Dosage & Administration
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Genvoya Prescribing Information
Patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before or when initiating antiretroviral therapy
Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of GENVOYA. Patients coinfected with HIV-1 and HBV who discontinue GENVOYA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.
Warnings and Precautions, New Onset or Worsening Renal Impairment (Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events [see Adverse Reactions (6.1, 6.2)] . GENVOYA is not recommended in patients with estimated creatinine clearance of 15 to below 30 mL per minute, or in patients with estimated creatinine clearance below 15 mL per minute who are not receiving chronic hemodialysis.Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions. Prior to or when initiating GENVOYA, and during treatment with GENVOYA on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue GENVOYA in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Cobicistat, a component of GENVOYA, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration [see Adverse Reactions (6.1)] . The elevation is typically seen within 2 weeks of starting therapy and is reversible after discontinuation. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg per dL from baseline should be closely monitored for renal safety. | 03/2021 |
GENVOYA is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 25 kg who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of GENVOYA
The efficacy and safety of GENVOYA were evaluated in the studies summarized in Table 15.
| Trial | Population | Study Arms (N) | Timepoint (Week) |
|---|---|---|---|
| Study 104Randomized, double blind, active controlled trial. Study 111 | Treatment-naïve adults | GENVOYA (866) STRIBILD (867) | 144 |
| Study 109Randomized, open label, active controlled trial. | Virologically-suppressedHIV-1 RNA less than 50 copies per mL.adults | GENVOYA (959) ATRIPLA®or TRUVADA®+atazanavir+cobicistat or ritonavir or STRIBILD (477) | 96 |
| Study 112Open label trial. | Virologically-suppressedadults with renal impairmentEstimated creatinine clearance between 30 and 69 mL per minute by Cockcroft-Gault method. | GENVOYA (242) | 144 |
| Study 1825 | Virologically-suppressedadults with ESRDEnd stage renal disease (estimated creatinine clearance of less than 15 mL per minute by Cockcroft-Gault method).receiving chronic hemodialysis | GENVOYA (55) | 48 |
| Study 106 (cohort 1) | Treatment-naïve adolescents between the ages of 12 to less than 18 years (at least 35 kg) | GENVOYA (50) | 48 |
| Study 106 (cohort 2) | Virologically-suppressedchildren between the ages of 6 to less than 12 years (at least 25 kg) | GENVOYA (52) | 48 |
In both Study 104 and Study 111, subjects were randomized in a 1:1 ratio to receive either GENVOYA (N=866) once daily or STRIBILD (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, TDF 300 mg) (N=867) once daily. The mean age was 36 years (range 18–76), 85% were male, 57% were White, 25% were Black, and 10% were Asian. Nineteen percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.5 log10copies per mL (range 1.3–7.0) and 23% of subjects had baseline viral loads greater than 100,000 copies per mL. The mean baseline CD4+ cell count was 427 cells per mm3(range 0–1360) and 13% had CD4+ cell counts less than 200 cells per mm3.
Pooled treatment outcomes of Studies 104 and 111 through Week 144 are presented in Table 16.
| GENVOYA (N=866) | STRIBILD (N=867) | |
|---|---|---|
HIV-1 RNA < 50 copies/mLThe primary endpoint was assessed at Week 48 and the virologic success rate was 92% in the GENVOYA group and 90% in the STRIBILD group, with a treatment difference of 2.0% (95% CI: -0.7% to 4.7%). The difference at Week 144 was primarily driven by discontinuations due to other reasons with last available HIV-1 RNA <50 copies/mL. | 84% | 80% |
HIV-1 RNA ≥ 50 copies/mL Included subjects who had ≥50 copies/mL in the Week 144 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL. | 5% | 4% |
No Virologic Data at Week 144 Window | 11% | 16% |
| Discontinued Study Drug Due to AE or DeathIncludes subjects who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. | 2% | 3% |
| Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLIncludes subjects who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc. | 9% | 11% |
| Missing Data During Window but on Study Drug | 1% | 1% |
Treatment outcomes were similar across subgroups by age, sex, race, baseline viral load, and baseline CD4+ cell count.
In Studies 104 and 111, the mean increase from baseline in CD4+ cell count at Week 144 was 326 cells per mm3in GENVOYA-treated subjects and 305 cells per mm3in STRIBILD-treated subjects.
