenfluramine and phentermine may potentiate the effect or concentration of circulating serotonin and result in valvular injury ... However, the precise process by which this might occur is not known." Id. Also on August 28, 1997, the FDA issued a press release stating that it was requesting that manufacturers of phentermine, fenfluramine, and dexfenfluramine stress the potential risk of combining fenfluramine and phentermine, and state the possible link between the use of these drugs and the development of cardiac valvular disease, in a black boxed warning at the beginning of the drug labels.
On September 2, 1998, researchers from the Massachusetts College of Pharmacy and Allied Health Sciences (MCP/AHS) and the Massachusetts Institute of Technology (MIT) stated at the International Congress of Obesity that the combination of "Fen-Phen" was potentially toxic because the two drugs taken together destroy the body's ability to control the amount of serotonin in blood plasma. According to the researchers, "too much serotonin damages blood vessels, particularly in the lungs, and may also harm heart valves." The researchers stressed that "[e]ach of these drugs has not caused these problems when taken alone."
Finally, on September 15, 1997, the FDA announced that it had asked manufacturers to voluntarily withdraw fenfluramine and dexfenfluramine from the market, and that the manufacturers had agreed. This action was apparently taken based on findings from doctors who had evaluated patients taking these two drugs by means of echocardiograms; such findings indicated that approximately 30 percent (a much higher than expected percentage) of patients who were evaluated had abnormal echocardiograms, even though they had no symptoms. In a Question and Answer Sheet accompanying the FDA press release, the FDA stated that phentermine was not being withdrawn because "no case of heart valve disease meeting FDA's case definition have been reported with phentermine alone." According to the FDA, "[a]nalysis of the data points to an association of heart valve disease with fenfluramine and dexfenfluramine."
F) The Litigation Flood
Following the withdrawal of fenfluramine and dexfenfluramine from the market, plaintiffs around the nation began to flood courts with complaints alleging that they had suffered injuries as a result of taking these drugs, or required medical monitoring to see if they developed any of the injuries which were allegedly caused by taking the drugs. The majority of the Fen-Phen litigation has been directed at the above-referenced manufacturers/distributors of the components of Fen-Phen, accusing them, among other things, of failing to warn users of health risks about which they knew or should have known. Increasingly, doctors and weight loss centers are also being drawn into the Fen-Phen suits, based on allegations of medical malpractice.