Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Alafenamide

1 INDICATIONS AND USAGE 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 [see Clinical Studies (14) ]. GENVOYA is a four-drug combination of elvitegravir (EVG), an HIV-1 integrase strand transfer inhibitor (INSTI), cobicistat (COBI), a CYP3A inhibitor, and emtricitabine (FTC) 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 )

2 DOSAGE AND ADMINISTRATION 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 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 ) 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 ) 2.1 Testing When Initiating and During Treatment with GENVOYA 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) ] . 2.2 Recommended Dosage in Adults and Pediatric Patients Weighing at Least 25 kg GENVOYA 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) ] . 2.3 Not Recommended in Patients with Severe Renal Impairment GENVOYA 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) ] . 2.4 Not Recommended in Patients with Severe Hepatic Impairment 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) ] . 2.5 Not Recommended During Pregnancy 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) ] .

6 ADVERSE REACTIONS The following adverse drug reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B [see Warnings and Precautions (5.1) ] Immune Reconstitution Syndrome [see Warnings and Precautions (5.3) ] New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.4) ] Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.5) ] Most common adverse reaction (incidence greater than or equal to 10%, all grades) is nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Treatment-Naïve Adults 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 Frequencies of adverse reactions are based on all adverse events attributed to study drugs by the investigator. (All Grades) Reported in ≥ 5% of HIV-1 Infected Treatment-Naïve Adults Receiving GENVOYA in Studies 104 and 111 (Week 144 analysis) GENVOYA N=866 STRIBILD N=867 Nausea 11% 13% Diarrhea 7% 9% Headache 6% 5% Fatigue 5% 4% The majority of events presented in Table 1 occurred at severity Grade 1. Clinical Trials in Virologically Suppressed Adults 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. Clinical Trials in Adult Subjects with Renal Impairment In an open-label trial (Study 112), 248 HIV-1 infected subjects with estimated creatinine clearance between 30 and 69 mL per minute (by Cockcroft-Gault method) were treated with GENVOYA for a median duration of 144 weeks. Of these subjects, 65% had previously been on a stable TDF-containing regimen. A total of 5 subjects permanently discontinued GENVOYA due to the development of renal adverse events through Week 96. Three of these five were among the 80 subjects with baseline estimated creatinine clearance of less than 50 mL/min and two subjects were among the 162 subjects with baseline estimated creatinine clearance of greater than or equal to 50 mL/min. There were no further renal discontinuations between Weeks 96 and 144. Overall, renally impaired subjects receiving GENVOYA in this study had a mean serum creatinine of 1.5 mg/dL at baseline and 1.4 mg/dL at Week 144. Otherwise, the safety profile of GENVOYA in subjects in this study was similar to that of subjects with normal renal function. Virologically-Suppressed Adults with End Stage Renal Disease (ESRD) Receiving Chronic Hemodialysis The safety of GENVOYA in subjects with end stage renal disease (ESRD) (estimated creatinine clearance of less than 15 mL/min) on chronic hemodialysis was assessed in 55 subjects (Study 1825) [see Clinical Studies (14.4) ]. The most commonly