Pregnancy: Risk Summary: Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman [see Pharmacology: Pharmacodynamics: Mechanism of Action under Actions]. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits [see Data as follows]. There are no available human data informing the drug-associated risk. 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 an embryofetal development study, daily oral administration of lenvatinib mesylate at doses ≥0.3 mg/kg [approximately 0.14 times the recommended clinical dose of 24 mg based on body surface area (BSA)] to pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed fetal ossifications, and dose-related increases in fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies. Greater than 80% postimplantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).
Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal external (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies at doses greater than or equal to 0.03 mg/kg (approximately 0.03 times the recommended clinical dose of 24 mg based on BSA). At the 0.03 mg/kg dose, increased post-implantation loss, including 1 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at a dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).
Lactation: Risk Summary: It is not known whether LENVIMA is present in human milk; however, lenvatinib and its metabolites are excreted in rat milk at concentrations higher than those in maternal plasma [see Data as follows]. Because of the potential for serious adverse reactions in breastfed infants, advise women to discontinue breastfeeding during treatment with LENVIMA and for at least 1 week after the last dose.
Data: Animal Data: Following administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related radioactivity was approximately 2 times higher [based on area under the curve (AUC)] in milk compared to maternal plasma.
Females and Males of Reproductive Potential: Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating LENVIMA [see Pregnancy as previously mentioned].
Contraception: Based on its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman [see Pregnancy as previously mentioned].
Females: Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 30 days after the last dose.
Infertility: LENVIMA may impair fertility in males and females of reproductive potential [see Pharmacology: Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions].