Hypnotic
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use eszopiclone in human pregnancy have been located. The animal data suggest low risk, but the absence of human pregnancy experience prevents further assessment. However, there is human pregnancy experience with racemic zopiclone. A small 1999 observational study compared the pregnancy outcomes of 40 women exposed in the 1st trimester to zopiclone with those of 40 nonexposed controls (1,2). The outcomes in the two groups were spontaneous abortions 7 vs. 3, respectively; elective abortions 1 vs. 0, respectively; and minor defects 1 vs. 1 (congenital dislocation of the hip in each group), respectively. No difference between the groups in the incidence of major defects was observed: 0/31 (0%) exposed vs. 1/37 (2.7%) controls. Taken in sum, the available data suggest that eszopiclone exposure in pregnancy probably is low risk, but until data are available, the safest course would be use a hypnotic agent with published human pregnancy experience.
FETAL RISK SUMMARY
Eszopiclone is an oral nonbenzodiazepine sedative/hypnotic. It is the active component [(S)-isomer] of racemic zopiclone [(R,S)-zopiclone], a sedative/hypnotic that has been available outside the United States since the 1980s. Eszopiclone is indicated for the treatment of insomnia. It is extensively metabolized to inactive metabolites. Plasma protein binding is low, in the range of 52%–59%, and the terminal elimination half-life is about 6 hours (3).
Reproduction studies with eszopiclone have been conducted in rats and rabbits. In rats, oral doses during organogenesis up to 800 times the maximum recommended human dose based on BSA (MRHD-BSA), a maternal toxic dose, revealed no evidence of structural defects in the fetuses. Slight reductions in fetal weight and evidence of developmental delay were observed with doses about 400 times the MRHD-BSA that also were maternal toxic. These fetal effects were not observed with a nontoxic maternal dose (about 200 times the MRHD-BSA). When eszopiclone was administered throughout pregnancy and lactation at doses ranging from about 200 to 600 times the MRHD-BSA, increased postimplantation loss, decreased postnatal pup weights and survival, and increased pup startle response were seen at all doses. No structural defects were observed in rabbits given oral doses during organogenesis up to 100 times the MRHD-BSA (3).
In female and male rats, the no-effect eszopiclone dose for fertility was 16 times the MRHD-BSA. The no-effect doses for increased preimplantation loss, abnormal estrus cycles, and decreases in sperm number and motility and increases in abnormal sperm were 80, 80, and 16 times, respectively, the MRHD-BSA (3).
Eszopiclone was not carcinogenic in female and male rats given gavage doses resulting in plasma concentrations about 80 and 20 times, respectively, the maximum recommended dose based on AUC (MRHD-AUC) (1). When racemic zopiclone was given in the diet to female and male rats, eszopiclone plasma concentrations were about 150 and 70 times, respectively, the MRHD-AUC. In this study, an increase in mammary gland adenocarcinoma (females) and thyroid gland follicular cell adenomas and carcinomas (males) were observed. Carcinogenicity (pulmonary carcinomas and carcinomas plus adenomas) also was noted in female mice given racemic zopiclone in a diet that resulted in eszopiclone plasma concentrations about eight times the MRHD-AUC. However, an increase in pulmonary tumors was not observed in female mice given gavage doses of eszopiclone resulting in plasma concentrations about 90 times the MRHD-AUC. In tests for mutagenicity or clastogenicity, eszopiclone and one of its metabolites produced mixed results. Results of various assays ranged from positive through equivocal to negative (3).
It is not known if eszopiclone crosses the human placenta. The low molecular weight (about 389), low plasma protein binding, and moderately long elimination half-life suggest that the drug will cross to the embryo and/or fetus. However, the extensive metabolism should limit the degree of embryo–fetal exposure.
BREASTFEEDING SUMMARY
No reports describing the use of eszopiclone [(S)-zopiclone)] during human lactation have been located. However, racemic zopiclone is excreted into breast milk. A 1982/1983 study found a milk:plasma AUC ratio of about 0.60 and 0.80 (both values reported) after a single 7.5-mg oral dose of zopiclone in three nursing mothers (4,5). For eszopiclone, the molecular weight (about 389), low plasma protein binding (52%–59%), and moderately long elimination half-life (about 6 hours) suggest that it also will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown, but sedation is a potential effect. In addition, there is concern for central nervous system toxicity with long-term use.
References
1.Diav-Citrin O, Okotore B, Lucarelli K, Koren G. Pregnancy outcome following first trimester exposure to zopiclone: a prospective controlled cohort study. Am J Perinatol 1999;16:157–60.
2.Diav-Citrin O, Okotore B, Lucarelli K, Koren G. Zopiclone use during pregnancy. Can Fam Physician 2000;46:63–4.
3.Product information. Lunesta. Sepracor, 2005.
4.Gaillot J, Heusse D, Houghton GW, Marc Aurele J, Dreyfus JF. Pharmacokinetics and metabolism of zopiclone. Int Pharmacopsychiatry 1982;17(Suppl 2):76–91.
5.Gaillot J, Heusse D, Houghton GW, Marc Aurele J, Dreyfus JF. Pharmacokinetics and metabolism of zopiclone. Pharmacology 1983;27(Suppl 2): 76–91.