reported adverse reaction (adverse event assessed as causally related by investigator and all grades) was nausea (7%). Serious adverse events were reported in 53% of subjects and the most common serious adverse events were pneumonia (13%), fluid overload (7%), hyperkalemia (7%) and osteomyelitis (7%). Overall 5% of subjects permanently discontinued treatment due to an adverse event. Renal Laboratory Tests and Renal Safety Treatment-Naïve Adults: 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. In two 144-week randomized, controlled trials in a total of 1,733 treatment-naïve adults with a median baseline estimated creatinine clearance of 115 mL per minute, mean serum creatinine increased by less than 0.1 mg per dL in the GENVOYA group and by 0.1 mg per dL in the STRIBILD group from baseline to Week 144. Virologically Suppressed Adults: In a study of 1,436 virologically-suppressed TDF-treated adults with a mean baseline estimated creatinine clearance of 112 mL per minute who were randomized to continue their treatment regimen or switch to GENVOYA, at Week 96 mean serum creatinine was similar to baseline for both those continuing baseline treatment and those switching to GENVOYA. Across these trials, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with GENVOYA. Bone Mineral Density Effects Treatment-Naïve Adults: In a pooled analysis of Studies 104 and 111, the effects of GENVOYA compared to STRIBILD on bone mineral density (BMD) change from baseline to Week 144 were assessed by dual-energy X-ray absorptiometry (DXA). The mean percentage change in BMD from baseline to Week 144 was −0.92% with GENVOYA compared to −2.95% with STRIBILD at the lumbar spine and −0.75% compared to −3.36% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 15% of GENVOYA subjects and 29% of STRIBILD subjects. BMD declines of 7% or greater at the femoral neck were experienced by 15% of GENVOYA subjects and 29% of STRIBILD subjects. The long-term clinical significance of these BMD changes is not known. Virologically Suppressed Adults: In Study 109, TDF-treated subjects were randomized to continue their TDF-based regimen or switch to GENVOYA; changes in BMD from baseline to Week 96 were assessed by DXA. Mean BMD increased in subjects who switched to GENVOYA (2.12% lumbar spine, 2.44% total hip) and decreased slightly in subjects who continued their baseline regimen (−0.09% lumbar spine, −0.46% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 2% of GENVOYA subjects and 6% of subjects who continued their TDF-based regimen. BMD declines of 7% or greater at the femoral neck were experienced by 2% of GENVOYA subjects and 7% of subjects who continued their TDF-based regimen. The long-term clinical significance of these BMD changes is not known. Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving GENVOYA in Studies 104 and 111 are presented in Table 2. Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥ 2% of Subjects Receiving GENVOYA in Studies 104 and 111 (Week 144 analysis) Laboratory Parameter Abnormality Frequencies are based on treatment-emergent laboratory abnormalities. GENVOYA N=866 STRIBILD N=867 Creatine Kinase (≥10.0 × ULN) 11% 10% LDL-cholesterol (fasted) (>190 mg/dL) 11% 5% Total cholesterol (fasted) (>300mg/dL) 4% 3% Amylase 3% 5% ALT 3% 3% AST 3% 4% Urine RBC (Hematuria) (>75 RBC/HPF) 3% 3% Serum Lipids: Subjects receiving GENVOYA experienced greater increases in serum lipids compared to those receiving STRIBILD. Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and total cholesterol to HDL ratio are presented in Table 3. Table 3 Lipid Values, Mean Change from Baseline, Reported in Subjects Receiving GENVOYA or STRIBILD in Trials 104 and 111 Excludes subjects who received lipid lowering agents during the treatment period. GENVOYA N=866 STRIBILD N=867 Baseline Week 144 Baseline Week 144 mg/dL Change The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 144 values. mg/dL Change Total Cholesterol (fasted) 162 [N=647] +31 [N=647] 165 [N=627] +14 [N=627] Triglycerides (fasted) 111 [N=647] +29 [N=647] 115 [N=627] +17 [N=627] LDL-cholesterol (fasted) 103 [N=647] +20 [N=643] 107 [N=628] +8 [N=628] HDL-cholesterol (fasted) 47 [N=647] +7 [N=647] 46 [N=627] +3 [N=627] Total Cholesterol to HDL ratio 3.7 [N=647] 0.2 [N=647] 3.8 [N=627] 0.1 [N=627] Clinical Trials in Pediatric Subjects: Safety in Pediatric Patients 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=52) through Week 48 (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. Bone Mineral Density Effects Cohort 1: Treatment-naïve adolescents (12 to less than 18 years; at least 35 kg) Among the subjects in cohort 1 receiving GENVOYA, mean BMD increased from baseline to Week 48, + 4.2% at the lumbar spine and + 1.3% for the total body less head (TBLH). Mean changes from baseline BMD Z-scores were −0.07 for lumbar spine and −0.20 for TBLH at Week 48. One GENVOYA subject had significant (at least 4%) lumbar spine BMD loss at Week 48. Cohort 2: Virologically-suppressed children (6 to less than 12 years; at least 25 kg) Among the subjects in cohort 2 receiving GENVOYA, mean BMD increased from baseline to Week 48, +3.9% at the lumbar spine and +4.2% for TBLH. Mean changes from baseline BMD Z-scores were -0.24 for lumbar spine and -0.19 for TBLH at Week 48. Six GENVOYA subjects had significant (at least 4%) lumbar spine BMD loss at Week 48; 2 subjects also had at least 4% TBLH BMD loss at Week 48. Change from Baseline in CD4+ cell counts Cohort 2: Virologically-suppressed children (6 to less than 12 years; at least 25 kg) Cohort 2 of Study 106 evaluated pediatric subjects (N=52) 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 Weeks 24 and 48. The mean baseline and mean change from baseline in CD4+ cell count and in CD4% from Week 2 to Week 48 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) ]. Table 4 Mean Change in CD4+ Count and CD4 Percentage from Baseline to Week 48 in Virologically-Suppressed Pediatric Patients from 6 to <12 Years Who Switched to GENVOYA Baseline Mean Change from Baseline Week 2 Week 4 Week 12 Week 24 Week 32 Week 48 CD4+ Cell Count (cells/mm 3 ) 961 (275.5) Mean (SD) -117 -114 -112 -118 -62 -66 CD4% 38 (6.4) +0.3% -0.1% -0.8% -0.8% -1.0% -0.6% 6.2 Postmarketing Experience The following events have been identified during post approval use of products containing TAF, including GENVOYA. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders Angioedema, urticaria, and rash Renal and Urinary Disorders Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome

12.3 Pharmacokinetics Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic (PK) properties of the components of GENVOYA are provided in Table 6. The multiple dose PK parameters of elvitegravir, cobicistat, emtricitabine, TAF and its metabolite tenofovir are provided in Table 7. Table 6 Pharmacokinetic Properties of the Components of GENVOYA Elvitegravir Cobicistat Emtricitabine TAF PBMCs = peripheral blood mononuclear cells; CES1 = carboxylesterase 1. Absorption T max (h) 4 3 3 1 Effect of light meal (relative to fasting): AUC Ratio Values refer to geometric mean ratio in AUC [fed / fasted] and (90% confidence interval). Elvitegravir light meal=~373 kcal, 20% fat; GENVOYA light meal=~400 kcal, 20% fat; elvitegravir and GENVOYA high fat meal=~800 kcal, 50% fat. Based on the effect