Hypnotic
PREGNANCY RECOMMENDATION:Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION:Limited Human Data—Probably Compatible*
PREGNANCY SUMMARY
Limited reports describing the use of flurazepam in human pregnancy have been located. The effects of this drug on the fetus should be similar to other benzodiazepines (see Diazepam). Maternal use near delivery may potentially cause neonatal motor depression and withdrawal.
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 molecular weight of flurazepam (about 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%) (three 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.
BREASTFEEDING SUMMARY
Studies measuring the amount of flurazepam excreted 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 effects of exposure to benzodiazepines during breastfeeding were reported in a 2012 study (5). In a 15-month period spanning 2010–2011, 296 women called the Motherisk Program in Toronto, Ontario, seeking advice on the use of these drugs during lactation, and 124 consented to the study. The most commonly used benzodiazepines were lorazepam (52%), clonazepam (18%), and midazolam (15%). Neonatal sedation was reported in only two infants. There was no significant difference between the characteristics of these 2 and the 122 that reported no sedation in terms of maternal age, gestational age at birth, daily amount of time nursing, amount of time infant slept each day, and the benzodiazepine dose (mg/kg/day). The only difference was in the number of CNS depressants that the mothers were taking: 3.5 vs. 1.7 (p = 0.0056). In the two infants with sedation, one mother reported using alprazolam (two doses of 0.25 mg), sertraline (50 mg/day), and zopiclone (about 2.5 mg every 3 days), whereas the other mother took clonazepam (0.25 mg twice daily), flurazepam (1 mg/day), bupropion (1 mg/day), and risperidone (0.75 mg/day). The infant in this latter case also was exposed in utero. The investigators concluded that their results supported the recommendation that the use benzodiazepines was not a reason to avoid breastfeeding (5).
The American Academy of Pediatrics classifies the effects of lorazepam on the nursing infant as unknown but may be of concern if exposure is prolonged (6).
*Potential toxicity if combined with other CNS depressants
References
1.Hoffmann-LaRoche Company, Personal Communication, 1979. As cited by Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: The 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.Kelly LE, Poon S, Madadi P, Koren G. Neonatal benzodiazepines exposure during breastfeeding. J Pediatr 2012;161:448–51.
6.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.