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These highlights do not include all the information needed to use GENVOYA safely and effectively. See full prescribing information for GENVOYA. GENVOYA ® (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets, for oral use Initial U.S. Approval: 2015
GENVOYA- elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide tablet
GENVOYA ® (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets, for oral use
Severe acute exacerbations of hepatitis B 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. Hepatic function should be monitored closely in these patients. If appropriate, anti-hepatitis B therapy may be warranted. ( 5.1)
Dosage and Administration, Testing When Initiating and During Treatment with GENVOYA ( 2.1) 08/2018
Dosage and Administration, Recommended Dosage ( 2.2) 12/2018
Dosage and Administration, Renal Impairment ( 2.3) 12/2018
Dosage and Administration, Not Recommended During Pregnancy ( 2.5) 11/2018
Warnings and Precautions, New Onset or Worsening Renal Impairment ( 5.4) 12/2018
GENVOYA is a four-drug combination of elvitegravir, an HIV-1 integrase strand transfer inhibitor (INSTI), cobicistat, a CYP3A inhibitor, and emtricitabine and tenofovir alafenamide (TAF), both HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs), and 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. ( 1)
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)
Recommended dosage: 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)
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)
Hepatic impairment: GENVOYA is not recommended in patients with severe hepatic impairment. ( 2.4)
Tablets: 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide. ( 3)
Strongly induce CYP3A, which may lead to lower exposure of one or more components and loss of efficacy of GENVOYA and possible resistance. ( 4)
Risk of adverse reactions or loss of virologic response due to drug interactions: The concomitant use of GENVOYA and other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of GENVOYA and possible development of resistance; and possible clinically significant adverse reactions from greater exposures of concomitant drugs. ( 5.2)
Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.3)
New onset or worsening renal impairment: Assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein when initiating GENVOYA and during therapy on a clinically appropriate schedule in all patients. Also assess serum phosphorus in patients with chronic kidney disease. ( 5.4)
Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.5)
Most common adverse reaction (incidence greater than or equal to 10%, all grades) is nausea. ( 6.1)
GENVOYA should not be administered with other antiretroviral medications for treatment of HIV-1 infection. ( 7.1)
GENVOYA can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of one or more components of GENVOYA. Consult the full prescribing information prior to and during treatment for potential drug-drug interactions. ( 4, 7.2, 7.3, 12.3)
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, 8.1)
Pediatrics: Not recommended for patients weighing less than 25 kg. ( 8.4)
Severe acute exacerbations of hepatitis B 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. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue GENVOYA. If appropriate, anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1)] .
Prior to or when initiating GENVOYA, test patients for hepatitis B virus infection . Prior 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)] .
GENVOYA is a four-drug fixed dose combination product containing 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide (TAF). The recommended dosage of GENVOYA is one tablet taken orally once daily with food in:GENVOYA is a four-drug fixed dose combination product containing 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 10 mg of tenofovir alafenamide (TAF). The recommended dosage of GENVOYA is one tablet taken orally once daily with food in:
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)] . 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)] .
GENVOYA is not recommended in patients with:GENVOYA is not recommended in patients with:
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)] . 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)] .
GENVOYA 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)] .
GENVOYA 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)] .
Coadministration of GENVOYA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of GENVOYA and possible resistance) are listed below . Coadministration of GENVOYA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of GENVOYA and possible resistance) are listed below [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)] .
Patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before or when initiating antiretroviral therapy [see Dosage and Administration (2.1)] .
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of GENVOYA, there have been no cases of Fanconi syndrome or Proximal Renal Tubulopathy (PRT). In clinical trials of GENVOYA in treatment-naïve subjects and in virologically suppressed subjects switched to GENVOYA with estimated creatinine clearance greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with GENVOYA. In a study of virologically suppressed subjects with baseline estimated creatinine clearance between 30 and 69 mL per minute treated with GENVOYA for a median duration of 144 weeks, GENVOYA was permanently discontinued due to worsening renal function in three of 80 (4%) subjects with a baseline estimated creatinine clearance between 30 and 50 mL per minute and two of 162 (1%) with a baseline estimated creatinine clearance greater than or equal to 50 mL per minute [see Adverse Reactions (6.1)] . 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.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.
Cobicistat, a component of GENVOYA, produces elevations of serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration . 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. 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.
The primary safety assessment of GENVOYA was based on Week 144 pooled data from 1,733 subjects in two randomized, double-blind, active-controlled trials, Study 104 and Study 111, in antiretroviral treatment-naïve HIV-1 infected adult subjects. A total of 866 subjects received one tablet of GENVOYA once daily [see Clinical Studies (14.2)] .
The most common adverse reaction (all Grades) reported in at least 10% of subjects in the GENVOYA group was nausea. The proportion of subjects who discontinued treatment with GENVOYA or STRIBILD ® due to adverse events, regardless of severity, was 1% and 2%, respectively. Table 1 displays the frequency of adverse reactions (all Grades) greater than or equal to 5% in the GENVOYA group.
Table 1	Adverse Reactions * (All Grades) Reported in ≥ 5% of HIV-1 Infected Treatment-Naïve Adults Receiving GENVOYA in Studies 104 and 111 (Week 144 analysis)
The safety of GENVOYA in virologically-suppressed adults was based on Week 96 data from 959 subjects in a randomized, open-label, active-controlled trial (Study 109) in which virologically-suppressed subjects were switched from a TDF-containing combination regimen to GENVOYA. Overall, the safety profile of GENVOYA in subjects in this study was similar to that of treatment-naïve subjects [see Clinical Studies (14.3)] . Additional adverse reactions observed with GENVOYA in Study 109 included suicidal ideation, suicidal behavior, and suicide attempt (<1% combined); all of these events were serious and all occurred in subjects with a preexisting history of depression or psychiatric illness.
Cobicistat (a component of GENVOYA) has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting glomerular filtration [see Clinical Pharmacology (12.2)] . Increases in serum creatinine occurred by Week 2 of treatment and remained stable through 144 weeks.
Table 3	Lipid Values, Mean Change from Baseline, Reported in Subjects Receiving GENVOYA or STRIBILD in Studies 104 and 111 *
The safety of GENVOYA in HIV-1 infected pediatric subjects was evaluated in treatment-naïve subjects between the ages of 12 to less than 18 years and weighing at least 35 kg (N=50) through Week 48 (cohort 1), and in virologically-suppressed subjects between the ages of 6 to less than 12 years and weighing at least 25 kg (N=23) through Week 24 (cohort 2) in an open-label clinical trial (Study 106) [see Clinical Studies (14.5)] . With the exception of a decrease in the mean CD4+ cell count observed in cohort 2 of Study 106, the safety profile in pediatric subjects who received treatment with GENVOYA was similar to that in adults. One 13-year-old female subject developed unexplained uveitis while receiving GENVOYA that resolved and did not require discontinuation of GENVOYA.
Cohort 2 of Study 106 evaluated pediatric subjects (N=23) who were virologically-suppressed and who switched from their antiretroviral regimen to GENVOYA. Although all subjects had HIV-1 RNA < 50 copies/mL, there was a decrease from baseline in CD4+ cell count at Week 24. The mean baseline and mean change from baseline in CD4+ cell count and in CD4% from Week 2 to Week 24 are presented in Table 4. All subjects maintained their CD4+ cell counts above 400 cells/mm 3 [see Pediatric Use (8.4) and Clinical Studies (14.5)].
GENVOYA is a complete regimen for the treatment of HIV-1 infection; therefore, coadministration of GENVOYA with other antiretroviral medications for treatment of HIV-1 infection should be avoided. Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided [see Contraindications (4), Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)] .
Because emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of GENVOYA with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.4)] .
Table 5 provides a listing of established or potentially clinically significant drug interactions [see Contraindications (4)] . The drug interactions described are based on studies conducted with either GENVOYA, the components of GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) as individual agents and/or in combination, or are predicted drug interactions that may occur with GENVOYA [for magnitude of interaction, see Clinical Pharmacology (12.3)] . The table includes potentially significant interactions but is not all inclusive.
Table 5	Established and Other Potentially Significant * Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
antacids ‡
↑ cobicistat Patients with CL cr greater than or equal to 60 mL/minute:
Patients with CL cr between 50 mL/minute and 60 mL/minute:
carbamazepine ‡
desipramine ‡
methylergonovine ↑ ergot derivatives Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4)] .
↓ TAF Coadministration is contraindicated due to potential for loss of therapeutic effect and development of resistance .
drospirenone/ethinyl estradiol ‡
naloxone ‡ ↑ buprenorphine
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, cobicistat, emtricitabine, and 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 increase in the overall risk of major birth defects for emtricitabine or cobicistat 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). The number of exposures to TAF and elvitegravir are insufficient to make a risk assessment compared to a reference population (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.
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.
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.
The 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)] .
The pharmacokinetics, safety, virologic and immunologic responses of GENVOYA in HIV-1 infected adult subjects with ESRD (estimated creatinine clearance of less than 15 mL per minute by Cockcroft-Gault method) receiving chronic hemodialysis were evaluated in 55 subjects in an open-label trial, Study 1825 [see Adverse Reactions (6.1) and Clinical Studies (14.4)] .
