A primer on fen-phen litigation: allegations and defenses.

• Author: Evans, John T.

A new wave of class actions targets the appetite suppressant known as Fen- Phen, which is alleged to have caused valvular heart disease in women

THE DIET drug known as Fen-Phen was recently implicated as a cause of valvular heart disease in women. Fen-Phen is a combination of Fenfluramine and Phentermine, two commonly prescribed appetite suppressants. Both drugs were approved by the Food and Drug Administration for the short-term management of obesity. However, the FDA has never approved the combined use of Fenfluramine and Phentermine. Consequently, physicians who prescribe Fen-Phen are using the drugs in an "off-label" manner not approved by the FDA. Notwithstanding the off-label use, reports show that prescriptions for Fen-Phen in 1996 exceeded 18 million.

The recent media coverage has attracted the attention of the plaintiffs' personal injury and product liability bars. This article will familiarize readers with the pharmacology, pathophysiology, and legal ramifications pertaining to Fen-Phen.

All the drugs discussed in this article affect, either directly or indirectly, the neurotransmitter serotonin. It is the effects of serotonin that are believed to cause severe regurgitant cardiac valvular disease and pulmonary hypertension. Serotonin is secreted by nuclei that originate in the brain stem. It acts as an inhibitor of pain pathways in the spinal cord and is believed to control the mood of the person and induce normal sleep. Serotonin is present in large concentrations in the chromaffin tissues of the intestine and other abdominal structures. It can cause vasodilation or vasoconstriction depending on the situation and focus of action.

Carcinoid tumors are tumors composed of chromaffin tissue. They secrete a large amount of serotonin. As discussed later, researchers believe that recent cases of cardiac valvular disease were caused by serotonin excess.

PHARMACOLOGY

Fen-Phen is the street name for the Fenfluramine-Phentermine combination. Although much of the media coverage has focused on Fen-Phen, there are actually four different drugs that warrant discussion.

1. Fenfluramine

   Fenfluramine hydrochloride is a Class IV controlled substance and is classified by the Physician's Desk Reference as an anorectic. As a Class IV controlled substance, it has a low potential for abuse. Fenfluramine is sold under the trade names Pondimin and Ponderol. It is produced by A.H. Robins, a subsidiary of American Home Care Products Inc.

   Fenfluramine is a sympathomimetic amine. Sympathomimetic drugs mimic sympathetic nervous system stimulation. The sympathomimetic amines induce vaso-constriction, increased arterial pressure, increased rate of blood coagulation, increased blood glucose, increased metabolism rate and decreased blood flow to the gastrointestinal tract. Fenfluramine's actions are somewhat different from other drugs in this category because it seems to produce more central nervous system depression than stimulation.

   According to the Physician's Desk Reference, Fenfluramine's mechanism of action is unclear. It may work to decrease appetite by affecting brain levels of serotonin, a neurotransmitter that regulates the enteric nervous system. Additionally, it may promote increased glucose utilization thereby activating the satiety center of the brain. Current medical journals, however, are less equivocal regarding Fenfluramine's mechanism of action. Current research shows that Fenfluramine promotes the rapid release of serotonin, inhibits its reuptake and may have receptor-agonist activity, thus making serotonin more susceptible to metabolism and breakdown.(1) Fenfluramine alters serotonin metabolism in the brain.

   The FDA approved Fenfluramine hydrochloride as an adjunct for short-term use as an appetite suppressant. It is to be used in conjunction with an over-all weight loss program that includes diet and exercise. It has not been approved as a combination drug, so its use is "off label."

   The drug is contraindicated in patients with glaucoma, hypersensitivity to sympathomimetic amines, history of drug abuse, history of psychosis and/or symptomatic cardiovascular disease. Fenfluramine has been shown to cause paranoia, depression and psychosis in alcoholics. It has been associated with numerous cases of pulmonary hypertension and there is one report of fatal cardiac arrest following induction of anesthesia. Fenfluramine is not recommended for use in children under 12 years of age. It is embryotoxic in rats, but there have been no adequate studies involving pregnant women.

   The usual dosage of Fenfluramine is 20 milligrams three times a day after meals. The dose can be increased by one tablet at weekly intervals. The maximum dose is two tablets three times a day for a total of 120 milligrams per day.

2. Phentermine

   Phentermine hydrochloride is also a Schedule IV controlled substance. It is marketed by Smith-Kline Beecham under the name Fastin. Like Fentluramine, Phentermine is a sympathomimetic amine with pharmacologic activity similar to amphetamines. It produces central nervous system stimulation, elevation of blood pressure, tolerance and tachyphylaxis. Tachyphylaxis is the rapid immunization of the body to a toxic dose of drug.

   According to the Physician's Desk Reference, Phentermine may or may not reduce obesity through appetite suppression. Its anorectic effects may be the result of central nervous system stimulation or other metabolic affects. Phentermine interferes with the pulmonary clearance of serotonin, which may explain its association with primary pulmonary hypertension.(2)

   Like Fenfluramine, the FDA approved Phentermine as a short-term adjunct in the management of exogenous obesity. The drug is not approved for use in combination with other anorectics.

   The contraindications for Phentermine are similar to those of Fenfluramine because they are both sympathomimetic amines. The usual dose of Phentermine is 30 milligrams daily before or one half hour after breakfast. Some patients may receive one-half tablet or one-half tablet twice a day.

3. Dexfenfluramine

   Dexfenfluramine hydrochloride, sold under the name Redux, is a purified form of Fenfluramine. Redux is manufactured in the United States by Interneuron Pharmaceuticals Inc. It licenses the drug to Wyeth-Ayerst.

   Fenfluramine is racemic, meaning that it has levo and dextro isomers. An...