Definition :
Fen-Phen was an anti-obesity regimen composed of fenfluramine or the closely related drug dexfenfluramine (marketed under the brand name Redux) and phentermine (sold under several brand names including Adipex-P, Anoxine-AM, Fastin, Ionamin. Obephen, 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.
Purpose :
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.
Description :
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 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 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 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 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 average 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 fenflurs-amine will be 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.
Precautions :
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 fenfluramine 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.
Interactions :
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 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.
Aftercare :
For those patients who had been exposed to fenfluramine, 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.
Parental concerns :
Phentermine is not indicated for patients under
the age of 16 years.
Post a Comment