Fen-phen refers to the use in combination of fenfluramine (fen) and phentermine (phen). Both drugs are prescription medications that were approved by the FDA as appetite suppressants for the short-term management of obesity for many years prior to the introduction of fen-phen; phentermine was approved in 1959 and fenfluramine in 1973. Although both drugs were given FDA approval, the prescription of Fen-Phen as a combination was off-label, meaning that Fen-Phen was never approved by the FDA as a drug combination. Combining drugs in this way is a typical practice of many doctors, as they are permitted to prescribe licensed drugs together if they decide to.
The idea of using the two drugs in combination was that of Dr. Michael Weintraub, a professor of clinical pharmacology at the University of Rochester. Dr. Weintraub considered that combining these two obesity medications with different actions on the brain and body might be more powerful than either drug alone. He put his theory to the test with a four-year study of 121 obese patients, two-thirds of whom were women. During the study, patients either took Fen-Phen or a placebo. Taking the placebo resulted in them feeling hungry and gaining weight, whereas the Fen-Phen decreased their hunger and they lost weight. By the end of the study, patients had lost an average of 30 pounds. Dr. Weintraub looked for side effects but assumed the drugs were safe, as they had separately received FDA approval many years before.
Dr. Weintraub was unable to publish his findings until 1992, when his work finally appeared in the journal Clinical Pharmacology & Therapeutics. Prior to the 1990s, journals were reluctant to print articles effectively endorsing the use of drug therapy, but the article was released at a moment when doctors and the general public were starting to look for other means to lose weight in order to attempt to control what was becoming an obesity epidemic. The timing was just right and Fen-Phen took off like no one could have predicted; patients called doctors demanding the drugs and doctors were quick to respond to demand, some of whom devoted their whole practices to selling Fen-Phen to thousands of patients.
As the Fen-Phen craze gathered momentum, the manufacturers of fenfluramine wanted to market dexfenfluramine, a more effective form of fenfluramine. Despite evidence showing that dexfenfluramine was thought to greatly increase the risk of an untreatable and often fatal condition, pulmonary hypertension, due to the rare nature of the disease â only one person in a million ordinarily develops it â an increase of up to 46 people in a million was not deemed a huge risk. Dexfenfluramine was reluctantly approved by the FDA in 1996, and sales soared as it was taken by over two million Americans, including in combination with phentermine as Dexfen-Phen.
Less than a year after the approval of dexfenfluramine, doctors at the Mayo Clinic in Rochester, Minneapolis, reported that 24 women taking fenfluramine, dexfenfluramine or Fen-Phen developed a rare and very serious heart valve abnormality. The FDA requested that doctors across the US report any patients with similar valve damage and soon accumulated more than 100 cases, most of which were associated with taking Fen-Phen and none of which were reported in patients taking phentermine alone. Within months, five medical centers independently told the FDA that they had examined a total of 291 patients, mostly women, and had found that a third of them had damaged heart valves. It was also discovered that the labelling information for fenfluramine had neglected to report accurate figures for the number of cases of pulmonary hypertension, a fatal lung disease, which had been observed in clinical trials for the drug. Based on the overwhelming evidence that fenfluramine and dexfenfluramine were linked to serious heart valve damage and pulmonary hypertension, the drugs were withdrawn from the market in September 1997.
The FDA were vigilant in their analysis of cases involving Fen-Phen and found that no cases of either heart valve damage or pulmonary hypertension were linked to taking phentermine alone. Phentermine continues to be prescribed as a weight loss medication and has even grown in popularity since the 1990s Fen-Phen craze, to the extent that it now accounts for approximately half of all prescriptions for weight loss medications in the US, and is still considered one of the leading medical treatments for the short-term management of obesity.