of food on elvitegravir, GENVOYA should be taken with food. 1.34 (1.19, 1.51) 1.03 (0.90, 1.17) 0.95 (0.91, 1.00) 1.15 (1.07, 1.24) Effect of high fat meal (relative to fasting): AUC Ratio 1.87 (1.66, 2.10) 0.83 (0.73, 0.95) 0.96 (0.92, 1.00) 1.18 (1.09, 1.26) Distribution % Bound to human plasma proteins ~99 ~98 <4 ~80 Source of protein binding data Ex vivo In vitro In vitro Ex vivo Blood-to-plasma ratio 0.73 0.5 0.6 1.0 Metabolism Metabolism CYP3A (major) UGT1A1/3 (minor) CYP3A (major) CYP2D6 (minor) Not significantly metabolized Cathepsin A In vivo, TAF is hydrolyzed within cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate. In vitro studies have shown that TAF is metabolized to tenofovir by cathepsin A in PBMCs and macrophages; and by CES1 in hepatocytes. Upon coadministration with the moderate CYP3A inducer probe efavirenz, TAF exposure was not significantly affected. (PBMCs) CES1 (hepatocytes) CYP3A (minimal) Elimination Major route of elimination Metabolism Metabolism Glomerular filtration and active tubular secretion Metabolism (>80% of oral dose) t 1/2 (h) t 1/2 values refer to median terminal plasma half-life. Note that the pharmacologically active metabolite, tenofovir diphosphate, has a half-life of 150–180 hours within PBMCs. 12.9 3.5 10 0.51 % Of dose excreted in urine Dosing in mass balance studies: elvitegravir (single dose administration of [ 14 C] elvitegravir coadministered with 100 mg ritonavir); cobicistat (single dose administration of [ 14 C] cobicistat after multiple dosing of cobicistat for six days); emtricitabine (single dose administration of [ 14 C] emtricitabine after multiple dosing of emtricitabine for ten days); TAF (single dose administration of [ 14 C] TAF). 6.7 8.2 70 <1% % Of dose excreted in feces 94.8 86.2 13.7 31.7 Table 7 Multiple Dose Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Alafenamide (TAF) and its Metabolite Tenofovir Following Oral Administration of GENVOYA with Food in HIV-Infected Adults Parameter Mean (CV%) Elvitegravir From Intensive PK analysis in a Phase 2 trial in HIV infected adults, Study 102 (N=19). Cobicistat Emtricitabine TAF From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection, Studies 104 and 111 (N=539). Tenofovir From Population PK analysis in two trials of treatment-naïve adults with HIV-1 infection, Studies 104 and 111 (N=841). CV = Coefficient of Variation; NA = Not Applicable C max (microgram per mL) 2.1 (33.7) 1.5 (28.4) 2.1 (20.2) 0.16 (51.1) 0.02 (26.1) AUC tau (microgram∙hour per mL) 22.8 (34.7) 9.5 (33.9) 11.7 (16.6) 0.21 (71.8) 0.29 (27.4) C trough (microgram per mL) 0.29 (61.7) 0.02 (85.2) 0.10 (46.7) NA 0.01 (28.5) Special Populations Geriatric Patients 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) ] . Pediatric Patients Mean exposures of elvitegravir, cobicistat, and TAF achieved in 24 pediatric subjects aged 12 to less than 18 years who received thedose of GENVOYA containing 150 mg EVG, 150 mg COBI, 200 mg FTC, and 10 mg TAF in Study 106 were decreased compared to exposures achieved in treatment-naïve adults receiving the same dose of GENVOYA, but were overall deemed acceptable based on exposure-response relationships; emtricitabine exposure in adolescents was similar to that in treatment-naïve adults (Table 8). 