Etripamil

8.1 Pregnancy Risk Summary There are no available data on the use of CARDAMYST during pregnancy to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Reproductive studies conducted with intravenous administration of etripamil in pregnant rats and rabbits during organogenesis did not show any evidence of fetal harm or malformations in rats at exposures up to approximately 3x the maximum concentration (C max ) and 0.4x the AUC at the maximum recommended human dose (MRHD) and in rabbits at exposures approximately equivalent to the C max and 10x the AUC at the MRHD, at which maternal toxicities were observed (see Data ).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data In pregnant rats, intravenous administration of etripamil throughout the period of organogenesis did not result in any adverse effects on embryofetal development at doses up to 0.375 mg/kg/day, approximately 3x the C max and 0.4x the AUC at the MRHD.

In pregnant rabbits, intravenous administration of etripamil throughout the period of organogenesis did not result in embryofetal abnormalities at doses up to 0.1 mg/kg/day, approximately equivalent to the C max and 10x the AUC at the MRHD. Abortion in one animal was noted at the high dose of 0.1 mg/kg/day, a dose that caused maternal toxicity. In the pre- and post-natal toxicity study in rats, intravenous administration of etripamil from gestation day 7 through the lactation period (post-partum day 20), did not show any adverse effects on pre- and postnatal development at doses up to 0.374 mg/kg/day, approximately 3x the C max and 0.4x the AUC at the MRHD.

Post-implantation loss was noted at 0.374 mg/kg/day, a dose that also caused significant maternal toxicity, including mortality, transient adverse clinical signs, and body weight reduction.