Tirbanibulin

8.1 Pregnancy Risk Summary There are no available data with KLISYRI use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of tirbanibulin to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal deaths and malformations at a systemic exposure that was at least 19 times the exposure associated with the maximum recommended human dose (MRHD).

Oral administration of tirbanibulin to pregnant rabbits during the period of organogenesis resulted in reduced mean fetal weight and size at a systemic exposure that was 41 times the exposure associated with the MRHD ( 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 risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data Animal Data Tirbanibulin induced fetal deaths and external, visceral, and skeletal malformations when administered orally to pregnant rats during the period of organogenesis at doses greater than or equal to 1.25 mg/kg/day, which resulted in systemic exposures at least 19 times the exposure associated with the MRHD on an Area Under the Curve (AUC) comparison basis. Tirbanibulin had no apparent effects on fetal development in rats at a dose of 0.5 mg/kg/day, which resulted in systemic exposures 5 times the exposure associated with the MRHD.

Tirbanibulin reduced mean fetal weight and size (crown-rump length) when administered orally to pregnant rabbits during the period of organogenesis at a dose of 3 mg/kg/day, which resulted in a systemic exposure 41 times the exposure associated with the MRHD on an AUC comparison basis. Tirbanibulin had no apparent effects on fetal development in rabbits at a dose of 1 mg/kg/day, which resulted in systemic exposures 14 times the exposure associated with the MRHD. Tirbanibulin was assessed for effects on peri- and post-natal development of rats in a study that involved oral administration to pregnant rats during the period of organogenesis through lactation at dosages up to 1.25 mg/kg/day.

These dosages resulted in systemic exposures up to 19 times the exposure associated with the MRHD on an AUC comparison basis. No adverse effects on maternal function or developmental, neurobehavioral, or reproductive performance of offspring were…