Fenfluramine primary pulmonary hypertension

After many health problems and deaths, the FDA removed Pondimin and Redux from market. Since then, there have been 200 reported cases of primary pulmonary hypertension relating to fen-phen and dexfen-phen. Of those cases, 40 have resulted in death. The FDA has received more than 100 reports of heart valve damage directly related to fen-phen or fenfluramine therapy there are no reports from individuals taking phentermine alone for weight loss. 

Blanpain, C., Le Poul, E., Parma, J., Knoop, C., Detheux, M., Parmentier, M., Vassart, G. and Abramowicz, M.J. (2003) Serotonin 5-HT(2B) receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension. Cardiovascular Research, 60 (3), 518-528. 

For instance, in September 2004, Bayer settled 2861 product liability cases for 1.09 billion for its cholesterol medicine cerivastatin (Baycol), which was linked to 100 deaths and withdrawn from market in 2001. In July 2004, the company settled 2771 cases for 1.06 billion. Bayer still has 7577 additional cases to settle (see Section 28.4.4.5 for additional information). In another example, a 1 billion jury verdict was upheld against Wyeth for its fenfluramine or dexfenfluramine and phentermine (Fen-Phen) drug combination, which was linked to primary pulmonary hypertension (PPH). Wyeth has set aside 16.6 billion to cover future liability on the drug (see Section 28.4.4.2 for more on this case). ... 

Brenot F, Herve P, Petitpretz P, Parent F, Duroux P, Simonneau G. Primary pulmonary hypertension and fenfluramine use. Br Heart J 1993 70 537-541. 

Tomita T, Zhao Q. Autopsy findings of heart and lungs in a patient with primary pulmonary hypertension associated with use of fenfluramine and phentermine. Chest 2002 121 649-652. 

Anorectic drugs, which are structurally related to the amphetamines, act mainly on the satiety centre in the hypothalamus and also increase general physical activity (1). All of them, except fenfluramine, stimulate the central nervous system and can cause restlessness, nervousness, irritabihty, and insomnia. Adverse effects also occur through sympathetic stimulation and gastrointestinal irritation. Drug interactions can occur with monoamine oxidase inhibitors. Dexamfetamine, phenmetrazine, and benzfetamine can cause dependence. Some of them have been associated with cardiac valvulopathy and primary pulmonary hypertension (2). 

In 1996, in a case-control study, 95 patients from 35 centers in France, Belgium, the UK, and the Netherlands were compared with 355 age- and sex-matched controls (14). The use of anorexic drugs (mainly derivatives of fenfluramine) was associated with an increased risk of primary pulmonary hypertension. Association with recognized risk factors such as a family history of primary pulmonary hypertension, infection with HIV, or the use of intravenous drugs was also confirmed. The absolute risk for obese patients who took anorexic agents for more than 3 months was 30 times higher than in non-users. 

Simonneau G, Fartoukh M, Sitbon O, Humbert M, Jagot JL, Herve P. Primary pulmonary hypertension associated with the use of fenfluramine derivatives. Chest 1998 114(Suppl. 3) 195S-9S. 

The principal side effects of phentermine are insomnia, restlessness, and euphoria. Some patients rapidly develop toleranee to this agent, resulting in discontinuation of therapy. The combination of phentermine with fenfluramine or dexfenfluramine was as-soeiated with inereased incidences of both primary pulmonary hypertension (PPH) and ear-diae valvulopathy, but it is unlikely that phentermine alone causes these same problems. Phentermine, nonetheless, contains a warning label listing PPH and cardiac valve lesions as possible adverse events. 

The Fen-Phen combination regimen started in 1992 after the publication of an article that showed dramatic weight loss when both drugs were taken together. In 1995, the FDA was asked to approve a new diet drug, dexfenfluramine or Redux. Developed by Interneuron Pharmaceuticals Inc., a Massachusetts company, Redux is a purified form of fenfluramine. However, prior reports had linked fenfluramine use with primary pulmonary hypertension (PPH), a rare but potentially fatal cardiopulmonary disease. The FDA finally approved fenfluramine and Redux went on the market in April 1996. In July 1997, the Mayo Clinic released results from a study that found 24 cases of heart... 

McCann UD, Seiden LS, Rubin LJ, Ricaurte GA. Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine A systematic review of the evidence. JAMA 1997 278 666-672. 

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