he estimated background risk of major birth defects and miscarriage for the indicatedpopulation is unknown. All pregnancies have 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.
Data
Animal Data
In pregnant rats and rabbits, no malformations were seen when brexanolone was given during theperiod of organogenesis at continuous intravenous doses up to 60 and 30 mg/kg/day,respectively. These doses were associated with maternal plasma levels 5 and 6 times the plasmalevels at the MRHD of 90 mcg/kg/hour, in rats and rabbits, respectively. In rats, a decrease infetal body weights was seen at 60 mg/kg/day (5 times the plasma level at the MRHD). In rabbits,increased numbers of late resorptions and a decrease in fetal body weights were seen at dosesequal to and greater than 15 mg/kg/day (3 times the plasma levels at the MRHD) with fewer live fetuses and a higher post implantation loss seen at 30 mg/kg/day (6 times the plasma levels at theMRHD) in the presence of maternal toxicity (decreased food consumption and decreased bodyweight gain and/or body weight loss). Effects in rats and rabbits were not seen at 2 and 1.2 timesthe plasma levels at the MRHD, respectively.
When brexanolone was administered to pregnant rats by continuous intravenous administrationat 30 and 60 mg/kg/day (2 and 5 times plasma levels at the MRHD, respectively) during theperiod of organogenesis and throughout pregnancy and lactation, increased numbers of deadpups and fewer live pups at birth were seen. This effect was not seen at 0.8 times the plasmalevels at the MRHD. Decreased pup viability between postnatal day 0 and 4 in the presence ofmaternal toxicity (decreased body weight gain and food consumption during lactation) was seenat 5 times the plasma levels at the MRHD. These effects were not seen at 2 times the plasmalevels at the MRHD. A neurobehavioral deficit, characterized by slower habituation in themaximal startle response in the auditory startle test, was seen in female offspring of dams dosedat 5 times the plasma levels at the MRHD. This effect was not seen at 2 times the plasma levels
at the MRHD.
8.2 Lactation
Risk Summary
Available data from a lactation study in 12 women indicate that brexanolone is transferred tobreastmilk in nursing mothers. However, the relative infant dose (RID) is low, 1% to 2% of thematernal weight-adjusted dosage (see Data). Also, as ZULRESSO has low oral bioavailability(<5%) in adults, infant exposure is expected to be low. There were no reports of effects ofZULRESSO on milk production.
There are no data on the effects of ZULRESSO on a breastfedinfant. Available data on the use of ZULRESSO during lactation do not suggest a significantrisk of adverse reactions to breastfed infants from exposure to ZULRESSO. The developmentaland health benefits of breastfeeding should be considered along with the mother’s clinical needfor ZULRESSO and any potential adverse effects on the breastfed child from ZULRESSO orfrom the underlying maternal condition.
Data
A study was conducted in twelve healthy adult lactating women treated with intravenousZULRESSO according to the recommended 60-hour dosing regimen (maximum dosage was
90 mcg/kg/hour). Concentrations of ZULRESSO in breast milk were at low levels (<10 ng/mL)in >95% of women by 36 hours after the end of the inf |
