The Rise and Fall of Fen-Phen

It is common in the medical industry to prescribe two medications together to combat multiple problems more effectively. Fen-Phen was the combination of two established anti-obesity drugs, fenfluramine and phentermine, first prescribed together in 1992. The combination was found to aid weight loss by boosting energy and alertness and suppressing appetite. Accordingly, Fen-Phen gained popularity in the 1990s and was hailed as the answer to the emerging obesity crisis. However, an independent medical study in 1996 found that an abnormally high amount of patients taking Fen-Phen showed signs of serious heart and lung conditions.  As requested by the FDA, fenfluramine was withdrawn from the market by its manufacturers in 1997. Here, we explain more about how and why Fen-Phen was introduced and what happened during its brief period of popularity during the 1990s.

What was Fen-Phen?

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 before 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.

Fenfluramine acts as a serotonin-releasing agent, while phentermine mainly works by releasing norepinephrine but also releases dopamine and serotonin. The brain releases these neurotransmitters to indicate feelings of fullness, reducing hunger. Phentermine also works outside the brain to release adrenaline, stimulating the mind and body to be more efficient and alert, increasing energy levels and concentration. Although the two had been shown to reduce weight independently, phentermine had never gained much popularity, and fenfluramine clinical trials showed far from impressive results; one 24-week study showed losses of just 16.5 pounds compared to 10 pounds with a placebo, and weight loss achieved was often only temporary.

The Rise of Fen-Phen

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 could not publish his findings until 1992 when his work finally appeared in the journal Clinical Pharmacology & Therapeutics. Before the 1990s, journals were reluctant to print articles effectively endorsing the use of drug therapy. Still, the article was released at a moment when doctors and the general public were starting to look for other means to lose weight to attempt to control what was becoming an obesity epidemic. The timing was just right, 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 – only one person in a million ordinarily develops it – 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.

The Fall of Fen-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 more than 100 cases soon accumulated, 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 labeling 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.

Phentermine & Other Weight Loss Medications

The FDA was vigilant in its analysis of Fen-Phen cases 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. It 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. It is still considered one of the leading medical treatments for the short-term management of obesity.

Phentermine is also prescribed in combination with other drugs, aimed to enhance and prolong the weight-loss effects. One of these is Qsymia, a combination of phentermine and topiramate, an anticonvulsant drug that can cause weight loss as a side effect. The combination of topiramate and phentermine was previously prescribed off-label but was approved as a combination by the FDA in 2012. Phentermine is also prescribed with low doses of anti-depressant drugs such as Prozac and Zoloft as the combination Phen-Pro. However, this combination is prescribed off-label as Phen-Pro has not been approved by the FDA. Unlike Fen-Phen, many trials have been carried out on these and other phentermine combinations, including follow-up studies to assess the long-term effects of phentermine combinations.

The rise and fall of the Fen-Phen craze is said to be a morality tale for our times, whereby what seemed to be a magic pill for the national obesity epidemic soared to immense popularity within a matter of years based on a single study involving just 121 patients. By comparison, phentermine, having been approved over 50 years ago, has shown that it is consistently effective in the short-term management of obesity, and this is why it has stood the test of time, unlike dangerous experimental combinations like Fen-Phen. There is no magic pill for weight loss; weight loss medications such as phentermine work by helping you to achieve your healthy lifestyle and maintain a goal weight for life, ensuring that this weight loss journey is your last and most successful!

Did you or anyone you know take the Fen-Phen combination? Or are you taking a phentermine combination now? We would love to hear you feedback and questions, please leave us a comment below and let us know!

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