FLURAZEPAM

Fetal Risk Summary

Flurazepam is a benzodiazepine used to induce sleep. No teratogenic or other adverse fetal or postnatal effects were observed in studies using rats and rabbits administered 80 mg/kg and 20 mg/kg, respectively, during various stages of gestation (1). Similarly, no reports of congenital abnormalities attributable to human exposure with flurazepam have been located. One group of investigators classified the risk to the fetus from exposure to flurazepam as “none-minimal,” but the quality of the data was judged to be “poor.” (2) Studies involving other members of this class, however, have found evidence that some of these agents may cause fetal abnormalities (see Chlordiazepoxide and Diazepam).

Although published data are lacking, the low molecular weight of flurazepam (approximately 461) suggests it is transferred to the fetus. Data from the manufacturer indicate that an active metabolite of flurazepam crosses the human placenta and may adversely affect the newborn (3). In a case cited in their product information, a woman ingested flurazepam, 30 mg nightly, for 10 days immediately preceding delivery. The newborn appeared sleepy and lethargic during the first 4 days of life. The effect was thought to be due to a long-acting metabolite, N1-desalkylflurazepam, found in the newborn's serum.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 73 newborns had been exposed to flurazepam during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Four (5.5%) (3 expected) major birth defects were observed, including (observed/expected) 2/1 cardiovascular defects, 1/0 oral clefts, and 1/0 polydactyly. These data do not support an association between the drug and congenital defects.

A brief 1982 case report described convulsions attributable to clomipramine in a newborn who was exposed to that drug and flurazepam throughout gestation (4). The 2360-g male infant was delivered vaginally at 33 weeks' gestation (the reason for the premature delivery was not stated) and had Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. Convulsions, consisting of myoclonic jerks that were unresponsive to phenobarbital, started at 7 hours of age and were eventually successfully treated with IV and oral clomipramine, although the infant remained jittery. The contribution of flurazepam, which is known to cause convulsions after abrupt withdrawal following prolonged use in adults, to the seizures observed in the newborn is unknown. However, a correlation between declining serum levels of clomipramine and its active metabolite and the condition of the infant probably indicates that the seizures were not due to flurazepam.

Breast Feeding Summary

Studies examining the excretion of flurazepam into breast milk have not been located. However, the passage of this agent and its active, long-acting metabolite into milk should be expected (see also Diazepam). The American Academy of Pediatrics classifies other benzodiazepines, such as diazepam, as agents whose effects on the nursing infant are unknown, but they may be of concern (5).

References

1. Hoffmann-LaRoche Company, personal communication, 1979. As cited by Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:285.
2. Friedman JM, Little BB, Brent RL, Cordero JF, Hanson JW, Shepard TH. Potential human teratogenicity of frequently prescribed drugs. Obstet Gynecol 1990;75:594–9.
3. Product information. Dalmane. Roche Laboratories, 1993.
4. Cowe L, Lloyd DJ, Dawling S. Neonatal convulsions caused by withdrawal from maternal clomipramine. Br Med J 1982;284:1837–8.
5. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.