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 From Intensive PK analysis in a trial in treatment-naïve pediatric subjects with HIV-1 infection, cohort 1 of Study 106 (N=24). Parameter Mean (CV%) Elvitegravir Cobicistat Emtricitabine TAF Tenofovir CV = Coefficient of Variation; NA = Not Applicable C max (microgram per mL) 2.2 (19.2) 1.2 (35.0) 2.3 (22.5) 0.17 (64.4) 0.02 (23.7) AUC tau (microgram∙hour per mL) 23.8 (25.5) 8.2 N=23 (36.1) 14.4 (23.9) 0.20 (50.0) 0.29 (18.8) C trough (microgram per mL) 0.30 (81.0) 0.03 N=15 (180.0) 0.10 (38.9) NA 0.01 (21.4) Exposures of the components of GENVOYA achieved in 23 pediatric subjects between the ages of 6 to less than 12 years who received the dose of GENVOYA containing 150 mg EVG, 150 mg COBI, 200 mg FTC, and 10 mg TAF in Study 106 were higher (20 to 80% for AUC) than exposures achieved in adults receiving the same dose of GENVOYA; the increase was not considered clinically significant as the safety profiles were similar in adult and pediatric patients (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 From Intensive PK analysis in a trial in virologically-suppressed pediatric subjects with HIV-1 infection, cohort 2 of Study 106 (N=23). Parameter Mean (CV%) Elvitegravir Cobicistat Emtricitabine TAF Tenofovir CV = Coefficient of Variation; NA = Not Applicable C max (microgram per mL) 3.1 (38.7) 2.1 (46.7) 3.4 (27.0) 0.31 (61.2) 0.03 (20.8) AUC tau (microgram∙hour per mL) 33.8 N=22 (57.8) 15.9 N=20 (51.7) 20.6 (18.9) 0.33 (44.8) 0.44 (20.9) C trough (microgram per mL) 0.37 (118.5) 0.1 (168.7) 0.11 (24.1) NA 0.02 (24.9) Race, Gender No clinically significant differences in pharmacokinetics of GENVOYA have been identified based on race or gender. Patients with Renal Impairment The pharmacokinetics of GENVOYA in HIV-1 infected subjects with mild or moderate renal impairment (estimated creatinine clearance between 30 and 69 mL per minute by Cockcroft-Gault method), and in HIV-1 infected subjects with ESRD (estimated creatinine clearance of less than 15 mL per minute by Cockcroft-Gault method) receiving chronic hemodialysis were evaluated in subsets of virologically suppressed subjects in respective open-label trials, Study 112 and Study 1825. The pharmacokinetics of elvitegravir, cobicistat, and tenofovir alafenamide were similar among healthy subjects, subjects with mild or moderate renal impairment, and subjects with ESRD receiving chronic hemodialysis; increases in emtricitabine and tenofovir exposures in subjects with renal impairment were not considered clinically relevant (Table 10). Table 10 Pharmacokinetics of GENVOYA in HIV-Infected Adults with Renal Impairment as Compared to Subjects with Normal Renal Function AUC tau (microgram∙hour per mL) Mean (CV%) Estimated Creatinine Clearance By Cockcroft-Gault method. ≥90 mL per minute (N=18) From a Phase 2 study in HIV-infected adults with normal renal function. 60–89 mL per minute (N=11) These subjects from Study 112 had an estimated creatinine clearance between 60 and 69 mL per minute. 30–59 mL per minute (N=18) Study 112. <15 mL per minute (N=12) Study 1825; PK assessed prior to hemodialysis following 3 consecutive daily doses of GENVOYA. Emtricitabine 11.4 (11.9) 17.6 (18.2) 23.0 (23.6) 62.9 (48.0) N=11. Tenofovir 0.32 (14.9) 0.46 (31.5) 0.61 (28.4) 8.72 (39.4) N=10. Patients with Hepatic Impairment 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) ] . Emtricitabine: The pharmacokinetics of emtricitabine has not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited. 