Other AreasFen-Phen

DrugsPondimin

Pondimin (fenfluramine hydrochloride) has been reported to be associated with the occurrence of serious regurgitant cardiac valvular disease, including disease of the mitral, aortic, and/or tricuspid valves. In one literature report, 24 patients, who received combination therapy with fenfluramine and phentermine for treatment of obesity, were found to have regurgitant cardiac valvular disease; five of these patients required valvular surgery. The valves of these five patients were found to have a gross pathologic and/or histologic appearance resembling that seen in patients with alterations in serotonin metabolism. In these reports and other reported cases, fenfluramine was taken generally in combination with phentermine. However, there are some reports in which the valvular disease was seen in patients taking fenfluramine alone.

Primary pulmonary hypertension - a rare, frequently fatal disease of the lungs - has been found to occur with increased frequency in patients receiving fenfluramine.

The safety and effectiveness of the combined use of fenfluramine and phentermine in the treatment of obesity have not been established, and there is no approved use of these products together in the treatment of obesity. Fenfluramine is approved only as a single agent for short-term use (i.e., a few weeks).

Pharmacologic Actions

Pondimin is the racemic mixture of the dextro and levorotatory stereoisomers of fenfluramine. The majority of the antiobesity effects of fenfluramine are produced by the dextrorotatory stereoisomer (d-fenfluramine, i.e., dexfenfluramine), which is a serotonin reuptake inhibitor and releasing agent. The levorotatory stereoisomer (l-fenfluramine) has a greater effect on dopaminergic neurotransmission than on appetite, and less of an effect on appetite than d-fenfluramine.

The anti-appetite effects of Pondimin are suppressed by serotonin blocking drugs and by drugs that lower brain levels of the amine. Furthermore, decreased serotonin levels produced by selective brain lesions suppress the action of Pondimin.

In a study of 20 normal males, fenfluramine increased glucose utilization, resulting in decreased blood glucose levels. The relationship between glucose utilization and serotonin has not been clarified.

Pharmacokinetics and Metabolism

Fenfluramine is well-absorbed from the gastrointestinal tract, and a maximal anorectic effect is generally seen after 2 to 4 hours. Fenfluramine is widely distributed in almost all body tissues. It is soluble in lipids and crosses the blood-brain barrier. Fenfluramine crosses the placenta readily in monkeys.

In man, fenfluramine is de-ethylated to the major, active metabolite, norfenfluramine, which is subsequently oxidized to m-trifluoromethyl benzoic acid (inactive) and excreted as the glycine conjugate, m-trifluoromethylhippuric acid. Other compounds found in the urine include unchanged fenfluramine and norfenfluramine.

The rate of excretion of fenfluramine is pH dependent, with much smaller amounts appearing in an alkaline than in an acid urine. The half-life of fenfluramine is about 20 hours; however, if urinary excretion is rapid and the pH is maintained in the acidic range (below pH 5), half-life can be reduced to 11 hours. Fenfluramine and norfenfluramine reach steady state concentrations in plasma within 3 to 4 days following chronic dosage.

Contraindications

Pondimin is contraindicated in patients with diagnosed pulmonary hypertension.

Pondimin is contraindicated in patients receiving monoamine oxidase (MAO) inhibitors. Do not administer fenfluramine during or within 14 days following the administration of MAO inhibitors, since hypertensive crises may result.

Fenfluramine is contraindicated in patients with glaucoma or with hypersensitivity to fenfluramine or sympathomimetic amines.

Do not administer fenfluramine to patients with alcoholism since psychiatric symptoms (paranoia, depression, psychosis) have been reported in some patients who had been administered this drug.

Fenfluramine should be avoided in patients with psychotic illness. There have been reports of schizophrenic patients who have become agitated, delusional, and assaultive.

Patients with a history of drug abuse should not receive this drug.

Pondimin (fenfluramine) should be avoided in patients with a history of anorexia nervosa or bulimia.

Warnings

Fenfluramine is an appetite suppressant, and appetite suppressants increase the risk of developing primary pulmonary hypertension, an often fatal disorder.

A 2 year, international (5 country), case-control (epidemiological) study identified 95 primary pulmonary hypertension (PPH) cases; 30 of these were classified as having been exposed to appetite suppressants in the past, either to commercially available medications, pharmacist-compounded preparations, or unknown weight loss agents. Of the 30 cases, 18 had been exposed to appetite suppressants for longer than three months. In this study, the use of appetite suppressants for longer than three months was associated with an increase in risk of developing PPH (odds ration = 23.1, 95% confidence interval = 6.9-77.7). There was no significant increase in risk for persons who had used these agents for 3 months or less. In the general population, the yearly occurrence of PPH is estimated to be about 1-2 cases per 1,000,000 persons. Therefore, the case-control study estimated the risk associated with the long-term use of appetite suppressants to be about 23-46 cases per million persons. According to the case-control study, obesity alone (body mass index greater than or equal to 30 kg/m²) was also associated with an increase of about two-fold in the risk of developing PPH.

PPH is a serious condition; the 4-year survival rate has been reported to be 55%.

The initial symptom of pulmonary hypertension is generally dyspnea. Other initial symptoms include: angina pectoris, syncope, or lower extremity edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope, or lower extremity edema. These patients should be evaluated for the etiology of these symptoms and the possible presence of pulmonary hypertension.

Most cases of pulmonary hypertension reported coincident with fenfluramine use involved women between the ages of 29 and 68, some of whom were receiving concomitant treatment with other medications (including other appetite suppressants). In the majority of these cases, symptoms of pulmonary hypertension developed in current users of fenfluramine or in patients who had used it within the past 12 months. Most patients required hospitalization, with treatment including diuretics, calcium antagonists, vasodilatory agents, ß-adrenergic blockers, and anticoagulants. In some cases, patients required heart-lung transplants. Death due to cardiac or hemodynamic/respiratory complications has occurred.

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