Fenfluramine withdrawal

An important distinction between the effects of sibutramine and i/-fenfluramine is highlighted by microdialysis studies (Heal et al. 1998). These show that the rate of increase in 5-HT efflux in the region of the PVN, after administration of sibutramine, is slow, progressive and long-lasting. This is because it relies on the accumulation of extracellular 5-HT following the inhibition of its reuptake after impulse-dependent release. This time-course contrasts with the rapid and transient increase in 5-HT efflux which results from the fenfluramine type of impulse-independent release from nerve terminals. In fact, this rapid increase in 5-HT release is thought to underlie the serious adverse side-effects of (i-fenfluramine that have led to its withdrawal from the clinic. 

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. 

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 statistics of expenditure and NDA approvals can mask a major source of R D cost and frustration in the industry late-stage development and postmarketing failures. These types of failures attract significant unwanted publicity and only occur after hundreds of millions of dollars have been spent. Well-publicized examples have included the recent late-stage failure of torcetrapib (Tall et al., 2007) and the postmarketing withdrawals of fenfluramine-phentermine (Fen-Phen) and Vioxx (Embi et al., 2006). 

Spending for prescription diet pills reached a record of approximately 467 million in 1996, according to the American Society of Bariatric Physicians, an association focused on weight loss. Fen-phen sales accounted for much of that record. After the withdrawal of dexfenlu-ramine and fenfluramine from the market, diet pill sales dropped. 

In light of these findings, the FDA obtained echocardiographic data from several US health care facilities. An uncontrolled survey of 284 patients taking fenfluramine in some form for a median of 14 mo (40) revealed VHD among 34% of the patients, a much larger prevalence than in the general population (41). Based on these data, the FDA recommended the voluntary withdrawal of... 

Anorectic drugs act mainly on the satiety centre in the hypothalamus (1). They also have metabohc effects involving fat and carbohydrate metaboUsm. Most of them are structurally related to amfetamine and increase physical activity. Their therapeutic effect tends to abate after some months, and part of this reduction in effect may be due to chemical alterations in the brain. Fenfluramine commonly produces drowsiness in normal doses, but has stimulaut effects in overdosage. Dexamfetamine, phenmetrazine, and benzfetamine all tend to cause euphoria, with a risk of addiction. Euphoria occasionally occurs with amfepramone (diethylpropion), phentermine, and chlorphentermine, but to a much lesser extent. Some adverse effects are due to sympathetic stimulation and gastrointestinal irritation these may necessitate withdrawal but are never serious. There are interactions with monoamine oxidase inhibitors and antihypertensive drugs. 

Progressive pulmonary hypertension occurred in two patients who took fenfluramine for only 8 months (SEDA-6, 9). The symptoms abated on withdrawal but returned in one patient when rechallenged. 

This was an unusual study because patients enrolled for a different purpose were analysed mid-way through the study in response to withdrawal of fenfluramine. Exposure to fenfluramine in this study was relatively short (2-3 months) and the prevalences of mitral regurgitation and aortic regurgitation in this study were much lower than previously described (25). 

Effects of withdrawal of therapy on valvulopathy In a patient who was followed-up for 2 years after withdrawal, multivalvular regurgitation associated with fenfluramine and phentermine may have regressed (23). 

In a few patients, hypertension was induced or aggravated by fenfluramine. The hypertension disappeared on withdrawal, but could not in all instances be reinduced by rechallenge (76). 

Depression can occur but is more common during the first few days following sudden withdrawal (SED-9, 12). An explanation for the depression and irritability encountered after sudden withdrawal may be a rapid reduction in 5-hydroxytryptamine through which the central effect of fenfluramine is mediated. 

Despite the withdrawal of the fenfluramines, the appetite suppressants phendimetrazine and phentermine have remained in widespread use for the treatment of obesity. 

Following the withdrawal of the fenfluramines, alternative combinations have been explored as appetite suppressants. In an open study of a combination of phentermine + fluoxetine in 16 obese patients with... 

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. 

Withdrawals from the market of ethically approved drugs in recent years [e.g., Pon-dimin (fenfluramine hydrochloride) and its sister compound Redux (dexfenflura-mine hydrochloride) for reasons of abnormal heart valve effects in 1996 Baycol/Li-pobay (cerivastatin) for occurrence of fatal rhabdomyolysis in 2001 Serzone (nefazo-dine) for associated Hver failure in 2003]... 

There is also an isolated case of cardiomyopathy attributed to the use of fenfluramine with mazindoL Before the withdrawal of the drug from the market, the manufacturer of fenfluramine recommended that concurrent use with other centrally acting anorectics should be avoided. ... 

Food and Drugs Administration. FDA announces withdrawal fenfluramine and dexfenfluramine (Fen-Phen). September 15lh, 1997. 

Exacerbation of depression has been seen in some patients given fenfluramine and several cases of withdrawal depression have been observed in patients taking amitriptyline and fenfluramine, following episodes of severe depression. The manufacturers have advised that fenfluramine should not be used in patients with a history of depression or in those being treated with antidepressants. On the other hand it has also been claimed that fenfluramine can be used safely and effectively with tricyclic antidepressants." One report describes a rise in the plasma levels of amitriptyline when fenfluramine 60 mg daily was given to patients taking amitriptyline 150 mg daily. ... 

Benfluorex, which is structurally related to fenfluramine, has been available since 1976 and has been used, mainfy in Erance, as an appetite suppressant [26 ] and to improve glycemic control and reduce insulin resistance in people with poorly controlled type 2 diabetes [27, 28, 29, 30, 31 ], including those with obesity [32 ",33, 34 ]. However, in 2009 the European Medicines Agency recommended the withdrawal of all medicines containing benfluorex in the European Union, because of the risks of cardiac valve disease (fenfluramine-like cardiovascular adverse effects) [35 J. 

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