e period of peak brain development increasesneuronal apoptosis in the developing brain of the offspring. There are no data on pregnancyexposures in primates corresponding to periods prior to the third trimester in humans [see Use inSpecific Populations (8.2)].
In an embryo-fetal reproduction study in rabbits, skeletal malformations were noted atmaternally toxic doses when ketamine was intranasally administered with a No ObservedAdverse Effect Level (NOAEL) at estimated esketamine exposures 0.3 times the exposures at themaximum recommended human dose (MRHD) of 84 mg/day. In addition, intranasaladministration of esketamine to pregnant rats during pregnancy and lactation at exposures thatwere similar to those at the MRHD resulted in a delay insensorimotor development in pupsduring the preweaning period and a decrease in motor activity in the post-weaning period.
The estimated background risk of major birth defects and miscarriage for the indicatedpopulation is unknown. All pregnancies have a background risk of birth defect, loss, or otheradverse outcomes. In the U.S. general population, the estimated background risk of major birthdefects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%,respectively。
Clinical Considerations
Disease-Associated Maternal and/or Embryo-Fetal RiskA prospective, longitudinal study followed 201 pregnant women with a history of majordepressive disorder who were euthymic and taking antidepressants at the beginning ofpregnancy. The women who discontinued antidepressants during pregnancy were more likely toexperience a relapse of major depression than women who continued antidepressants. Considerthe risk of untreated depression when discontinuing or changing treatment with antidepressant
medication during pregnancy and postpartum.
Data
Animal Data
Based on published data, when female monkeys were treated intravenously with racemicketamine at anesthetic dose levels in the third trimester of pregnancy, neuronal cell death wasobserved in the brains of their fetuses. This period of brain development translates into the thirdtrimester of human pregnancy. The clinical significance of these findings is not clear; however,studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits.
Racemic ketamine was administered intranasally to pregnant rats during the period oforganogenesis at doses of 15, 50, and 150 mg/kg/day. The No Observed Adverse Effect level(NOAEL) for embryo-fetal toxicity in rats was the highest dose of 150 mg/kg/day. Estimating50% of the exposure to be from esketamine, the NOAEL associated with esketamine plasmaexposure (AUC) is 12-times the AUC exposure at the MRHD of 84 mg/day. In pregnant rabbits,racemic ketamine was administered intranasally from gestational day 6 to 18 at doses of 10, 30,and 100 mg/kg/day. The high dose was lowered from 100 to 50 mg/kg after 5 days of dosing dueto excessive mortality in the pregnant rabbits. Skeletal malformations were observed at doses≥ 30mg/kg/day, which were maternally toxic. The NOAEL for skeletal malformations was
associated with a plasma esketamine exposure (AUC) that was 0.3 times the AUC exposure atMRHD of 84 mg/day.
Administration of esketamine to pregnant rats during pregnancy and lactation at intranasal dosesequivalent to 4.5, 15, and 45 mg/kg/day (based on a 200-gram rat) produced AUC exposures0.07, 0.5, and 0.7 times the MRHD of 84 mg/day, respectively. Maternal t |