In Study 109, the efficacy and safety of switching from ATRIPLA, TRUVADA plus atazanavir (given with either cobicistat or ritonavir), or STRIBILD to GENVOYA once daily were evaluated in a randomized, open-label trial of virologically-suppressed (HIV-1 RNA less than 50 copies per mL) HIV-1 infected adults (N=1436). Subjects must have been suppressed (HIV-1 RNA less than 50 copies per mL) on their baseline regimen for at least 6 months and had no known resistance-associated substitutions to any of the components of GENVOYA prior to study entry. Subjects were randomized in a 2:1 ratio to either switch to GENVOYA at baseline (N=959), or stay on their baseline antiretroviral regimen (N=477). Subjects had a mean age of 41 years (range 21–77), 89% were male, 67% were White, and 19% were Black. The mean baseline CD4+ cell count was 697 cells per mm3(range 79–1951).
Subjects were stratified by prior treatment regimen. At screening, 42% of subjects were receiving TRUVADA plus atazanavir (given with either cobicistat or ritonavir), 32% were receiving STRIBILD, and 26% were receiving ATRIPLA.
Treatment outcomes of Study 109 through 96 weeks are presented in Table 17.
| GENVOYA (N=959) | ATRIPLA or TRUVADA+atazanavir +cobicistat or ritonavir or STRIBILD (N=477) | |
|---|---|---|
HIV-1 RNA < 50 copies/mL | 93% | 89% |
HIV-1 RNA ≥ 50 copies/mLIncluded subjects who had ≥50 copies/mL in the Week 96 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL. | 2% | 2% |
No Virologic Data at Week 48 Window | 5% | 9% |
| Discontinued Study Drug Due to AE or DeathIncludes subjects who discontinued due to AE or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. | 1% | 3% |
| Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mLIncludes subjects who discontinued for reasons other than an AE, death or lack or loss of efficacy; e.g., withdrew consent, loss to follow-up, etc. | 3% | 6% |
| Missing Data During Window but on Study Drug | 1% | <1% |
Treatment outcomes were similar across subgroups receiving ATRIPLA, TRUVADA plus atazanavir (given with either cobicistat or ritonavir), or STRIBILD prior to randomization. In Study 109, the mean increase from baseline in CD4+ cell count at Week 96 was 60 cells per mm3in GENVOYA-treated subjects and 42 cells per mm3in subjects who stayed on their baseline regimen.
In Study 112, the efficacy and safety of GENVOYA once daily were evaluated in an open-label clinical trial of 248 HIV-1 infected subjects with renal impairment (estimated creatinine clearance between 30 and 69 mL per minute by Cockcroft-Gault method). Of the 248 enrolled, 6 were treatment-naïve and 242 were virologically suppressed (HIV-1 RNA less than 50 copies per mL) for at least 6 months before switching to GENVOYA
The mean age was 58 years (range 24–82), with 63 subjects (26%) who were 65 years of age or older. Seventy-nine percent were male, 63% were White, 18% were Black, and 14% were Asian. Thirteen percent of subjects identified as Hispanic/Latino. The mean baseline CD4+ cell count was 664 cells per mm3(range 126–1813). At Week 144, 81% (197/242 virologically suppressed subjects) maintained HIV-1 RNA less than 50 copies per mL after switching to GENVOYA. All six treatment-naïve subjects were virologically suppressed at Week 144. Five subjects among the entire study population had virologic failure at Week 144.
In Study 1825, the efficacy and safety of GENVOYA once daily were evaluated in an open-label clinical trial of 55 virologically-suppressed (HIV-1 RNA less than 50 copies per mL for at least 6 months before switching to GENVOYA) HIV-1 infected subjects with ESRD (estimated creatinine clearance of less than 15 mL per minute by Cockcroft-Gault method) receiving chronic hemodialysis for at least 6 months
Subjects had a mean age of 48 years (range 23–64), 76% were male, 82% were Black, 18% were White, and 15% identified as Hispanic/Latino. The mean baseline CD4+ cell count was 545 cell per mm3(range 205–1473). At Week 48, 82% (45/55) maintained HIV-1 RNA less than 50 copies per mL after switching to GENVOYA. Two subjects had HIV-1 RNA ≥ 50 copies per mL by Week 48. Seven subjects discontinued the study drug due to AE or other reasons while suppressed. One subject did not have an HIV-1 RNA measurement at Week 48.
