Fen-phen and Redux: a tale of three drugs.

The story of how fen-phen and Redux came to be used by 6 million Americans is chilling.

This past summer, doctors at the Mayo Clinic in Rochester, Minnesota, reported a link between serious heart valve damage and use of the popular "miracle" diet drug regimen called fen-phen.(1) Fen-fluramine (the "fen" in fen-phen)--also known as Pondimin--and that drug's pharmaceutical cousin, dexfenfluramine--sold as Redux--were taken off the shelves in September. But the recall has come too late for the hundreds and possibly thousands of people who have already been injured by the drugs.

The story of how fen-phen and Redux came to be used by an estimated 6 million Americans is chilling. It is an account of dangerous and potentially deadly practices among the manufacturing, medical, and weight-loss industries. Fenfluramine and the other drug that makes up the fen-phen regimen, phentermine, have been on the market for more than two decades. Fenfluramine is an appetite suppressant that was sold by A.H. Robins, Inc., and Wyeth-Ayerst Laboratories Co., divisions of American Home Products Corp. Phentermine is a type of amphetamine that has been sold under many names and made by many companies.

Fenfluramine is believed to help cause weight loss by increasing the levels of the brain chemical serotonin, which controls satiety, or a feeling of fullness. Phentermine, which acts on another brain chemical, dopamine, increases the body's metabolism and is thought to have a role in reducing minor side effects caused by fenfluramine, such as drowsiness.

Both drugs were approved by the FDA as short-term diet aids, but they were never approved by it for use together as part of a diet concoction.

The fen-phen craze started in 1992 after the publication of a single article in an obscure medical journal.(2) The article included the results of a study of 121 obese patients who lost an average of 30 pounds while taking both drugs. Neither this study nor any other examined the safety of taking the drugs together.

After the article appeared, demand for the drugs surged, and some doctors began to prescribe fen-phen for people who were not substantially overweight and therefore not at risk of the diseases associated with morbid obesity. Many doctors, including some associated with weight-loss clinics, prescribed fen-phen to people who simply wanted to shed a few pounds, a so-called cosmetic use.(3)

Worse yet, some doctors prescribed the drugs without first doing thorough patient examinations, or any examinations at all. In many cases, patients were not told of the risks associated with use of the drugs. In fact, the drugs often were offered as an inducement to join weight-loss clinics and were promoted as free of side effects.(4)

`Miracle' drug

Then, in 1995, the FDA was asked to approve the sale of a new diet drug--dexfenfluramine, or Redux. Developed by Interneuron Pharmaceuticals Inc., a Massachusetts company, Redux is a purified form of fenfluramine.

FDA approval did not come easily because of concerns about the drug's safety. For a number of years, reports had linked fenfluramine use with primary pulmonary hypertension (PPH), a rare (at least until use of the drug became widespread) but potentially fatal cardiopulmonary disease about which little was known.

PPH had already made an appearance with another weight-reducing drug, Menocil (aminorex fumarate). This drug was sold in Europe between 1967 and 1973 and was withdrawn from the market when many cases of PPH were shown to be associated with taking it.

One reason PPH is so deadly is that it is hard to diagnose in its initial stages, and, therefore, treatment is often delayed. Symptoms, which are vague, include shortness of breath, loss of stamina, and swelling in the lower extremities.

One study revealed that when dexfenfluramine was sold in France earlier this decade, so many people developed PPH the French government in 1995 severely restricted its use to the morbidly obese.(5)

In 1995, the FDA's advisory committee initially voted against approving the drug, but later that year the committee recommended approval by a 6-5 vote. Lawyers who have studied the minutes of the two meetings have found that many doctors warned of serious risks from abuse of Redux, and there is some evidence that the second vote was taken when the doctors who were most vehemently opposed to approval were absent.

Redux went on the market in April 1996 with a number of conditions. It could be given only to patients who were obese (which is defined as having a body/mass index of 30 kg/[m.sup.2] or greater); it was to be given only under the supervision of doctors who specialized in treating obese people; and it was to be prescribed only in conjunction with a behavior modification program of diet and exercise.

