Dexfenfluramine Phentermine

The beneficial effect of steroid therapy was confirmed 8 years later in a larger group of patients [23]. Curiously, an asymptomatic aortic insufficiency was observed in one third of the patients with CHN [19, 24]. This cardiac complicafion was supposed to be the result of an extrarenal toxicity of Chinese herbs [25]. However, the attention was drawn to the role of appetite suppressants in the development of valvular heart diseases [26]. Since most of the CHN patients we have seen have been given appetite suppressants (fenfluramine, dexfenfluramine, phentermine alone or in combination) besides the Chinese herbs, the puzzling association of aortic insufficiency with CHN may more likely be linked to the concomitant use of (dex)-fenflu-... 

Methysergide, ergotamine Fenfluramine, dexfenfluramine, phentermine Pergolide... 

Common adverse reactions seen with phentermine use include heart palpitations, tachycardia, elevated blood pressure, stimulation, restlessness, dizziness, insomnia, euphoria, dysphoria, tremor, headache, dry mouth, constipation, and diarrhea. Phentermine should be avoided in patients with unstable cardiac status, hypertension, hyperthyroidism, agitated states, or glaucoma. In combination with fenfluramine or dexfenfluramine, pulmonary hypertension and valvular heart disease have been reported. The risk of developing either serious adverse effect cannot be ruled out with use of phentermine alone. Since phentermine is related to the amphetamines, the... 

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liability cases for 1.09 billion for its cholesterol medicine cerivastatin (Baycol), which was linked to 100 deaths and withdrawn from market in 2001.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). ... 

On September 15,1997, FDA asked the manufacturers of dexfenfluramine (Redux manufactured for Intemeuron Pharmaceuticals by Wyeth-Ayerst) and fenfluramine (Pondimin Wyeth-Ayerst) to voluntarily withdraw both treatments from the market because of findings that indicate approximately 30% of patients taking the combined drugs had abnormal echocardiograms, even if they had no symptoms. Both companies agreed. FDA is not requesting the withdrawal of phentermine, the third widely used medication for obesity. 

Fenfluramine has not been systematically studied in the treatment of BN, but dexfenfluramine has been evaluated with disappointingly mixed results. Due to an association with the development of heart valve abnormalities and pulmonary hypertension, particularly when coadministered with phentermine (lonamin) in the so-called Fen-Phen strategy, these medications have recently been removed from the U.S. market. 

Since the withdrawal of fenfluramine and dexfenfluramine, some clinicians have begun coadministering fluoxetine and phentermine. Perhaps this combination will produce the clinical benefit of the Fen-Phen combination without the dangerous complications. Because the efficacy and long-term risk of this combination are unknown, augmentation of fluoxetine with phentermine cannot be recommended for routine practice. 

The newest appetite suppressant, sibutramine (Meridia), works by blocking the reuptake of both serotonin and norepinephrine. It does not stimulate nerve cells to release serotonin, as do fenfluramine and dexfenfluramine. Administered at 20 mg/ day, sibutramine effectively reduces weight in obese patients, but its use has not been assessed in eating disorder patients. The most common side effects of this medication are insomnia, dry mouth, and constipation. It has not been associated with the more serious heart and lung complications observed with fenfluramine and dexfenfluramine. Because sibutramine acts in part through modulation of norepinephrine, there is no rational basis for coadministering phentermine, which acts via this same mechanism. 

Until approximately 10 years ago, the most popular and successful appetite suppressants were the nonselective 5-HT2 agonists fenfluramine and dexfenfluramine. Combined with phentermine as Fen-Phen and Dex-Phen, they... 

The diet pills developed to replace amphetamines became known as anorectics or appetite suppressants and are central nervous system stimulants. The FDA approved phentermine in 1959, fenfluramine in 1973, and dexfenfluramine in 1996. 

Off-label use during the 1990s became an issue after doctors in the United States and other countries began prescribing fenfluramine (Pondimin) or dexfenfluramine (Redux) in combination with phentermine. The combinations known informally as fen-phen (sometimes also written as phen-fen ) or fen-dex had not been approved by the FDA, a process that involves research and hearings. 

In 1997, the manufacturers withdrew fenfluramine and dexfenfluramine from the market. Phentermine is still sold because no cases of heart valve disease were reported when that drug was taken alone, according to the FDA report. 

These findings precipitated the widespread use of a fenfluramine-phentermine combination therapy that came to be known as Fen-Phen. The combined use of the two anorexigens had never been approved by the FDA, nor had the longterm safety of the therapy ever been established. Nevertheless, weight loss clinics specializing in Fen-Phen therapy were established throughout the country. In 1996, the FDA narrowly approved the more potent, less adverse-effect-prone (+)stereoisomer of fenfluramine, dexfenfluramine, for less-than-l-yr use in the treatment of obesity. The New York Times reported that in 1996, 18 million prescriptions had been written for fenfluramine alone or in combination with phentermine and that about 6 million Americans took the drug (37). 

