Risk Summary 

ENTADFI is contraindicated in pregnancy and not indicated for use in females [see Contraindications (4)]. Based on animal studies and its mechanism of action, finasteride, a component of ENTADFI, may cause abnormal development of external genitalia in a male fetus if administered to a pregnant female [see Clinical Pharmacology (12.1)]. In animal reproduction studies, oral administration of finasteride to pregnant rats during the period of major organogenesis resulted in a dose-dependent increase in hypospadias that occurred in 3.6 to 100% of male offspring at maternal doses approximately 0.1 to 86 times the maximum recommended human dose (MRHD) of 5 mg/day; decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development in male offspring at maternal doses approximately 0.03 times the MRHD and decreased anogenital distance in male offspring at maternal doses approximately 0.003 times the MRHD (see Data). Finasteride is a Type II 5α-reductase inhibitor that prevents conversion of testosterone to 5α-dihydrotestosterone (DHT), a hormone necessary for normal development of male genitalia. Abnormal male genital development is an expected consequence when conversion of testosterone to 5α-dihydrotestosterone (DHT) is inhibited by 5α-reductase inhibitors. These outcomes are similar to those reported in male infants with genetic 5α-reductase deficiency.

In animal reproduction studies, no adverse developmental effects were observed with oral administration of tadalafil to pregnant rats or mice during organogenesis at exposures up to 44 times the maximum recommended human dose (MRHD) of 5 mg/day (See Data).

Females of reproductive potential, including pregnant females, should not handle crushed or open ENTADFI capsules because of possible exposure of a male fetus [see Warnings and Precautions (5.7)].

Data

Animal Data

Finasteride:

In an embryo-fetal development study, pregnant rats received finasteride during the period of major organogenesis (gestation days 6 to 17). At maternal doses of oral finasteride approximately 0.1 to 86 times the maximum recommended human dose (MRHD) of 5 mg/day (based on AUC at animal doses of 0.1 to 100 mg/kg/day) there was a dose-dependent increase in hypospadias that occurred in 3.6 to 100% of male offspring. Exposure multiples were estimated using data from nonpregnant rats. Days 16 to 17 of gestation is a critical period in male fetal rats for differentiation of the external genitalia. At oral maternal doses approximately 0.03 times the MRHD (based on AUC at animal dose of 0.03 mg/kg/day), male offspring had decreased prostatic and seminal vesicular weights, delayed preputial separation and transient nipple development. Decreased anogenital distance occurred in male offspring of pregnant rats that received approximately 0.003 times the MRHD (based on AUC at animal dose of 0.003 mg/kg/day). No abnormalities were observed in female offspring at any maternal dose of finasteride.

Slightly decreased fertility was observed in male offspring after administration of about 3 times the MRHD (based on AUC at animal dose of 3 mg/kg/day) to female rats during late gestation and lactation. No effects on fertility were seen in female offspring under these conditions.

No evidence of male external genital malformations or other abnormalities were observed in rabbit fetuses exposed to finasteride during the period of major organogenesis (gestation days 6-18) at maternal oral doses up to 100 mg/kg/day, (finasteride exposure levels were not measured in rabbits). However, this study may not have included the critical period for finasteride effects on development of male external genitalia in the rabbit.

The fetal effects of maternal finasteride exposure were evaluated during the period of embryonic and fetal development from gestation day 20-100 in the rhesus monkey. Intravenous administration of finasteride to pregnant monkeys at doses as high as 800 ng/day (estimated maximal blood concentration of 1.86 ng/mL or about 143 times the highest estimated exposure of pregnant women to finasteride from semen of men taking 5 mg/day) resulted in no abnormalities in male fetuses. However, oral administration of finasteride (2 mg/kg/day or approximately 18,000 times the highest estimated blood levels of finasteride from semen of men taking 5 mg/day) to pregnant monkeys resulted in external genital abnormalities in male fetuses. No other abnormalities were observed in male fetuses and no finasteride-related abnormalities were observed in female fetuses at any dose.

Tadalafil:

Animal reproduction studies showed no evidence of teratogenicity, embryotoxicity, or fetotoxicity when tadalafil was given orally to pregnant rats or mice at exposures up to 44 times the indicated dose of 5 mg/day during organogenesis. In a prenatal/postnatal developmental study in rats, postnatal pup survival decreased following maternal exposure to tadalafil doses greater than 40 times the indicated dose based on AUC. Signs of maternal toxicity occurred at doses greater than 64 times the indicated dose based on AUC. Surviving offspring had normal development and reproductive performance.

In another rat prenatal and postnatal development study at doses of 60, 200, and 1000 mg/kg, a reduction in postnatal survival of pups was observed. The no observed effect level (NOEL) for maternal toxicity was 200 mg/kg/day and for developmental toxicity was 30 mg/kg/day. This gives approximately 64- and 40 fold exposure multiples, respectively, of the human AUC for the indicated dose of 5 mg.

Tadalafil and/or its metabolites cross the placenta, resulting in fetal exposure in rats.