No dosage adjustment of GENVOYA is recommended in patients with estimated creatinine clearance greater than or equal to 30 mL per minute, or in adult patients with ESRD (estimated creatinine clearance below 15 mL per minute) who are receiving chronic hemodialysis. On days of hemodialysis, administer GENVOYA after completion of hemodialysis treatment [see Dosage and Administration (2.2)] .
GENVOYA is not recommended in patients with severe renal impairment (estimated creatinine clearance of 15 to below 30 mL per minute), or in patients with ESRD who are not receiving chronic hemodialysis, as the safety of GENVOYA has not been established in these populations [see Dosage and Administration (2.3), Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)] .
No dosage adjustment of GENVOYA is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. GENVOYA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, GENVOYA is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)] .
It has a molecular formula of C 23H 23ClFNO 5 and a molecular weight of 447.88. It has the following structural formula:
Cobicistat: The chemical name for cobicistat is 2,7,10,12-tetraazatridecanoic acid, 12-methyl-13-[2-(1-methylethyl)-4-thiazolyl]-9-[2-(4-morpholinyl)ethyl]-8,11-dioxo-3,6-bis(phenylmethyl)-, 5-thiazolylmethyl ester, (3 R,6 R,9 S)-.
It has a molecular formula of C 40H 53N 7O 5S 2 and a molecular weight of 776.02. It has the following structural formula:
Emtricitabine: The chemical name of emtricitabine is 4-amino-5-fluoro-1-(2 R-hydroxymethyl-1,3-oxathiolan-5 S-yl)-(1 H)-pyrimidin-2-one. Emtricitabine is the (-)-enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position.
Tenofovir alafenamide (TAF): The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N-[( S)-[[(1 R)-2-(6-amino-9 H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2 E)-2-butenedioate (2:1).
It has an empirical formula of C 21H 29O 5N 6P∙½(C 4H 4O 4) and a formula weight of 534.5. It has the following structural formula:
GENVOYA is a fixed-dose combination of antiretroviral drugs elvitegravir (plus the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir alafenamide [see Microbiology (12.4)] .
Dosing in mass balance studies: elvitegravir (single dose administration of [ 14C] elvitegravir coadministered with 100 mg ritonavir); cobicistat (single dose administration of [ 14C] cobicistat after multiple dosing of cobicistat for six days); emtricitabine (single dose administration of [ 14C] emtricitabine after multiple dosing of emtricitabine for ten days); TAF (single dose administration of [ 14C] TAF).
T max (h) 4 3 3 1
Effect of light meal (relative to fasting): AUC Ratio * 1.34
Effect of high fat meal (relative to fasting): AUC Ratio * 1.87
CYP2D6 (minor) Not significantly metabolized Cathepsin A † (PBMCs)
t 1/2 (h) ‡ 12.9 3.5 10 0.51
% Of dose excreted in urine § 6.7 8.2 70 <1%
% Of dose excreted in feces § 94.8 86.2 13.7 31.7
Cobicistat *
TAF †
Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been fully evaluated in the elderly (65 years of age and older). Age does not have a clinically relevant effect on exposures of TAF up to 75 years of age [see Use in Specific Populations (8.5)] .
Table 8	Multiple Dose Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Alafenamide (TAF) and its Metabolite Tenofovir Following Oral Administration of GENVOYA in HIV-Infected Pediatric Subjects Aged 12 to less than 18 Years *
(25.5) 8.2 †
(81.0) 0.03 ‡
(180.0) 0.10 †
Exposures of the components of GENVOYA achieved in 23 pediatric subjects between the ages of 6 to less than 12 years who received GENVOYA in Study 106 were higher (20 to 80% for AUC) than exposures achieved in adults following the administration of GENVOYA; however, the increase was not considered clinically significant (Table 9) [see Use in Specific Populations (8.4)] .
Table 9	Multiple Dose Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Alafenamide (TAF) and its Metabolite Tenofovir Following Oral Administration of GENVOYA in HIV-Infected Pediatric Subjects Aged 6 to less than 12 Years *
(microgram∙hour per mL) 33.8 †
(57.8) 15.9 ‡
(51.7) 20.6 †
(N=18) †
Elvitegravir and Cobicistat: A study of the pharmacokinetics of elvitegravir (administered with the CYP3A inhibitor cobicistat) was performed in healthy subjects and subjects with moderate hepatic impairment (Child-Pugh Class B). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment and healthy subjects [see Use in Specific Populations (8.7)] .
Tenofovir Alafenamide (TAF): Clinically relevant changes in TAF and tenofovir pharmacokinetics were not observed in subjects with mild to moderate (Child-Pugh Class A and B) hepatic impairment [see Use in Specific Populations (8.7)] .
Table 11	Drug Interactions: Changes in Pharmacokinetic Parameters for Elvitegravir in the Presence of the Coadministered Drug *
Maximum strength antacid † 20 mL single dose given 4 hours before elvitegravir 50 single dose Ritonavir
Atorvastatin 10 single dose 150 once daily ‡ Cobicistat
150 once daily ‡ 16 0.91
Ledipasvir/ Sofosbuvir 90/400 once daily 150 once daily ‡ Cobicistat
150 once daily ‡ 30 0.98
Sertraline 50 single dose 150 once daily ‡ Cobicistat 150 once daily ‡ 19 0.88
Sofosbuvir/ Velpatasvir 400/100 once daily 150 once daily ‡ Cobicistat
150 once daily ‡ 24 0.87
Sofosbuvir/ Velpatasvir/ Voxilaprevir 400/100/100 + 100 Voxilaprevir § once daily 150 once daily ‡ Cobicistat
150 once daily ‡ 29 0.79
Table 12	Drug Interactions: Changes in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered Drug *
Table 13	Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir Alafenamide (TAF) in the Presence of the Coadministered Drug *
Ledipasvir/ Sofosbuvir 90/400 once daily 10 once daily † 30 0.90
Sertraline 50 single dose 10 once daily † 19 1.00
Sofosbuvir/ Velpatasvir 400/100 once daily 10 once daily † 24 0.80
Sofosbuvir/ Velpatasvir/ Voxilaprevir 400/100/100 + 100 Voxilaprevir ‡ once daily 10 once daily † 29 0.79
Table 14 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of GENVOYA or the Individual Components *
Atorvastatin 10 single dose 150 once daily † 150 once daily † 200 once daily † 10 once daily † 16 2.32
Ledipasvir 90 once daily 150 once daily † 150 once daily † 200 once daily † 10 once daily † 30 1.65
GS-331007 ‡ 1.29
Norgestimate/ ethinyl estradiol § 0.180/0.215/ 0.250 norgestimate once daily 150 once daily § 150 once daily § 200 once daily § N/A 13 2.08
Norgestromin 0.180/0.215/ 0.250 norgestimate once daily / 0.025 ethinyl estradiol once daily N/A N/A 200 once daily ¶ 25 once daily ¶ 15 1.17
Sertraline 50 single dose 150 once daily † 150 once daily † 200 once daily † 10 once daily † 19 1.14
(0.98,1.20) # 0.92
(0.83,1.03) # 0.94
(0.85,1.04) #
(4.09,5.74) # 6.25
(5.08,7.69) # 4.94
(4.04,6.04) #
Sofosbuvir 400 once daily 150 once daily † 150 once daily † 200 once daily † 10 once daily † 24 1.23
Sofosbuvir 400 once daily 150 once daily † 150 once daily † 200 once daily † 10 once daily † 29 1.27
GS-331007 ‡ 1.28
Voxilaprevir 100 + 100 Þ once daily 1.92
Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, the MAGI-CCR5 cell line, and primary peripheral blood mononuclear cells. The EC 50 values for emtricitabine were in the range of 0.0013–0.64 microM. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC 50 values ranged from 0.007–0.075 microM) and showed strain specific activity against HIV-2 (EC 50 values ranged from 0.007–1.5 microM).
Tenofovir Alafenamide (TAF): The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells and CD4-T lymphocytes. The EC 50 values for TAF ranged from 2.0 to 14.7 nM.
Fertility was normal in the offspring of rats exposed daily from before birth ( in utero) through sexual maturity at daily exposures (AUC) of approximately 18 times higher than human exposures at the recommended 150 mg daily dose.
Fertility was normal in the offspring of rats exposed daily from before birth ( in utero) through sexual maturity at daily exposures (AUC) of approximately 1.2 times higher than human exposures at the recommended 150 mg daily dose.
Emtricitabine did not affect fertility in male rats at approximately 140 times or in male and female mice at approximately 60 times higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice 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 200 mg daily dose.