Gardin JM, Schumacher D, Constantine G, Davis KD, Leung C, Reid CL. Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or phentermine/fenfluramine. JAMA 2000 283 1703-1709. 

Fenfluramine (approved in 1973, withdrawn in 1997) and phentermine (appetite suppressant approved in 1959 and still available). Wyeth-Ayerst Laboratories, a subsidiary of American Home Products Corp. of Madison, New Jersey, manufactured and marketed fenfluramine under the brand name Pondimin. Wyeth-Ayerst also marketed Redux (dexfenfluramine), which was manufactured for Interneuron Pharmaceuticals. See http //www.fda.gov/cder/news/phen/fenphenpr81597.htm... 

Fenfluramine, dexfenfluramine, and phentermine have been used alone or in combination as an alternative to diet and surgery in the management of obesity. This therapy was halted in 1997 after reports of valvular lesions affecting almost one-third of patients treated with these drugs. The combination of fenfluramine and phentermine is called fen-phen. 

The fenfluramines and phentermine can cause valvular heart disease (8-10), and this has been reviewed (11). Fenfluramine was voluntarily withdrawn by the manufacturers on 15 September 1997, and the US Department of Health and Human Services issued interim recommendations for people previously exposed to fenfluramine or dexfenfluramine with cardiac valvulopathies (SEDA-22, 3). 

The above study was based on information derived from the General Practice Research Database in the UK. Subjects who had been given at least one prescription for dexfenfluramine, fenfluramine, or phentermine after 1 January 1988, and who were 70 years or younger at the time of their first prescription were included. Subjects were considered to have a new cardiac abnormality if they had no history, on the basis of clinical records, of cardiac valvular abnormahties and if there was evidence of a new valvular disorder on the basis of echocardiography or chnical examination after exposure to appetite suppressants. All the data had been recorded before the pubhcation of recent reports of an association between appetite suppressants and cardiac valve disorders (25,27,30-32) or primary pulmonary hjq)ertension (14). Hence, it was possible to exclude the possibihty that enhanced awareness of possible serious adverse effects of appetite suppressants had led to closer surveillance of patients who were taking these drugs. Nevertheless, the study did not provide information on the frequency of idiopathic cardiac valve disorders that are asymptomatic or otherwise not chnicaUy diagnosed. 

Kancherla MK, Salti HI, Mulderink TA, Parker M, Bonow RO, Mehlman DJ. Exhocardiographic prevalence of mitral and/or aortic regurgitation in patients exposed to either fenfluramine-phentermine combination or to dexfenfluramine. Am J Cardiol 1999 84(ll) 1335-8. 

In a systematic review of 1279 patients taking fenfluramine, dexfenfluramine, or phentermine, evaluated in seven uncontrolled cohort studies, 236 (18%) and 60 (5%) had aortic and mitral regurgitation respectively (2). Pooled data from six controlled cohort studies yielded, for aortic regurgitation, a relative risk ratio... 

New pharmacological treatments have been developed for the treatment of obesity. These include the combination of phentermine and fenfluramine (phen-fen) and, alternatively, dexfenfluramine (Redux). Phentermine (Fastin, lonamin) is a stimulant and fenfluramine (Pondimin) is a serotonin agonist. In combination they have persistent appetite suppression and weight loss effects. These medications can cause anxiety and insomnia and must be used with extreme caution if taken with antidepressants, especially SSRIs. Dexfenfluramine works similarly, but avoids the side effect of increased anxiety, and instead tends to cause diarrhea, dry mouth, and somnolence. There have also been reports of pulmonary hypertension, a potentially fatal condition, especially when taken for longer than three months. Some researchers (Ricuarte et al. 1991 McCann et al. 1994) have expressed concern because rats given these medications showed evidence of neuronal toxicity. Thus, they are effective medications, but must be used with caution. 

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. 

In September 1997, the FDA requested the manufacturers of fenfluramine and dexfenfluramine to voluntarily withdraw their products from the market. This was done following case reports of valvular heart disease in patients taking either medication as monotherapy or in combination with another anorexic agent, phentermine. Because no association has been found between phentermine alone and valvular heart disease, it is still available. Isolated case reports of pulmonary hypertension and phentermine monotherapy have been reported, but present data do not support an association. Although fenfluramine and phentermine were both approved by the FDA to be used as anorectic agents, the combination therapy, fen-phen, was never approved. 

The debate regarding the appropriateness of obesity pharmacotherapy remains heated, fueled by the recognized national need to treat a growing epidemic, the lack of longterm outcomes studies, and the medical and litigious fallout from the failed use of fen-phen (fenfluramine-phentermine) and dexfenfluramine (Redux). 

Food and Drug Administration. Fen-phen Safety Update Information fenfluramine, phentermine, dexfenfluramine. http //www.fda.gov/cder/ news/feninfo.htm, 2003. 

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