In Study 106, an open-label, single arm trial the efficacy, safety, and pharmacokinetics of GENVOYA in HIV-1 infected pediatric subjects were evaluated in treatment-naïve adolescents between the ages of 12 to less than 18 years weighing at least 35 kg (N=50) and in virologically-suppressed children between the ages of 6 to less than 12 years weighing at least 25 kg (N=52).
Subjects in cohort 1 treated with GENVOYA once daily had a mean age of 15 years (range 12-17); 44% were male, 12% were Asian, and 88% were Black. At baseline, mean plasma HIV-1 RNA was 4.6 log10copies per mL (22% had baseline plasma HIV-1 RNA greater than 100,000 copies per mL), mean (SD) CD4+ cell count was 471 (212.2) cells per mm3, and mean (SD) CD4+ percentage was 23.6% (8.8%).
In subjects in cohort 1 treated with GENVOYA, 92% (46/50) achieved HIV-1 RNA less than 50 copies per mL at Week 48. The mean increase from baseline in CD4+ cell count at Week 48 was 224 cells per mm3. Three of 50 subjects had virologic failure at Week 48; no emergent resistance to GENVOYA was detected through Week 48.
Subjects in cohort 2 treated with GENVOYA once daily had a mean age of 10 years (range: 7–11), a mean baseline weight of 31.7 kg, 42% were male, 25% were Asian, and 71% were Black. At baseline, the mean (SD) CD4+ cell count was 961 (275.5) cells per mm3and the mean (SD) CD4 percentage was 38.2% (6.4%). After switching to GENVOYA, 98% (51/52) of subjects in cohort 2 remained suppressed (HIV-1 RNA < 50 copies/mL) at Week 48. No subject qualified for resistance analysis through Week 48. The mean change from baseline in CD4+ cell count was -66 (203.6) cells per mm3and the mean (SD) change in CD4 percentage was -0.6% (4.4%) at Week 48. All subjects maintained CD4+ cell counts above 400 cells/mm3
- Testing: Prior to or when initiating GENVOYA test for hepatitis B virus infection. Prior to or when initiating GENVOYA, and during treatment on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. ()
2.1 Testing When Initiating and During Treatment with GENVOYAPrior to or when initiating GENVOYA, test patients for hepatitis B virus infection
[see Warnings and Precautions (5.1)].Prior to or when initiating GENVOYA, and during treatment with GENVOYA on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus
[see Warnings and Precautions (5.4)]. - Recommended dosage in adult and pediatric patients weighing at least 25 kg: One tablet taken orally once daily with food in patients with body weight at least 25 kg and a creatinine clearance greater than or equal to 30 mL per minute, or in adult patients with creatinine clearance less than 15 mL per minute who are receiving chronic hemodialysis. On days of hemodialysis, administer GENVOYA after hemodialysis. ()
2.2 Recommended Dosage in Adults and Pediatric Patients Weighing at Least 25 kgGENVOYA is a four-drug fixed dose combination product containing elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir alafenamide (TAF). The recommended dosage of GENVOYA is one tablet containing 150 mg EVG,150 mg COBI, 200 mg FTC, and 10 mg TAF taken orally once daily with food in:
- adults and pediatric patients with body weight at least 25 kg and creatinine clearance greater than or equal to 30 mL per minute; or
- adults with creatinine clearance below 15 mL per minute who are receiving chronic hemodialysis. On days of hemodialysis, administer GENVOYA after completion of hemodialysis treatment[see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)].
- Renal impairment: GENVOYA is not recommended in patients with estimated creatinine clearance of 15 to below 30 mL per minute, or below 15 mL per minute who are not receiving chronic hemodialysis. ()
2.3 Not Recommended in Patients with Severe Renal ImpairmentGENVOYA is not recommended in patients with:
- severe renal impairment (estimated creatinine clearance of 15 to below 30 mL per minute); or
- end stage renal disease (ESRD; estimated creatinine clearance below 15 mL per minute) who are not receiving chronic hemodialysis[see Dosage and Administration (2.2)and Use in Specific Populations (8.6)].
- Hepatic impairment: GENVOYA is not recommended in patients with severe hepatic impairment. ()
2.4 Not Recommended in Patients with Severe Hepatic ImpairmentGENVOYA is not recommended in patients with severe hepatic impairment (Child-Pugh Class C)
[see Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)].
