Pregnancy & Breastfeeding
8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , HYRNUO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of HYRNUO in pregnant women to inform a drug-associated risk. In embryo-fetal development studies, oral administration of sevabertinib to pregnant rats during the period of organogenesis resulted in alterations to growth at maternal exposures ≥0.18 times the human exposure based on area under the curve (AUC) at the clinical dose of 20 mg twice daily. Animal studies with disrupted or depleted HER2/EGFR and in vitro assays have demonstrated that inhibition of HER2 and/or EGFR results in structural abnormalities, alteration to growth, and embryo-fetal and infant mortality (see Data ) . Advise pregnant women of the potential risk to a fetus. 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 In embryo-fetal development studies, sevabertinib was administered orally to pregnant rats during the period of organogenesis from gestation day 6 to 17 at doses ranging from 1.5 to 11 mg/kg/day. Sevabertinib treatment resulted in maternal toxicity (reduced body weight and body weight gain) and a reduction in fetal weights at ≥6 mg/kg/day (≥0.18 times the human exposure based on AUC at the clinical dose). Additional Nonclinical Data A literature-based assessment of the effects on reproduction in mouse models with disrupted or depleted HER2 / EGFR demonstrated that HER2/EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. In a human-induced pluripotent stem cell-based assay, sevabertinib reduced cardiomyocyte and hepatocyte differentiation markers.