Soon after the drug was approved, Wyeth-Ayerst reportedly sent salespeople to visit all types of doctors, not just obesity specialists.(6) Weight-loss clinics began marketing Redux as a new miracle drug, with side effects of fenfluramine eliminated.(7)

In August 1996, a study linking fenfluramine use with PPH was published in the New England Journal of Medicine.(8) Researchers in an international study group reported that patients who took the drug for as little as three months increased their risk of developing PPH by 23 times. The study also showed that this increased risk was linked to higher serotonin levels.

Shocking news

The most startling news, however, and what led to the recall of fenfluramine and Redux, was the report by the Mayo Clinic in July of last year. Clinic doctors said they found 24 cases of heart valve damage in fen-phen users (all women). This study, which was reported the following month in the New England Journal of Medicine, was so important that details were released prepublication, breaking a long-standing tradition of embargoing news about medical research until it is published.(9)

The women in the Mayo study had used fen-phen for an average of 12 months. The hearts of the affected women had been damaged in a very particular and peculiar way, and this bolstered a conclusion that the damage had been caused by something that all the women had been exposed to--fen-phen.

The valves were described as glistening white or waxy in appearance, with plaquelike encasements of the leaflets and chords and with a "stuck on" appearance. Often, more than one valve was damaged. In five cases, valve replacement surgery was required.

The doctors said that this peculiar type of valve damage had been observed in people with carcinoid syndrome--which involves increased serotonin levels--and people who took large amounts of ergotamine--a chemical similar to serotonin. This could have put manufacturers on notice that fenfluramine and Redux might cause the same damage.

Many of the women affected also had primary pulmonary hypertension, and the Mayo doctors speculated about the possible relationship between PPH and valve damage.

The women who had valve damage had similar signs and symptoms: murmur, dyspnea, edema, palpitations, congestive heart failure, chest pain, and in one case, supraventricular tachycardia. These are among the most common complaints of former fen-phen and Redux users who have contacted lawyers in recent months out of concern that they may have been injured by the drugs.

Echocardiograms, showed regurgitation associated with the mitral, aortic, and tricuspid valves; increased thickness in each of these valves; diminished ejection fraction (the amount of blood propelled from the heart); and right ventricular systolic pressure change. The Mayo doctors concluded that patients taking fen-phen and Redux should be warned about primary pulmonary hypertension and valve disease.

In late 1996, the FDA had requested that Wyeth-Ayerst send out a "dear doctor" letter regarding fenfluramine.(10) The letter cautioned doctors against use of the drug for cosmetic weight loss or for patients with a body/mass index below 30. The letter, however, did not advise doctors not to use the fen-phen combination.

After the Mayo Clinic study was released, the FDA issued another letter to doctors, warning that other cases of similar heart valve damage had come to its attention.(11) Soon after, it was revealed that the Mayo Clinic doctors had made their data available to Wyeth-Ayerst in March 1997.(12)

It may be determined through discovery that American Home Products had even earlier notice about valve damage (in animals or humans). But it is clear the company issued no warning for some time after receiving notice from the Mayo doctors. During this time, some users sustained valve damage.

At the time of the recall, the FDA issued a Q&A sheet that reported that the agency had received reports on 291 asymptomatic patients who had been examined by five doctors.(13) Thirty percent of these patients had abnormal valve findings, primarily aortic regurgitation. It was this bombshell that led to the withdrawal of the drugs.

Brain injury

Patients who took fen-phen and Redux may have also sustained brain injuries. The neurotoxic effects of fenfluramine drugs were highlighted last August in an article in the Journal of the American Medical Association (JAMA).(14) The article reviewed hundreds of studies on the effects of fenfluramines on animal brain nerve cells.

Virtually every study documented long-term brain serotonin neurotoxicity. In all

Paul D. Rheingold is a partner with Rheingold, Valet & Rheingold in New York City. animal species studied (seven, including monkeys), researchers found long-term, if not permanent, damage to the serotonin axons. The drug dosages and lengths of time that the animals took the drugs were not markedly different from those common to human use of the drugs.

