FENFLURAMINE
Drugs in Pregnancy and Lactation.
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Name: FENFLURAMINE
Class: Anorexiant
Risk Factor: CM
Fetal Risk Summary
Fenfluramine is a sympathomimetic amine used as an anorectic agent in the treatment of obesity. Although its mechanism of action is unknown, it may be related to brain levels of serotonin or to increased glucose utilization (1). The mechanism of action of its dextrorotatory isomer, dexfenfluramine, is thought to be related to serotonin reuptake inhibition and release (see Dexfenfluramine).
A 1971 report described reproductive studies of fenfluramine, conducted in mice, rats, rabbits, and monkeys (Macaca mulatta), that found no evidence of structural teratogenicity but observed a dose-related reduction in the birth weight of rat pups (2). A decrease in birth weight was not seen in the other animals. Mice received 10 mg/kg/day; rats, 2, 10, or 20 mg/kg/day; rabbits, 10 or 40 mg/kg/day; and monkeys, 2 mg/kg/day. An unexplained increase in stillbirths of rat pups was observed in the group receiving 2 mg/kg/day. In pregnant monkeys, both fenfluramine and its deethylated metabolite readily crossed the placenta and were measured in amniotic fluid, 1.1 µg/10 mL and 0.36 µg/10 mL, respectively (maternal serum levels not specified) (2).
A significant increase in mortality, as well as a significant reduction in body weight, was observed during the preweaning period in offspring of rats given fenfluramine 20 mg/kg/day orally on days 7–20 of gestation (3). Moreover, although the body weight of fenfluramine-exposed offspring was no different from that of controls by 70 days of age, there was a significant reduction (4.7%) in brain weight. The amount of DNA in the brain and the neuronal cell count density in the cerebellum and hippocampus, however, were similar to those of controls. Behavioral teratogenicity was observed during several tests conducted during the preweaning period, with locomotor development (pivoting) being the most altered. The abnormal behavioral results were also described in a second, similar publication by some of these authors (4).
Two commercial formulations of fenfluramine (Pondimin and Redux) were given to adult female mice before mating and through gestational day 14 (5). Pregnancy outcomes in the two treated groups were compared to a placebo group (5). The doses used (10 mg/kg/day Pondimin and 5 mg/kg/day Redux) were equivalent to the human daily dose based on body surface area. No differences were observed between the three groups in conception rates, maternal food consumption and weight gain, duration of gestation, number of live births, and pup sex ratio. Body weight, length, and head circumference at birth through postnatal day 60 were also similar, as was the time to reach sexual maturation and development milestones (5).
A possible mechanism by which fenfluramine inhibits cortical serotonin fiber outgrowth in newborn rat pups was described in a 1994 paper (6). Using an in vitro preparation, the investigators demonstrated that fenfluramine invoked a large increase in serotonin release in fetal tissues, but not in the mother. They postulated that the increased extraneuronal concentration of serotonin in the fetus may be a mechanism by which fenfluramine has produced neurobehavior teratogenicity in animals (6). In an earlier study, however, researchers concluded that the serotonin-releasing action of fenfluramine had no effect on the development of descending spinal serotonergic pathways in rats (7).
A total of 40 women, 30 during the 3rd trimester and 10 during the first 3 days after delivery, were treated with fenfluramine 20 mg 3 times daily for obesity in a study published in 1969 (8). No adverse effects in the fetus or newborn were mentioned, but follow-up of the infants did not appear to have been conducted.
Six congenital malformations from pregnancies exposed to fenfluramine have been reported by the WHO International Drug Monitoring System (F. Rosa, personal communication, FDA, 1997). The anomalies were a urinary tract malformation, a fatal multiple defect involving the limbs and the gastrointestinal tract, ectromelia of one limb, a clubfoot, an atrial septal defect, and multiple nonspecified malformations. The FDA has received two reports involving the use of the combination, fenfluramine and phentermine, in early pregnancy (F. Rosa, personal communication, FDA, 1997). A spontaneous abortion occurred in one of the pregnancies. In the other, an infant with bilateral valvular abnormalities, both aortic and pulmonary, with moderate stenosis and displacement was delivered. Since valvular toxicity has been reported in adults taking the combination, a causal relationship in the pregnancy case is potentially possible. No other details of these cases were available.
In summary, fenfluramine is a behavioral teratogen in at least one animal species. It is not known if this occurs in humans, but, except for the cases above, only one study has described the use of fenfluramine during human pregnancy. Both fenfluramine and its metabolite readily cross the placenta in monkeys and presumably, because of the drug's low molecular weight (about 268), in humans. Because the benefits from use of this agent during gestation seem small and the potential risks seem large, the use of fenfluramine during pregnancy should be considered contraindicated. If weight loss is needed during pregnancy, then nonpharmacologic methods such as diet control combined with professional assistance should be used.
Breast Feeding Summary
No reports describing the use of fenfluramine during human lactation have been located. Its relatively low molecular weight (about 268) probably ensures its excretion into milk. Fenfluramine has demonstrated behavioral toxicity in animals exposed during pregnancy through a mechanism thought to involve the release of serotonin from neurons. Because fenfluramine is readily absorbed from the gastrointestinal tract and has a long plasma half-life (about 20 hours), the nursing infant could be exposed to a potentially neurotoxic agent during a period of rapid brain development. Therefore, the use of fenfluramine during breast feeding should be considered contraindicated.
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References
- Product information. Pondimin. A.H. Robins, 1997.
- Gilbert DL, Franko BV, Ward JW, Woodard G, Courtney KD. Toxicologic studies of fenfluramine. Toxicol Appl Pharmacol 1971;19:705–11.
- Vorhees CV, Brunner RL, Butcher RE. Psychotropic drugs as behavioral teratogens. Science 1979;205:1220–5.
- Butcher RE, Vorhees CV. A preliminary test battery for the investigation of the behavioral teratology of selected psychotropic drugs. Neurobehav Toxicol 1979;1(Suppl 1):207–12.
- Rayburn WF, Stewart JD, Gonzalez CL, Christensen HD. Effect of the antiobesity drug fenfluramine given prenatally on growth and development of mice offspring (abstract). Am J Obstet Gynecol 1998;178:S138.
- Kramer K, Azmitia EC, Whitaker-Azmitia PM. In vitro release of [3H]5-hydroxytryptamine from fetal and maternal brain by drugs of abuse. Brain Res Dev Brain Res 1994;78:142–6.
- Bell J III, Zhang X, Whitaker-Azmitia PM. 5-HT3 receptor-active drugs alter development of spinal serotonergic innervation: lack of effect of other serotonergic agents. Brain Res 1992;571:293–7.
- Soto ER, Urdapilleta JD. Fenfluoramina. Droga anorexigenica en la practica obstetrica. Ginecol Obstet Mex 1969;25:425–32.
Q&A about Fenfluramine
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I have read so many wrong answers about this drug. Phentermine was never banned! Doctors still prescribe it every day. It is availiable on the internet. Fenfluramine, is the drug that was banned. Thanks to the Media, people think now, that when a drug name starts with anything "phen or fen " its horrible. Search for the truth before telling someone about something as serious as drug information.
