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Fen-Phen was an anti-obesity regimen composed of fenfluramine or the closely related drug dexfenflur-amine (marketed under the brand name Redux) and phentermine (sold under several brand names including Adipex-P, Anoxine-AM, Fastin, Ionamin. Obe-phen, Obermine, Obestin-30 and Phentrol). The combination was found to cause damage to heart valves, and fenfluramine and dexfenfluramine were removed from the United States market in 1997.
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. It’s 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 the amphetamines.
Fenfluramine was approved by the FDA in 1973 and dexfenfluramine (Redux) was approved for use in 1996. Fenfluramine is the racemic form of dexfenflur-amine. The drugs were approved for short term use as part of a program of diet and exercise. Although fen-fluramine is chemically related to the amphetamines, its action appears to be based on increasing levels of.
serotonin in the brain and blood stream. Ddexfenflur-amine had been marketed in Europe for over a decade without detection of an association between dexfen-fluramine 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 1992, a research group from the University of Rochester published reports indicating that the combination of fenfluramine and phentermine might be a valuable adjunct to diet and exercise in a controlled program of weight loss. A total of 121 patients were initially enrolled in the study, and 9 dropped out during the active study period. After the first 34 weeks of the study, patients on the fen-phen regimen had lost an average of 14.2 Kg, compared with a 4.9 Kg. weight loss in the placebo control group. The researchers noted that upon discontinuation of the drugs, patients regained most of the weight lost during the study, and after 210 weeks, the agerage weight loss was only 1.4 Kg below the baseline. Patients who had received active drug tended to regain weight more rapidly than those who received placebo. The authors concluded that despite long periods of time at weights much lower than baseline, permanent resetting of weight control mechanisms could not be shown for most participants.
In spite of the disappointing long term results, these reports lead 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 (roughly $209 million in 2006 dollars). No long term studies were performed for these dtrugs, 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 30th, the FDA had received a total of 144 reports of heart value problems associated with fenfluramine, with or without phentermine.
On November 19, 1997, the Centers for Communicable Disease Cintrol 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 (5%), 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 Admibnistration 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 fenflursamine will be monitored for heart valve problems for a period of 20 years.
Although fenphen has been associeted 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 (eg, 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 persons who had taken a combination of phentermine with fenflur-amine or dexfenfluramine for weight loss. The etiology of these valvulopathies has not been established and their course in individuals after the drugs are 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 have taken 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.
Mono-amine 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 fura-zolidone, 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 who had been exposed to fen-fluramine, aftercare depends on the extent of damage. For those patients with significant heart valve damage, surgical valve replacement may be in order. Those who received the drug but show no damage should 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.
Phentermine is not indicated for patients under the age of 16 years.
Reynolds JEF, Prasad AB Martindale The Extra Pharmacopoeia 28th edition, The Pharmaceutical Press, London 1982.
Kannengiesser MH, Hunt PE, Raynaud JP
Weintraub M, Sundaresan PR, 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. Clin Pharmacol Ther 1992 May;51(5):595-601.
Weintraub M, Sundaresan PR, et alLong-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. Clin. Pharmacol Ther 1992 May;51(5):595-601.
Weintraub M, Sundaresan PR, et alLong-term weight control study V (weeks 190 to 210). Follow-up of participants after cessation of medication. Clin. Pharmacol Ther 1992 May;51(5):615-8.
Connolly HM, Crary JL, McGoon MD, et alValvular heart disease associated with fenfluraminephentermine. N Engl J Med 1997;337:581 8.
American Obesity Association. 1250 24th Street, NW, Suite 300, Washington, DC 20037. 800-98-OBESE (800-986-2373).
Food and Drug Administration. U.S. Department of Health and Human Services, Public Health Service, 5600 Fishers Lane, Rockville, MD 20857.
Weight-control Information Network (WIN). National Institute of Diabetes and Digestive and Kidney Diseases. 1 Win Way, Bethesda, MD 20892-3665. 877-946-4627. 202-828-1025.
Sam Uretsky, PharmD.