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) ] . Hepatitis B and/or Hepatitis C Virus Co-infection Elvitegravir: Limited data from population pharmacokinetic analysis (N=24) indicated that hepatitis B and/or C virus infection had no clinically relevant effect on the exposure of elvitegravir (administered with the CYP3A inhibitor cobicistat). Cobicistat: There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B and/or C virus infection on the pharmacokinetics of cobicistat. Emtricitabine and Tenofovir Alafenamide (TAF): Pharmacokinetics of emtricitabine and TAF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus. Drug Interaction Studies [see also Contraindications (4) and Drug Interactions (7) ] The drug-drug interaction studies described in Tables 11–14 were conducted with GENVOYA, elvitegravir (coadministered with cobicistat or ritonavir), cobicistat administered alone, or TAF (administered alone or coadministered with emtricitabine). As GENVOYA should not be administered with other antiretroviral medications, information regarding drug-drug interactions with other antiretrovirals agents is not provided. The effects of coadministered drugs on the exposure of elvitegravir, emtricitabine, and TAF are shown in Table 11, Table 12, and Table 13 respectively. The effects of GENVOYA or its components on the exposure of coadministered drugs are shown in Table 14. For information regarding clinical recommendations, see Drug Interactions (7) . Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Elvitegravir in the Presence of the Coadministered Drug All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) Elvitegravir Dose (mg) CYP3A Inhibitor Cobicistat or Ritonavir Dose (mg) N Mean Ratio of Elvitegravir Pharmacokinetic Parameters (90% CI); No effect = 1.00 C max AUC C min Maximum strength antacid Maximum strength antacid contained 80 mg aluminum hydroxide, 80 mg magnesium hydroxide, and 8 mg simethicone, per mL. 20 mL single dose given 4 hours before elvitegravir 50 single dose Ritonavir 100 single dose 8 0.95 (0.84,1.07) 0.96 (0.88,1.04) 1.04 (0.93,1.17) 20 mL single dose given 4 hours after elvitegravir 10 0.98 (0.88,1.10) 0.98 (0.91,1.06) 1.00 (0.90,1.11) 20 mL single dose given 2 hours before elvitegravir 11 0.82 (0.74,0.91) 0.85 (0.79,0.91) 0.90 (0.82,0.99) 20 mL single dose given 2 hours after elvitegravir 10 0.79 (0.71,0.88) 0.80 (0.75,0.86) 0.80 (0.73,0.89) Atorvastatin 10 single dose 150 once daily Study conducted with GENVOYA. Cobicistat 150 once daily 16 0.91 (0.85,0.98) 0.92 (0.87,0.98) 0.88 (0.81,0.96) Carbamazepine 200 twice daily 150 once daily Cobicistat 150 once daily 12 0.55 (0.49,0.61) 0.31 (0.28,0.33) 0.03 (0.02,0.40) Famotidine 40 once daily given 12 hours after elvitegravir 150 once daily Cobicistat 150 once daily 10 1.02 (0.89,1.17) 1.03 (0.95,1.13) 1.18 (1.05,1.32) 40 once daily given simultaneously with elvitegravir 16 1.00 (0.92,1.10) 1.03 (0.98,1.08) 1.07 (0.98,1.17) Ketoconazole 200 twice daily 150 once daily Ritonavir 100 once daily 18 1.17 (1.04,1.33) 1.48 (1.36,1.62) 1.67 (1.48,1.88) Ledipasvir/ Sofosbuvir 90/400 once daily 150 once daily Cobicistat 150 once daily 30 0.98 (0.90,1.07) 1.11 (1.02,1.20) 1.46 (1.28,1.66) Omeprazole 40 once daily given 2 hours before elvitegravir 50 once daily Ritonavir 100 once daily 9 0.93 (0.83,1.04) 0.99 (0.91,1.07) 0.94 (0.85,1.04) 20 once daily given 2 hours before elvitegravir 150 once daily Cobicistat 150 once daily 11 1.16 (1.04,1.30) 1.10 (1.02,1.19) 1.13 (0.96,1.34) 20 once daily given 12 hours after elvitegravir 11 1.03 (0.92,1.15) 1.05 (0.93,1.18) 1.10 (0.92,1.32) Rifabutin 150 once every other day 150 once daily Cobicistat 150 once daily 12 0.91 (0.84,0.99) 0.79 (0.74,0.85) 0.33 (0.27,0.40) Rosuvastatin 10 single dose 150 once daily Cobicistat 150 once daily 10 0.94 (0.83,1.07) 1.02 (0.91,1.14) 0.98 (0.83,1.16) Sertraline 50 single dose 150 once daily Cobicistat 150 once daily 19 0.88 (0.82,0.93) 0.94 (0.89,0.98) 0.99 (0.93,1.05) Sofosbuvir/ Velpatasvir 400/100 once daily 150 once daily Cobicistat 150 once daily 24 0.87 (0.80,0.94) 0.94 (0.88,1.00) 1.08 (0.97,1.20) Sofosbuvir/ Velpatasvir/ Voxilaprevir 400/100/100 + 100 