Tafnext Use In Pregnancy & Lactation

Pregnancy: Risk Summary: Available data from the APR show no statistically significant difference in the overall risk of birth defects for tenofovir alafenamide (TAF) compared with the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data as follows). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%.
In animal studies, no adverse developmental effects were observed when tenofovir alafenamide was administered during the period of organogenesis at exposure equal to or 51 times (rats and rabbits, respectively) the tenofovir alafenamide exposure at the recommended daily dose of Tenofovir Alafenamide (see Data as follows). No adverse effects were observed in the offspring when TDF was administered through lactation at tenofovir exposures of approximately 12 times the exposure at the recommended daily dosage of Tenofovir Alafenamide.
Data: Human Data: Based on prospective reports to the APR of over 660 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 520 exposed in the first trimester and over 130 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.2% (95% CI: 2.6% to 6.3%) and 3.0% (95% CI: 0.8% to 7.5%) following first and second/third trimester exposure, respectively, to TAF-containing regimens. Methodologic limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation.
Animal Data: Embryonic fetal development studies performed in rats and rabbits revealed no evidence of impaired fertility or harm to the fetus. The embryo-fetal NOAELs (no observed adverse effect level) in rats and rabbits occurred at tenofovir alafenamide exposures similar to and 51 times higher than, respectively, the exposure in humans at the recommended daily dose. Tenofovir alafenamide is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 54 (rats) and 85 (rabbits) times higher than human tenofovir exposures at the recommended daily dose. Tenofovir alafenamide was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at tenofovir alafenamide exposures approximately similar to (rats) and 51 (rabbits) times higher than the exposure in humans at the recommended daily dose of Tenofovir Alafenamide. Tenofovir alafenamide is rapidly converted to tenofovir; the observed tenofovir exposures in rats and rabbits were 54 (rats) and 85 (rabbits) times higher than human tenofovir exposures at the recommended daily dose. Since tenofovir alafenamide is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after tenofovir alafenamide administration compared to TDF, another prodrug for tenofovir administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on gestation day 7 [and lactation day 20] at tenofovir exposures of approximately 12 [18] times higher than the exposures in humans at the recommended daily dose ofTenofovir Alafenamide.
Lactation: Risk Summary: It is not known whether Tenofovir Alafenamide and its metabolites are present in human breast milk, affect human milk production, or have effects on the breastfed infant. Tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF (see Data as follows). It is not known if tenofovir alafenamide can be present in animal milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Tenofovir Alafenamide and any potential adverse effects on the breastfed infant from Tenofovir Alafenamide or from the underlying maternal condition.
Data: Animal Data: Studies in rats and monkeys have demonstrated that tenofovir is secreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11 (see Data). Tenofovir was excreted into the milk of lactating monkeys following a single subcutaneous (30 mg/kg) dose of tenofovir at concentrations up to approximately 4% of plasma concentration, resulting in exposure (AUC) of approximately 20% of plasma exposure.