FENLURAMINE/DEXFENFLURAMINE WITHDRAWL

By Jack Landskroner

On September 15, 1997, the Food and Drug Administration asked for the voluntary withdrawal of two medications used in the management of obesity. Wyeth-Ayerst Laboratories, a division of American Home Products, promptly withdrew its product, fenfluramine, also known as Pondimin, and dexfenfluramine, popularly known as Redux which is distributed.

The use of fenfluramine had become increasingly widespread since 1984 when Dr. Michael Weintraub published the results of his study in the Archives of Internal Medicine. In his article, he described the excellent resulting weight losses that patients had obtained when using a combination therapy of fenfluramine with phentermine. It is estimated that as many as 18 million prescriptions for these drugs were written for fenfluramine and dexfenfluramine before they were withdrawn from the market in the early stages.

Both fenfluramine and phentermine, also known is Ionamin, are appetite suprressants, similar in chemical structure to amphtamines. Both have been approved for over twenty years by the FDA as anti-obesity drugs when each was used alone. Redux was recently approved in 1996.

It was not until the Weintraub study that the use of fenfluramine, or later, dexfenfluramine with phentermine together became the fashionable method of promoting weight loss. The comination therapy, commonly known as “fen-phen” or dexfen-phen”, was felt to be superior to the individual drugs. Dosages of both drugs could be decreased, side effects were lessened, and the drugs continued to be effective for longer periods of time and with greater weight loss than if used alone.

It was known to the world wide medical community that there was a risk, with these drugs, of primary pulmonary hypertension (PPH). This condition causes a constriction of the vessels of the lungs and heart that leads to heart/lung transplant or death in over half of the persons diagnosed. This potentially life threatening condition is occasionally but rarely reversible. For those patients who had used the weight-loss drugs for more than 3 months, it was estimated that the incidence of PPH was 23 to 46 cases per million, while in the general population, the incidence is 1 to 2 cases per million patients. PPH occurred regardless of whether the drugs were taken in combination or individually. The New England Journal of Medicine revisited this subject publishing an article reporting the increased risk of PPH associated with the use of these drug combinations and from fenfluramine alone. At that time, the manufacturers changed their warnings dramatically to detail these known risks.

More recently, there was a study done at the Mayo Clinic, prompted by the presentation of several cases in which patients taking the combination therapy appeared to develop valvular heart disease. In the study, 24 women were examined. These patients had normal cardiovascular examinations prior to starting the weight-loss drugs except for systemic high blood pressure, which is a common finding in obese patients. Most of the woman were seen because they were experiencing symptoms of heart disease – shortness of breath, swelling of the legs and feet, palpitations, or chest pain.

All of the patients underwent an echocardiogram, which revealed valvular damage, Five of these patients had to undergo surgery for replacement or repair of one or more of their heart valves. The study suggested that there was a need for further investigation into the possibility of a link between the use of the weight-loss drugs and the incidence of heart valve disease. Early studies indicate that as many as 30% of those receiving the drugs may have heart valve damage.

Regardless of the questions over the validity of the study, the FDA issued a Health Advisory to physicians on July 8, 1997. In this advisory, the FDA described the results of the study stressing that the combination therapy was not approved by the FDA, and requesting that nay further cases be reported to them.

Two weeks later, Marc Deitch, M.D. of Wyeth-Ayerst issued his own statement to physicians. Warnings were to be added to the medication inserts describing the “potentially serious and unusual form of valvular heart disease which has been reported in patients taking fenfluramine and phentermine.” The pharmaceutical company also stressed that the drugs were not to be used in combination, and that it was initiating its own studies to supplement the Mayo Clinic study.

On August 8, 1997, Terrance Coyne, M.D., of Medeva Pharmaceuticals, the makers of phentermine, issued a statement regarding their labeling changes which would warn against the use of phentermine with other appetite suppressants.

By August 22, 1997, the FDA had information about 58 additional cases of cardiac valvular disease in patients on fenfluramine and phentermine, two of whom were men.

Thus, the FDA, armed with this new evidence of the significant side effects associated with fenfluramine and dexfenfluramine, requested Wyeth-Ayerst to voluntarily withdraw the two drugs from the market.

As of 1997, the Physicians Desk Reference (PDR), the recognized authoritative publication on prescription medication, published warnings to physicians to inform his or her patients of these risks and the severity of PPH, particularly when the drugs are used for more than 3 months. It appears that prior to the 1997 PDR Publication, manufacturers whose sales of these products were skyrocketing, did not adequately warn of these risks.

With the publication of this information, physicians were placed on notice of these risks and dangers and therefore had a duty to fully warn and obtain full consent of their patient before prescribing these drugs. Moreover, the drug companies duty to manufacture a safe product and fully inform and warn all consumers of the dangers of their product was and is incumbent upon them before placing a product on the open market. The safety of the consumer must always outweigh the profits of these mammoth companies.

Patients who were taking either fenfluramine or dexfenfluramine are encouraged to immediately stop taking the medication. Often there are no symptoms of valvular heart disease. Other patients may experience shortness of breath, excessive tiredness, chest pain, fainting, and swelling of the legs. All patients are urged to see their physician for a complete cardiac evaluation. An echocardiogram may be ordered depending on the findings.

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