Hypnotic
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of zaleplon in human pregnancy have been located. The agent does compare favorably to other hypnotic benzodiazepine receptor agonists due to its rapid onset (15 minutes), short elimination half-life, and the absence of active metabolites (1). The drug is not an animal teratogen and the risk of human teratogenicity is probably low. However, information from studies in one of the animal species suggests that long-term use could potentially result in human embryo–fetal toxicity. Therefore, the use of zaleplon in pregnancy should be restricted to occasional, short-term treatment (e.g., 7–10 days).
FETAL RISK SUMMARY
The oral hypnotic, zaleplon, is chemically unrelated to benzodiazepines, barbiturates, and other known hypnotic agents, but it is a benzodiazepine receptor agonist. It is indicated for the short-term (e.g., 7–10 days) treatment of insomnia. Zaleplon undergoes substantial presystemic metabolism that significantly reduces its absolute bioavailability. Nearly all of zaleplon is metabolized to inactive metabolites. Plasma protein binding is moderate (about 60%) and the terminal-phase elimination half-life is short (about 1 hour). Zaleplon has an abuse potential similar to benzodiazepines and benzodiazepine-like hypnotics (2).
Reproduction studies have been conducted in rats and rabbits. No evidence of teratogenicity was observed in rats treated throughout organogenesis with doses up to about 49 times the maximum recommended human dose of 20 mg based on BSA (MRHD). At the maximum dose, pre- and postnatal growth was decreased in rat offspring, but this dose was also maternally toxic (clinical signs and reduced body weight). Fertility and reproductive performance in female rats was also impaired at the maximum dose. The no-effect dose during organogenesis for reduced growth in offspring was 5 times the MRHD. However, treatment of pregnant rats in late gestation and during lactation, with a dose that did not cause maternal toxicity (about 3.4 times the MRHD or greater), did result in an increased incidence of stillbirth and postnatal death, as well as decreased growth and physical development. The toxicity was thought to have resulted from both in utero and lactational exposure to the drug. For exposure in late gestation and during lactation, the no-effect dose was about half the MRHD. In rabbits, no evidence of teratogenicity or embryo/fetal toxicity was observed at doses up to 48 times the MRHD given throughout organogenesis (2).
It is not known if zaleplon crosses the human placenta. The molecular weight (about 305) is low enough, but the short elimination half-life will limit the amount of drug available at the maternal:fetal interface.
In a study published in 2011, data from the Swedish Medical Birth Registry, covering the period 1995–2007, identified 1318 women who gave birth to 1341 infants and who reported the use of a hypnotic benzodiazepine receptor agonist at the first prenatal visit (3). The three most commonly reported agents and the number of exposed infants were zopiclone (N = 692) (not available in USA), zolpidem (N = 603), and zaleplon (N = 32). The reference group during the study period was 1,106,001 women who gave birth to 1,125,734 infants. The rate of congenital malformations was similar in the exposed and nonexposed groups, 4.3% (N = 58) and 4.7% (N = 52,773), adjusted odds ratio (aOR) 0.89, 95% confidence interval (CI) 0.68–1.16. One mother who had two infants with probably unrelated malformations (cleft lip and hypospadias) had used zopiclone in both pregnancies. For relatively severe defects, there were 42 exposed infants (3.1%) compared with 36,321 nonexposed infants (3.2%), aOR 0.95, 95% CI 0.0.69–1.30. The authors concluded that use of these agents did not appear to increase the risk of malformations (3).
BREASTFEEDING SUMMARY
Small amounts of zaleplon are excreted into breast milk (2,4). In a study by the manufacturer, the peak drug concentrations in milk occurred about 1 hour after a 10-mg dose. The mean plasma elimination half-life in five lactating women (mean weight 65.1 kg) was about 1 hour, similar to nonlactating women (2,4). The average milk:plasma ratio was 0.5 (4). The investigators estimated the maximum infant exposure during a feeding at peak milk concentrations to be in the range of 1.28–1.66 mcg (4). As the women did not breastfeed during the study, the effects of this exposure on a nursing infant are unknown. For a 65.1-kg woman nursing a 4-kg infant, the maximum estimated infant dose, as a percentage of the mother’s dose, is 0.27%. It is doubtful if this amount from a 10-mg dose would have a clinically significant effect on a nursing infant. In addition, within 5 hours of a dose, about 97% of the drug will be eliminated from the maternal plasma and milk.
References
1.Hunt CE, ed. Sleep problems and sleep disorders. As cited in Clinical Updates in Women’s Health Care. Washington, DC: American College of Obstetricians and Gynecologists, 2004;3 (April):66–7.
2.Product information. Sonata. Monarch Pharmaceuticals, 2004.
3.Wikner BN, Kallen B. Are hypnotic benzodiazepine receptor agonists teratogenic in humans? J Clin Psychopharmacol 2011;31:356–9.
4.Darwish M, Martin PT, Cevallos WH, Tse S, Wheeler S, Troy SM. Rapid disappearance of zaleplon from breast milk after oral administration to lactating women. J Clin Pharmacol 1999;39:670–4.