The combination of these two drugs had been reported to be significantly more effective than placebo in promoting weight loss when used in combination with diet, exercise, and behavior modification.
Phentermine was first approved for use by the United States Food & Drug Administration (FDA) in 1959. Its claimed advantage over other appetite suppressants available at the time was a reduced risk of abuse. While the drug was chemically related to the amphetamines, with the same side effects, the incidence of these side effects was reportedly lower than with amphetamines.
Fenfluramine was approved by the FDA in 1973 and dexfenfluramine (Redux) was approved for use in 1996. Fenfluramine is the racemic form of dexfenfluramine. The drugs were approved for short term use as part of a program of diet and exercise. Although fenfluramine is chemically related to the amphetamines, its action appeared to be based on increasing levels of serotonin in the brain and bloodstream. Dexfenfluramine had been marketed in Europe for over a decade without detection of an association between dexfenfluramine and heart valve problems; however, the FDA noted that the number of patients having heart valve problems was very low compared to the total number of patients using the drug, and heart valve screening is not a routine part of drug monitoring.
Neither fenfluramine nor phentermine had been approved for use in long-term treatment or combination therapy. The drugs were indicated only as short-term adjuncts in patients with obesity.
In spite of the disappointing long-term results, these reports led to the wide use of the fen-phen regimen for people attempting to lose weight. In 1996, fenfluramine was the 46th most frequently prescribed drug in the United States, with sales of $176 million per year. No long-term studies were performed for these drugs, and they were never approved for use in combination therapy.
On July 8, 1997, The New England Journal of Medicine published a report from the Mayo Clinic describing 24 cases of regurgitational valvular heart disease in women who had been treated with fenfluramine and phentermine. By September 30, the FDA had received a total of 144 reports of heart valve problems associated with fenfluramine, with or without phentermine.
On November 19, 1997, the Centers for Disease Control and Prevention published a review of the cases of heart valve damage associated with fenfluramine:
… Of these 113 cases, 111 (98%) occurred among women; the median age of case-patients was 44 years (range: 22–68 years). Of these 113 cases, two (2%) used fenfluramine alone; 16 (14%), dexfenfluramine alone; 89 (79%), a combination of fenfluramine and phentermine; and six (S%), a combination of all three drugs. None of the cases used phentermine alone. The median duration of drug use was 9 months (range: 1–39 months). Overall, 87 (77%) of the 113 cases were symptomatic. A total of 27 (24%) case-patients required cardiac valve-replacement surgery; of these, three patients died after surgery….
The Food & Drug Administration removed fenfluramine from the market. Approximately 18,000 people sued American Home Products, which had marketed the drug, to recover damages, either from the costs of actual injuries or the cost of tests to determine whether any damage had been done. In a class action lawsuit, American Home Products agreed to establish a trust fund with a reported value of $3.75 billion, with the money to be distributed among victims of the drug, depending on extent of injury. People exposed to fenfluramine were monitored for heart valve problems for a period of 20 years.
Although fen-phen has been associated with another very important adverse effect, primary pulmonary hypertension, the focus of all regulatory and legal problems has been on the heart valve problems associated with the drug.
Phentermine hydrochloride tablets and capsules are indicated only as short-term monotherapy for the management of exogenous obesity. The safety and efficacy of combination therapy with phentermine and any other drug products for weight loss, including selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, fluvoxamine, paroxetine), have not been established. Therefore, coadministration of these drug products for weight loss is not recommended.
Serious regurgitant cardiac valvular disease, primarily affecting the mitral, aortic, and tricuspid valves, has been reported in otherwise healthy people who took a combination of phentermine with fenfluramine or dexfenfluramine for weight loss. The etiology of these valvulopathies has not been established and their course in individuals after the drugs were stopped is not known. The possibility of an association between valvular heart disease and the use of phentermine alone cannot be ruled out; there have been rare cases of valvular heart disease in patients who reportedly took phentermine alone.
Tolerance to the anorectic effect usually develops within a few weeks. When this occurs, the recommended dose should not be exceeded in an attempt to increase the effect; rather, the drug should be discontinued.
Phentermine hydrochloride may decrease the hypotensive effect of guanethidine.
Monoamine oxidase inhibitors (MAOIs) may increase the pressor response to the anorexiants. Possible hypertensive crisis and intracranial hemorrhage may occur. This interaction may also occur with furazolidone, an antimicrobial with MAOI activity. Avoid combining with phentermine hydrochloride. There should be a 14-day interval between use of any MAOI and phentermine.
For those patients were exposed to fenfluramine, aftercare depended on the extent of damage. For patients with significant heart valve damage, surgical valve replacement would have been in order. Those who received the drug but showed no damage were to be monitored by a cardiologist for the possibility of late-onset damage.
Although phentermine alone has been associated with rare instances of valvular heart disease, there are no recommendations for routine aftercare or monitoring.
See also Diet drugs ; Obesity .
Connolly, Heidi M., et al. “Valvular Heart Disease Associated with Fenfluramine–Phentermine.” New England Journal of Medicine 337 (August 28, 1997): 581–88.
Weintraub, M., et al. “Long-Term Weight Control Study II (Weeks 34 to 104). An Open-Label Study of Continuous Fenfluramine Plus Phentermine Versus Targeted Intermittent Medication as Adjuncts to Behavior Modification, Caloric Restriction, and Exercise.” Clinical Pharmacology and Therapeutics 51, no. 5 (May 1992): 595–601.
Weintraub, M., et al. “Long-Term Weight Control Study V (Weeks 190 to 210). Follow-Up of Participants after Cessation of Medication.” Clinical Pharmacology and Therapeutics 51, no. 5 (May 1992): 615–18.
Cohen, Kate. “Fen-Phen Nation.” PBS Frontline, November 13, 2003. http://www.pbs.org/wgbh/pages/frontline/shows/prescription/hazard/fenphen.html (accessed March 27, 2018).
U.S. Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993-0002, (888) INFO-FDA (463-6332), http://www.fda.gov .
Sam Uretsky, PharmD