8.1 Pregnancy

Risk Summary

Based on the mechanism of action and findings in animals, TIVDAK can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data on TIVDAK use in pregnant women to inform a drug-associated risk. In an animal reproduction study, administration of the small molecule component of TIVDAK, MMAE, to pregnant rats during organogenesis caused embryo-fetal mortality and structural abnormalities at exposures below the clinical exposure at the recommended dose (see Data). Advise patients of the potential risk to a fetus.

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%-4% and 15%-20%, respectively.

Data
Animal Data

No embryo-fetal development studies in animals have been performed with tisotumab vedotin-tftv. In an embryo-fetal development study in pregnant rats, administration of two intravenous doses of MMAE, the small molecule component of TIVDAK, on gestational days 6 and 13 caused embryo-fetal mortality and structural abnormalities, including protruding tongue, malrotated limbs, gastroschisis, and agnathia compared to controls at a dose of 0.2 mg/kg (approximately 0.5-fold the human area under the curve [AUC] at the recommended dose).

8.2 Lactation

Risk Summary

There are no data on the presence of tisotumab vedotin-tftv in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women not to breastfeed during treatment with TIVDAK and for 3 weeks after the last dose.

8.3 Females and Males of Reproductive Potential

TIVDAK can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy testing

Verify pregnancy status in females of reproductive potential prior to initiating TIVDAK treatment.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with TIVDAK and for 2 months after the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TIVDAK and for 4 months after the last dose.

Infertility

Females

Based on findings in animal studies with MMAE-containing antibody-drug conjugates (ADCs), TIVDAK may impair female fertility. The effect on fertility is reversible [see Nonclinical Toxicology (13.1)].

Males

Based on findings from animal studies, TIVDAK may impair male fertility [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Safety and effectiveness of TIVDAK in pediatric patients have not been established.

Nonclinical studies of tisotumab vedotin-tftv suggest a lack of anti-tumor activity and penetrance to brain based on limited in vivo data from tissue factor (TF)-expressing subcutaneous or orthotopic pediatric models of high‑grade gliomas/glioblastomas (HGG/GBM) and diffuse intrinsic pontine glioma (DIPG).

8.5 Geriatric Use

Of the 425 patients with cervical cancer treated with TIVDAK across clinical trials, 14% were ≥65 years of age and 2.4% were ≥75 years of age. Grade ≥3 adverse reactions occurred in 60% of patients ≥65 years and in 55% of patients <65 years. Drug was discontinued due to an adverse reaction in 25% of patients ≥65 years and in 13% of patients <65 years. Clinical studies of TIVDAK did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients.

8.6 Hepatic Impairment

Avoid use of TIVDAK in patients with moderate or severe hepatic impairment [aspartate aminotransferase (AST) > 3 x upper limit of normal (ULN) or total bilirubin > 1.5 × ULN] [see Clinical Pharmacology (12.3)].

In patients with mild hepatic impairment (total bilirubin ≤ ULN and AST >ULN or total bilirubin > 1 to 1.5 × ULN and any AST), closely monitor patients for adverse reactions of TIVDAK, but no dosage adjustment in the starting dose of TIVDAK is recommended.