Study 111 * Treatment-naïve adults GENVOYA (866)
Study 109 † Virologically-suppressed ‡ adults GENVOYA (959)
ATRIPLA ® or TRUVADA ®+atazanavir+cobicistat or ritonavir or STRIBILD (477) 96
Study 112 § Virologically-suppressed ‡ adults with renal impairment ¶ GENVOYA (242) 144
Study 1825 § Virologically-suppressed ‡ adults with ESRD # 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-suppressed children between the ages of 6 to less than 12 years (at least 25 kg) GENVOYA (23) 24
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 log 10 copies 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 mm 3 (range 0–1360) and 13% had CD4+ cell counts less than 200 cells per mm 3.
Table 16	Pooled Virologic Outcomes of Randomized Treatment in Studies 104 and 111 at Week 144 * in Treatment-Naïve Subjects
HIV-1 RNA < 50 copies/mL † 84% 80%
Discontinued Study Drug Due to AE or Death § 2% 3%
Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mL ¶ 9% 11%
In Studies 104 and 111, the mean increase from baseline in CD4+ cell count at Week 144 was 326 cells per mm 3 in GENVOYA-treated subjects and 305 cells per mm 3 in 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 mm 3 (range 79–1951).
Table 17	Virologic Outcomes of Study 109 at Week 96 * in Virologically-Suppressed Subjects who Switched to GENVOYA
HIV-1 RNA ≥ 50 copies/mL † 2% 2%
Discontinued Study Drug Due to AE or Death ‡ 1% 3%
Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA < 50 copies/mL § 3% 6%
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 mm 3 in GENVOYA-treated subjects and 42 cells per mm 3 in 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] .
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 mm 3 (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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] .
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 mm 3 (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.
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 log 10 copies per mL (22% had baseline plasma HIV-1 RNA greater than 100,000 copies per mL), median CD4+ cell count was 456 cells per mm 3 (range: 95 to 1110), and median CD4+ percentage was 23% (range: 7% to 45%).
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 mm 3. 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: 8–11), a mean baseline weight of 31.6 kg, 39% were male, 13% were Asian, and 78% were Black. At baseline, median CD4+ cell count was 969 cells/mm 3 (range: 603 to 1421), and median CD4% was 39% (range: 30% to 51%).
After switching to GENVOYA, 100% (23/23) of subjects in cohort 2 remained suppressed (HIV-1 RNA < 50 copies/mL) at Week 24. From a mean (SD) baseline CD4+ cell count of 966 (201.7), the mean change from baseline in CD4+ cell count was -150 cells/mm 3 and the mean (SD) change in CD4% was -1.5% (3.7%) at Week 24. All subjects maintained CD4+ cell counts above 400 cells/mm 3 [see Adverse Reactions (6.1) and Pediatric Use (8.4)].
GENVOYA may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products including St. John's wort [see Contraindications (4) and Drug Interactions (7)] .
Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing emtricitabine and/or TDF, and may likewise occur with discontinuation of GENVOYA [see Warnings and Precautions (5.1)] . Advise the patient to not discontinue GENVOYA without first informing their healthcare provider.
Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.3)] .
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to GENVOYA. Advise patients that they should stop GENVOYA if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.5)] .
Inform patients that it is important to take GENVOYA on a regular dosing schedule with food and to avoid missing doses as it can result in development of resistance [see Dosage and Administration (2.2)] .
Advise patients that GENVOYA is not recommended during pregnancy and to alert their healthcare provider if they become pregnant while taking GENVOYA [see Dosage and Administration (2.5) and Use in Specific Populations (8.1)]. Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to GENVOYA [see Use in Specific Populations (8.1)] .
GENVOYA ® (jen-VOY-uh)
Important: Ask your healthcare provider or pharmacist about medicines that should not be taken with GENVOYA. For more information, see the section " What should I tell my healthcare provider before taking GENVOYA?"
For more information about side effects, see " What are the possible side effects of GENVOYA?"
St. John's wort ( Hypericum perforatum) or a product that contains St. John's wort.
See " What is the most important information I should know about GENVOYA?"
207561-GS-012
GENERIC: elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide
NDC: 70518-0568-0
IMPRINT: GSI;510
tenofovir alafenamide fumarate 10mg in 1
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70518-0568(NDC:61958-1901)
TENOFOVIR ALAFENAMIDE FUMARATE (UNII: FWF6Q91TZO) (TENOFOVIR ANHYDROUS - UNII:W4HFE001U5) TENOFOVIR ALAFENAMIDE 10 mg
NDC:70518-0568-0 30 in 1 BLISTER PACK; Type 0: Not a Combination Product 06/06/2017
NDA NDA207561 06/06/2017
Document Id: 7e53a8f9-1ac5-2777-e053-2a91aa0a9187
Set id: a22331e0-b0ea-47fa-a073-c60d175e652b