Pregnancy & Breastfeeding
8.1 Pregnancy Risk Summary Based on findings in animal studies and its mechanism of action, FOTIVDA can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY (12.1) ] . There are no available data on FOTIVDA use in pregnant woman to inform the drug-associated risk. In embryo-fetal developmental studies, oral administration of tivozanib to pregnant animals during the period of organogenesis caused maternal toxicity, fetal malformations and embryo- fetal death at doses below the maximum recommended clinical dose on a mg/m 2 basis [see DATA ] . Advise pregnant woman of the potential risk to a fetus. The estimated 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% to 4% and 15% to 20% respectively. Data Animal Data In an embryo-fetal developmental study in pregnant rats, daily oral administration of tivozanib at doses ≥ 0.03 mg/kg/day (0.2 times the maximum recommended clinical dose on a mg/m 2 basis) during the period of organogenesis resulted in maternal toxicity, increases in early and late resorptions, and an increase in fetal external malformations (body edema, short/kinked tail), and skeletal developmental delays. In an embryo-fetal developmental study in pregnant rabbits, daily oral administration of tivozanib at 1 mg/kg/day (14.5 times the maximum recommended clinical dose on a mg/m 2 basis) during the period of organogenesis resulted in fetal malformations including ventricular septal defects and major vessel anomalies. No maternal toxicity was reported at doses up to 1 mg/kg/day.