ZOLPIDEM

Fetal Risk Summary

Zolpidem is a nonbenzodiazepine hypnotic of the imidazopyridine class. In subjects with normal liver function, a single 5-mg dose zolpidem had a relatively short elimination half-life (2.6 hours, range 1.4–4.5 hours) (1).

In reproductive studies in rats no teratogenic effects were observed, but dose-related toxicity was observed in the fetuses (delayed maturation as characterized by incomplete ossification of the skull) at doses of 20 and 100 mg base/kg (1). The no-effect dose (4 mg base/kg) was 5 times the maximum human dose on a mg/m2 basis (MHD). In rabbits, increased postimplantation fetal loss and incomplete ossification of the sternum in surviving fetuses were observed at 16 mg base/kg, both possibly related to reduced maternal weight gain (1). The no-effect dose in rabbits was 4 mg base/kg (7 times the MHD). No teratogenic effects of the drug were observed. Shepard reviewed a reproductive toxicity study in rats during organogenesis that found no teratogenicity, but did observe a decrease in fetal weight at doses ranging from 5 to 125 mg/kg and an increase in wavy ribs at the highest dose (2).

It is not known if zolpidem crosses the human placenta. The molecular weight (about 765 for the tartrate salt) is low enough, however, that embryo/fetal exposure to the drug should be expected.

The FDA did not receive any reports of adverse fetal or newborn outcomes from pregnancy exposures to zolpidem between its approval in December 1992 and 1996 (personal communication, F. Rosa, FDA, 1996).

A 1998 noninterventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (3). Data were obtained by questionnaires sent to the prescribing physicians 1 month after the expected or possible date of delivery. In 831 (78%) pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Zolpidem was taken during the 1st trimester in 18 pregnancies. The outcomes of these pregnancies included two spontaneous abortions, six elective abortions and 11 normal, term infants (one set of twins) (3).

Although no congenital malformations were observed in the above study, the data are too limited to assess the safety of zolpidem in the human embryo or fetus. Moreover, the study lacked the sensitivity to identify minor anomalies because of the absence of standardized examinations. Late-appearing major defects may also have been missed due to the timing of the questionnaires. Further, chronic maternal use of sedatives/hypnotics has been associated with withdrawal symptoms in newborns.

Breast Feeding Summary

Zolpidem is excreted into human breast milk, but the effects, if any, on a nursing infant have not been studied. In a 1989 report, five lactating women were administered a single 20-mg dose 3–4 days after delivery of a full-term infant (4). Breast feeding was halted for 24 hours after drug administration. Milk and serum samples were collected before and 1.5 (serum only), 3, 13, and 16 hours after the dose. The total amount of zolpidem in milk at 3 hours (both breasts emptied with an electric breast pump and the milk pooled for each woman) ranged from 0.76 to 3.88 µg, representing 0.004%–0.019% of the dose. The drug was not detected in milk (detection level 0.5 ng/mL) at the other sampling times. The dose used in this study is twice the current maximum recommended human hypnotic dose.

In healthy adult patients, zolpidem has a relatively short serum half-life (about 2.6 hours) and accumulation is not expected to occur. The small amount of drug measured in milk after a dose that was twice the recommended human dose probably indicates that few, if any, adverse effects would occur in a nursing infant whose mother was consuming this hypnotic. In those instances in which the mother is taking zolpidem, however, she should observe her nursing infant for increased sedation, lethargy, and changes in feeding habits. Based on the one study above, the American Academy of Pediatrics considers zolpidem to be compatible with breast feeding (5).

References

1. Product information. Ambien. G.D. Searle, 2000.
2. Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:231.
3. Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:882–9.
4. Pons G, Francoual C, Guillet Ph, Moran C, Hermann Ph, Bianchetti G, Thiercelin J-F, Thenot J-P, Olive G. Zolpidem excretion in breast milk. Eur J Clin Pharmacol 1989;37:245–8.
5. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.