Each GENVOYA tablet contains 150 mg of elvitegravir (EVG), 150 mg of cobicistat (COBI), 200 mg of emtricitabine (FTC), and 10 mg of tenofovir alafenamide (TAF) (equivalent to 11.2 mg of tenofovir alafenamide fumarate).
The tablets are green, capsule-shaped, film-coated tablets, debossed with "GSI" on one side of the tablet and the number "510" on the other side of the tablet.
- Pregnancy: Not recommended for use during pregnancy because of substantially lower exposures of cobicistat and elvitegravir during pregnancy. GENVOYA should not be initiated in pregnant individuals. (,
2.5 Not Recommended During PregnancyGENVOYA is not recommended for use during pregnancy because of substantially lower exposures of cobicistat and elvitegravir during the second and third trimesters
[see Use in Specific Populations (8.1)].GENVOYA should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with GENVOYA
[see Use in Specific Populations (8.1)].)8.1 PregnancyPregnancy Exposure RegistryThere 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 SummaryGENVOYA 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.DataHuman DataA 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 DataElvitegravir: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.
- Lactation: Breastfeeding is not recommended due to the potential for HIV transmission. ()
8.2 LactationRisk SummaryThe Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.
Based on published data, emtricitabine has been shown to be present in human breast milk; it is unknown if elvitegravir, cobicistat, and TAF are present in human breast milk. Elvitegravir and cobicistat are present in rat milk, and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF
[see Data]. It is unknown if TAF is present in animal milk.It is not known if GENVOYA affects milk production or has effects on the breastfed child. Because of the potential for 1) HIV transmission (in HIV-negative infants); 2) developing viral resistance (in HIV-positive infants); and 3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving GENVOYA.
DataAnimal DataElvitegravir:During the pre/postnatal developmental toxicology study at doses up to 2000 mg/kg/day, a mean elvitegravir milk to plasma ratio of 0.1 was measured 30 minutes after administration to rats on lactation day 14.Cobicistat:During the pre/postnatal developmental toxicology study at doses up to 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation day 10.Tenofovir Alafenamide:Studies in rats and monkeys have demonstrated that tenofovir is secreted in milk. During the pre/postnatal developmental toxicology study, 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. Tenofovir was excreted into the milk of lactating rhesus 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. - Pediatrics: Not recommended for patients weighing less than 25 kg. ()
8.4 Pediatric UseThe safety and effectiveness of GENVOYA for the treatment of HIV-1 infection was established in pediatric patients with body weight greater than or equal to 25 kg
[see Indications and Usage (1)and Dosage and Administration (2.2)].Use of GENVOYA in pediatric patients less than 18 years of age and weighing at least 25 kg is supported by studies in adults and by an open-label study in antiretroviral treatment-naïve HIV-1 infected pediatric subjects aged 12 to less than 18 years and weighing at least 35 kg (cohort 1 of Study 106, N=50) and in virologically-suppressed pediatric subjects aged 6 to less than 12 years and weighing at least 25 kg (cohort 2 of Study 106, N=52). The safety and efficacy of GENVOYA in adolescent subjects was similar to that in adults
[see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.5)].The safety and efficacy of GENVOYA in subjects 6 to 12 years of age weighing at least 25 kg was similar to that in antiretroviral treatment-naïve adults and adolescents with the exception of a decrease from baseline CD4+ cell count
[see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.5)].A pharmacokinetic evaluation of a reduced strength GENVOYA formulation containing 90 mg of EVG, 90 mg of COBI, 120 mg of FTC, and 6 mg TAF was performed in 27 virologically-suppressed pediatric patients at least 2 years of age and weighing at least 14 to less than 25 kg (cohort 3 of Study 106). Virologic, immunologic, and safety outcomes were similar to those observed in cohort 2 of Study 106. No clinically meaningful differences in drug exposures except EVG were identified between pediatric patients in cohort 3 receiving the reduced strength formulation and adults receiving the GENVOYA tablet containing 150 mg of EVG,150 mg of COBI, 200 mg of FTC, and 10 mg TAF. The median observed EVG Ctroughvalues in subjects in cohort 3 were significantly lower than the values correlated with efficacy in adults. Therefore, efficacy cannot be extrapolated from adults to pediatric patients weighing 14 to 25 kg.
Safety and effectiveness of GENVOYA in pediatric patients weighing less than 25 kg have not been established.