Afinitor Use In Pregnancy & Lactation

Pregnancy: Risk Summary: Based on animal studies and the mechanism of action [see Pharmacology under Actions], AFINITOR can cause fetal harm when administered to a pregnant woman. There are limited case reports of AFINITOR use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the recommended dose of AFINITOR 10 mg orally once daily (see Data as follows). Advise pregnant women of the potential risk to the fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively.
Data: Animal Data: In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities.
Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m²) with resulting exposures of approximately 4% of the human exposure at the recommended dose of AFINITOR 10 mg orally once daily based on area under the curve (AUC). In rabbits, embryo-toxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m²), approximately 1.6 times the recommended dose of AFINITOR 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA) based on body surface area. The effect in rabbits occurred in the presence of maternal toxicities.
In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m²), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.
Lactation: Risk Summary: There are no data on the presence of everolimus or its metabolites in human milk, the effects of everolimus on the breastfed infant or on milk production. Everolimus and its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because of the potential for serious adverse reactions in breastfed infants from everolimus, advise women not to breastfeed during treatment with AFINITOR and for 2 weeks after the last dose.
Females and Males of Reproductive Potential: Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to starting AFINITOR [see as follows].
Contraception: AFINITOR can cause fetal harm when administered to pregnant women [see previously mentioned].
Females: Advise female patients of reproductive potential to use effective contraception during treatment with AFINITOR and for 8 weeks after the last dose.
Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AFINITOR and for 4 weeks after the last dose.
Infertility: Females: Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR. Based on these findings, AFINITOR may impair fertility in female patients [see Adverse Reactions, Pharmacology: Nonclinical Toxicology under Actions].
Males: Cases of reversible azoospermia have been reported in male patients taking AFINITOR. In male rats, sperm motility, sperm count, plasma testosterone levels and fertility were diminished at AUC similar to those of the clinical dose of AFINITOR 10 mg orally once daily. Based on these findings, AFINITOR may impair fertility in male patients [see Pharmacology: Nonclinical Toxicology under Actions].