gs from animal studies, and its mechanism of action [see ClinicalPharmacology (12.1)], VITRAKVI can cause embryo-fetal harm when administered to apregnant woman. There are no available data on VITRAKVI use in pregnant women.
Administration of larotrectinib to pregnant rats and rabbits during the period of organogenesisresulted in malformations at maternal exposures that were approximately 11- and 0.7-times,respectively, those observed at the clinical dose of 100 mg twice daily (see Data). Advisepregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects andmiscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Human Data
Published reports of individuals with congenital mutations in TRK pathway proteins suggest thatdecreases in TRK-mediated signaling are correlated with obesity, developmental delays,cognitive impairment, insensitivity to pain, and anhidrosis.
Animal Data
Larotrectinib crosses the placenta in animals. Larotrectinib did not result in embryolethality atmaternally toxic doses [up to 40 times the human exposure based on area under the curve (AUC)at the clinical dose of 100 mg twice daily] in embryo-fetal development studies in pregnant ratsdosed during the period of organogenesis; however, larotrectinib was associated with fetalanasarca in rats from dams treated at twice-daily doses of 40 mg/kg [11 times the humanexposure (AUC) at the clinical dose of 100 mg twice daily]. In pregnant rabbits, larotrectinibadministration was associated with omphalocele at twice-daily doses of 15 mg/kg (0.7 times the
human exposure at the clinical dose of 100 mg twice daily).
8.2 Lactation
Risk Summary
There are no data on the presence of larotrectinib or its metabolites in human milk and no data onits effects on the breastfed child or on milk production. Because of the potential for seriousadverse reactions in breastfed children, advise women not to breastfeed during treatment withlarotrectinib and for 1 week after the final dose.
8.3 Females and Males of Reproductive Potential
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating VITRAKVI[see Use in Specific Populations (8.1)].
ContraceptionVITRAKVI can cause embryo-fetal harm when administered to a pregnant woman [see Use inSpecific Populations (8.1)].
Females
Advise female patients of reproductive potential to use effective contraception during treatmentwith VITRAKVI and for at least 1 week after the final dose.
Males
Advise males with female partners of reproductive potential to use effective contraception duringtreatment with VITRAKVI and for 1 week after the final dose.
Infertility
Females
Based on histopathological findings in the reproductive tracts of female rats in a 1-monthrepeated-dose study, VITRAKVI may reduce fertility [See Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
The safety and effectiveness of VITRAKVI in pediatric patients was established based upon datafrom three multicenter, open-label, single-arm clinical trials in adult or pediatric patients 28 daysand older [see Adverse Reactions (6.1), Clinical Studies (14)].
The efficacy of VITRAKVI was eva luated in 12 pediatric patients and is described in theClinical Studies section [see Clinical Studies (14)]. The safety of VITRAKVI was eva luated in 44 pediatric patients who received VITRAKVI. Of these 44 patient |
