Risk Summary

There are limited and incomplete human data from clinical trials and postmarketing reports on the use of SYMDEKO or its individual components, tezacaftor and ivacaftor, in pregnant women to inform a drug-associated risk. Although there are no animal reproduction studies with the concomitant administration of tezacaftor and ivacaftor, separate reproductive and developmental studies were conducted with tezacaftor and ivacaftor in pregnant rats and rabbits. In animal reproduction studies, oral administration of tezacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse developmental effects at doses that produced maternal exposures up to approximately 3 times the exposure at the maximum recommended human dose (MRHD) in rats and 0.2 times the MRHD in rabbits (based on summed AUCs for tezacaftor and M1 metabolite). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse developmental effects at doses that produced maternal exposures up to approximately 6 and 16 times the exposure at the MRHD, respectively. No adverse developmental effects were observed after oral administration of either tezacaftor or ivacaftor to pregnant rats from the period of organogenesis through lactation at doses that produced maternal exposures approximately 1 and 4 times the exposures at the MRHD, respectively (see Data). 

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Tezacaftor

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days 6-17, tezacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 3 times the MRHD (based on summed AUCs for tezacaftor and M1 metabolite at maternal oral doses up to 100 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation Days 7-20, tezacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 0.2 times the MRHD (based on summed AUCs for tezacaftor and M1 metabolite at maternal oral doses up to 25 mg/kg/day). Lower fetal body weights were observed in rabbits at a maternally toxic dose that produced exposures approximately 1 times the MRHD (at a maternal dose of 50 mg/kg/day). In a pre- and postnatal development (PPND) study in pregnant rats dosed from gestation Day 6 through lactation Day 18, tezacaftor had no adverse developmental effects on pups at an exposure of approximately 1 times the MRHD (based on summed AUCs for tezacaftor and M1 metabolite at a maternal dose of 25 mg/kg/day). Decreased fetal body weights and early developmental delays in pinna detachment, eye opening, and righting reflex occurred at a maternally toxic dose (based on maternal weight loss) that produced exposures approximately 2 times the exposure at the MRHD (based on summed AUCs for tezacaftor and M1 metabolite at a maternal oral dose of 50 mg/kg/day). Placental transfer of tezacaftor was observed in pregnant rats.

Ivacaftor

In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days 7-17, ivacaftor was not teratogenic and did not affect fetal survival at exposures up to 6 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation Days 7-19, ivacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 16 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). In a PPND study in pregnant rats dosed from gestation Day 7 through lactation Day 20, ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 4 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 6 times the MRHD. Placental transfer of ivacaftor was observed in pregnant rats and rabbits.