No similar human studies have been done. But several articles have recently been published that report psychotic behavior in humans who have taken fenfluramine or Redux.(15)

The authors of the JAMA article declined to say whether the type of nerve cell destruction observed in animals would be duplicated or could explain neurological or behavioral changes in humans. They did point out that levels of serotonin (known to L-tryptophan litigators as 5-HT)(16) are known to affect memory, cognition, sleep, mood, and behavior.

Many people who have taken these drugs have complained of a variety of neuropsychological problems. The most dramatic are cases of true psychotic breaks or manias--extremely odd behavior totally out of character for the person affected.

One woman said she took a butcher knife to her husband. Some people said they had to be hospitalized. Lesser complaints include mood or behavior changes, and cognitive and memory loss. Aside from the symptoms of PPH, heart valve damage, and neuropsychological injury, many former fen-phen and Redux users also complain of dizziness, headache, and flushing. These symptoms are also reported by some people taking antidepressant drugs that increase serotonin levels, like Prozac and Zoloft. The symptoms, when severe, are sometimes called "serotonin syndrome."

The JAMA article also reviewed published studies on the association of PPH in both animals and humans who have taken fenfluramines. The authors concluded that patients who have taken the drugs for more than three months are 20 times more likely to develop PPH.

Relevant questions about fen-phen and Redux remain unanswered. For example, what role, if any, does phentermine play in the cardiovascular side effects seen in people who have taken fen-phen? What is the relationship between primary pulmonary hypertension and heart valve damage? How do these drugs cause the serious side effects that have been reported? How many people have been injured?

The litigation challenge

Much litigation has already been commenced alleging serious injuries from Redux and fen-phen. Virtually all the suits involve products liability claims against the drug manufacturers, and many also include malpractice claims against the clinic or doctor who prescribed the drugs.(17)

In the products liability cases, the main defendant has been American Home Products and its Wyeth-Ayerst and A.H. Robins units. Most plaintiffs who used fen-phen have sued the phentermine manufacturer as well. Six manufacturers sold phentermine under a trade name, and a number of others sold it generically. In some cases, it is difficult to determine which of these manufacturers made the phentermine taken by a particular plaintiff, especially when the drug was dispensed by a clinic.

The malpractice suits generally include claims based on conduct that is quite wide of the expected standard of care. Often, no physician prescribed the drugs--instead, they were passed out by nurses or clinic operators. Often, no physical examination was done for patients when they were initially put on the drugs or any time later. Electrocardiograms may not have been done.

Many doctors also failed to comply with the requirements that go along with the use of a controlled substance--a category that both fenfluramines and phentermine fall into. Under federal law and the law of every state, special rules relate to controlled substances. These include requirements for drug labeling and the type and frequency of patient medical exams.(18)

Some lawyers are also considering filing suit against the FDA for approving Redux and allowing fenfluramine and phentermine to be taken together. Certainly, whether the FDA was as vigilant as the public would expect is an appropriate question. Any litigation against the government, however, is likely to be unsuccessful. The FDA is protected by a discretionary defense, and the agency is generally not in the position to tell doctors how to prescribe drugs it approves.

Some suits are styled as class actions, and several of these seek to set up a medical monitoring class. Some immediate medical monitoring is needed--even asymptomatic users should have an echocardiogram since the FDA study showed that 30 percent of Redux and fen-phen users had valve changes. Whether long-term monitoring is needed is yet to be determined.

Many of the actions filed in federal court have asked the Judicial Panel on Multidistrict Litigation to set up multidistrict litigation for these cases.(19) The panel heard these petitions in late November, but at the time of this writing had not issued a decision. If the cases are consolidated, the panel can select a transferee judge to handle the discovery phase of the federal cases.

Ultimate responsibility

It is still too early to determine the scope of damage caused by these drugs. If the FDA's preliminary data that 30 percent of the millions of users have been injured are right, a medical tragedy has taken place.

There is blame enough to go around. The doctors who set up store-front fen-phen clinics and prescribed the drugs are obvious culprits. So are drug companies that profited financially from the fad and may have neglected to pass on information about deadly side effects.

