Genvoya (Page 4 of 11)

7.6 Drugs without Clinically Significant Interactions with GENVOYA

Based on drug interaction studies conducted with the components of GENVOYA, no clinically significant drug interactions have been observed or are expected when GENVOYA is combined with the following drugs: famciclovir, famotidine, ledipasvir, methadone, omeprazole, prasugrel (active metabolite), sertraline, sofosbuvir, velpatasvir, and voxilaprevir.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to GENVOYA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

GENVOYA is not recommended during pregnancy [see Dosage and Administration (2.5)]. A literature report evaluating the pharmacokinetics of antiretrovirals during pregnancy demonstrated substantially lower exposures of elvitegravir and cobicistat in the second and third trimesters (see Data).

Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. However, elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir alafenamide (TAF) use during pregnancy have been evaluated in a limited number of individuals as reported to the APR. Available data from the APR show no statistically significant difference in the overall risk of major birth defects for EVG, COBI, FTC or TAF compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15-20%.

In animal studies, no adverse developmental effects were observed when the components of GENVOYA were administered separately during the period of organogenesis at exposures up to 23 and 0.2 times (rat and rabbits, respectively: elvitegravir), 1.6 and 3.8 times (rats and rabbits, respectively: cobicistat), 60 and 108 times (mice and rabbits, respectively; emtricitabine) and equal to and 53 times (rats and rabbits, respectively; TAF) the exposure at the recommended daily dosage of these components in GENVOYA (see Data). Likewise, no adverse developmental effects were seen when elvitegravir or cobicistat was administered to rats through lactation at exposures up to 18 times or 1.2 times, respectively, the human exposure at the recommended therapeutic dose, and when emtricitabine was administered to mice through lactation at exposures up to approximately 60 times the exposure at the recommended daily dose. No adverse effects were observed in the offspring when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of GENVOYA.

Data

Human Data

A prospective study, reported in the literature, enrolled 30 pregnant women living with HIV who were receiving elvitegravir and cobicistat-based regimens in the second or third trimesters of pregnancy and through 6 to 12 weeks postpartum to evaluate the pharmacokinetics (PK) of antiretrovirals during pregnancy. Twenty-eight women completed the study through the postpartum period. Paired pregnancy/postpartum PK data were available from 14 and 24 women for the second and third trimesters, respectively. Exposures of elvitegravir and cobicistat were substantially lower during the second and third trimesters compared to postpartum. The proportion of pregnant women who were virologically suppressed was 77% in the second trimester, 92% in the third trimester, and 76% postpartum. No correlation was observed between viral suppression and elvitegravir exposure. HIV status was also assessed for infants: 25 were uninfected, 2 had indeterminate status, and no information was available for 3 infants.

Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of GENVOYA are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.

Elvitegravir (EVG):

Based on prospective reports to the APR of over 440 exposures to EVG-containing regimens during pregnancy resulting in live births (including over 350 exposed in the first trimester and 70 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.0% (95% CI: 1.5% to 5.2%) and 1.4% (95% CI: 0.0% to 7.7%) following first and second/third trimester exposure, respectively, to EVG-containing regimens.

Cobicistat (COBI):

Based on prospective reports to the APR of over 560 exposures to COBI-containing regimens during pregnancy resulting in live births (including over 470 exposed in the first trimester and over 80 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6% (95% CI: 2.1% to 5.7%) and 1.1% (95% CI: 0.0% to 6.2%) following first and second/third trimester, respectively, to COBI-containing regimens.

Emtricitabine (FTC):

Based on prospective reports to the APR of over 5,400 exposures to FTC-containing regimens during pregnancy resulting in live births (including over 3,900 exposed in the first trimester and over 1,500 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.6% (95% CI: 2.2% to 3.2%) and 2.7% (95% CI: 1.9% to 3.7%) following first and second/third trimester exposure, respectively, to FTC-containing regimens.

Tenofovir Alafenamide (TAF):

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.

Animal Data

Elvitegravir:

Elvitegravir was administered orally to pregnant rats (0, 300, 1000, and 2000 mg/kg/day) and rabbits (0, 50, 150, and 450 mg/kg/day) through organogenesis (on gestation days 7 through 17 and days 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with elvitegravir in rats at exposures (AUC) approximately 23 times and in rabbits at approximately 0.2 times the human exposures at the recommended daily dose. In a pre/postnatal developmental study, elvitegravir was administered orally to rats at doses of 0, 300, 1000, and 2000 mg/kg from gestation day 7 to day 20 of lactation. At doses of 2000 mg/kg/day of elvitegravir, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 18 times the human exposures at the recommended daily dose.

Cobicistat:

Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, 125 mg/kg/day on gestation day 6 to 17. Increases in post-implantation loss and decreased fetal weights were observed at a maternal toxic dose of 125 mg/kg/day. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.6 times higher than human exposures at the recommended daily dose.

In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during gestation days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.8 times higher than human exposures at the recommended daily dose.

In a pre/postnatal developmental study in rats, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation day 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 1.2 times the human exposures at the recommended daily dose.

Emtricitabine:

Emtricitabine was administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 108 times higher than human exposures at the recommended daily dose.

In a pre/postnatal development study with emtricitabine, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended daily dose.

Tenofovir Alafenamide (TAF):

TAF 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 TAF exposures similar to (rats) and approximately 53 (rabbits) times higher than the exposure in humans at the recommended daily dose of GENVOYA. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 59 (rats) and 93 (rabbits) times higher than human tenofovir exposures at the recommended daily doses. Since TAF is rapidly converted to tenofovir and lower tenofovir exposures in rats and mice were observed after TAF administration compared to TDF 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 14 [21] times higher than the exposures in humans at the recommended daily dose of GENVOYA.

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