An impulse to blame the victim should be resisted. Some people might say, "If you took these drugs, it's because you were fat. And if you were fat, it's your fault." Society attaches a stigma to being overweight, and this can cloud culpability issues in these cases.

It is important to remember that it is because of the stigma of being overweight that people often feel compelled to try to lose weight and that some people, especially the obese, must lose weight to avoid serious health problems. Drug manufacturers, doctors, clinics--all who profited by negligently selling or prescribing these drugs--should now bear the responsibility for the injuries that resulted.

Notes

(1.) See Heidi M. Connolly et al., Valvular Heart Disease Associated with Fenfluramine-Phentermine, 337 NEW ENG. J. MED. 581 (1997).

(2.) Michael Weintraub et al., Long-term Weight Control Study, 51 CLINICAL PHARMACOL. THERAPY 586 (1992).

(3.) Robert Langreth &Laura Johannes, Is Marketing of Diet Pill Too Aggressive? WALL ST. J., Nov. 21, 1996, at B1.

(4.) Robert Langreth, Critics Claim Diet Clinics Misuse Obesity Drugs, WALL ST J., Mar. 31, 1997, at B1.

(5.) Douglas Lavin & Stephen D. Moore, French Diet-Pill Maker Vows to Return, WALL ST. J., Sept. 22,1997, at A19.

(6.) See Langreth & Johannes, supra note 3.

(7.) Id.

(8.) See Lucien Abenhaim, Appetite-Suppressant Drugs and the Risk of Primary Pulmonary Hypertension, 335 NEW ENG. J. MED. 609 (1996).

(9.) See Laura Johannes & Richard B. Schmitt, Lawyers Prepare for Deluge of Diet-Drug Suits, WALL ST J., Sept. 17, 1997, at B1, B10.

(10.) Food& Drug Admin., New Safety Information Summaries: Redux (Dexfenfluramine Hydrochloride) (cont'd) (last updated Jan. 17, 1997) http://www.fda.gov/medwatch/safety/dearlet.htm.

(11.) See Stuart L. Nightingale, Health Advisory on Concomitant Fenfluramine and Phentermine Use, 278 JAMA 379 (1997).

(12.) Johannes& Schmitt, supra note 9, at B1.

(13.) Food & Drug Admin., Questions and Answers About Withdrawal of Fenfluramine (Pondimin) and Dexfenfluramine (Redux) (last updated Sept. 18, 1997) http://www.fda.gov/cder/news/fenphenqa2.htm.

(14.) Una D. McCann et al., Brain Serotonin Neurotoxicity and Primary Pulmonary Hypertension from Fenfluramine and Dexfenfluramine, 278 JAMA 666 (1997).

(15.) See, e.g., Anthony J. Cleare, Phentermine, Psychosis, and Family History, 16 J. CLINICAL PSYCHOPHARMACOLOGY 470 (1996); Charles L. Raison & Haven M. Klein, Psychotic Mania Associated with Fenfluramine and Phentermine Use, 711 AM. J. PSYCHIATRY 511 (1997). And see the many articles in the bibliography to the McCann article cited at note 14.

(16.) In the L-tryptophan Showa Denko mass tort litigation, basic brain chemistry explained that tryptophan was metabolized into serotonin, known as 5-HT (5-hydroxtryptamine). The process goes on to produce melatonin.

(17.) A litigation group has been set up at ATLA. The cochairs of the group are Michelle Parfitt, Washington, D.C.; Samuel Pollack Boston, Massachusetts; and Paul Rheingold, New York, N.Y. The group plans to meet at the Winter Convention in Hawaii in February 1998.

(18.) Fenfluramine, dexfenfluramine, and phentermine are all itemized in Schedule IV. 21 U.S.C. [sections] 812 (1994), 21 C.F.R. [sections] 1308.14 (1997).

(19.) This is pursuant to 28 U.S.C. [sections] 1407 (1997). For a description of multidistrict litigation, see PAUL RHEINGOLD, MASS TORT LITIGATION ch. 4 (1996).