Voxilaprevir Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. once daily 150 once daily Cobicistat 150 once daily 29 0.79 (0.75,0.85) 0.94 (0.88,1.00) 1.32 (1.17,1.49) Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered Drug All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) Emtricitabine Dose (mg) N Mean Ratio of Emtricitabine Pharmacokinetic Parameters (90% CI); No effect = 1.00 C max AUC C min Famciclovir 500 single dose 200 single dose 12 0.90 (0.80,1.01) 0.93 (0.87,0.99) NC Table 13 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir Alafenamide (TAF) in the Presence of the Coadministered Drug All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) TAF Dose (mg) N Mean Ratio of TAF Pharmacokinetic Parameters (90% CI); No effect = 1.00 C max AUC C min NC = Not Calculated Cobicistat 150 once daily 8 once daily 12 2.83 (2.20,3.65) 2.65 (2.29,3.07) NC Ledipasvir/ Sofosbuvir 90/400 once daily 10 once daily Study conducted with GENVOYA. 30 0.90 (0.73,1.11) 0.86 (0.78,0.95) NC Sertraline 50 single dose 10 once daily 19 1.00 (0.86,1.16) 0.96 (0.89,1.03) NC Sofosbuvir/ Velpatasvir 400/100 once daily 10 once daily 24 0.80 (0.68,0.94) 0.87 (0.81,0.94) NC Sofosbuvir/ Velpatasvir/ Voxilaprevir 400/100/100 + 100 Voxilaprevir Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. once daily 10 once daily 29 0.79 (0.68,0.92) 0.93 (0.85,1.01) NC Table 14 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of GENVOYA or the Individual Components All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) Elvitegravir Dose (mg) CYP3A Inhibitor Cobicistat Dose (mg) FTC Dose (mg) TAF Dose (mg) N Mean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI); No effect = 1.00 C max AUC C min FTC = emtricitabine; TAF = tenofovir alafenamide N/A = Not Applicable; NC = Not Calculated Atorvastatin 10 single dose 150 once daily Study conducted with GENVOYA. 150 once daily 200 once daily 10 once daily 16 2.32 (1.91,2.82) 2.60 (2.31,2.93) NC Buprenorphine 16 – 24 once daily 150 once daily 150 once daily N/A N/A 17 1.12 (0.98,1.27) 1.35 (1.18,1.55) 1.66 (1.43,1.93) Norbuprenorphine 1.24 (1.03,1.49) 1.42 (1.22,1.67) 1.57 (1.31,1.88) Carbamazepine 200 twice daily 150 once daily 150 once daily N/A N/A 12 1.40 (1.32,1.49) 1.43 (1.36,1.52) 1.51 (1.41,1.62) Carbamazepine-10,11-epoxide 0.73 (0.70,0.78) 0.65 (0.63,0.66) 0.59 (0.57,0.61) Desipramine 50 single dose N/A 150 once daily N/A N/A 8 1.24 (1.08,1.44) 1.65 (1.36,2.02) NC Digoxin 0.5 single dose N/A 150 once daily N/A N/A 22 1.41 (1.29,1.55) 1.08 (1.00,1.17) NC Famciclovir 500 single dose N/A N/A 200 single dose N/A 12 0.93 (0.78,1.11) 0.91 (0.84,0.99) N/A Ledipasvir 90 once daily 150 once daily 150 once daily 200 once daily 10 once daily 30 1.65 (1.53,1.78) 1.79 (1.64,1.96) 1.93 (1.74,2.15) Sofosbuvir 400 once daily 1.28 (1.13,1.47) 1.47 (1.35,1.59) N/A GS-331007 The predominant circulating inactive metabolite of sofosbuvir. 1.29 (1.24,1.35) 1.48 (1.44,1.53) 1.66 (1.60,1.73) Naloxone 4–6 once daily 150 once daily 150 once daily N/A N/A 17 0.72 (0.61,0.85) 0.72 (0.59,0.87) N/A Norgestimate/ ethinyl estradiol Study conducted with STRIBILD. 0.180/0.215/ 0.250 norgestimate once daily 150 once daily 150 once daily 200 once daily N/A 13 2.08 (2.00,2.17) 2.26 (2.15,2.37) 2.67 (2.43,2.92) 0.025 ethinyl estradiol once daily 0.94 (0.86,1.04) 0.75 (0.69,0.81) 0.56 (0.52,0.61) Norgestromin 0.180/0.215/ 0.250 norgestimate once daily / 0.025 ethinyl estradiol once daily N/A N/A 200 once daily Study conducted with DESCOVY. 25 once daily 15 1.17 (1.07,1.26) 1.12 (1.07,1.17) 1.16 (1.08,1.24) Norgestrel 1.10 (1.02,1.18) 1.09 (1.01,1.18) 1.11 (1.03,1.20) Ethinyl estradiol 1.22 (1.15,1.29) 1.11 (1.07,1.16) 1.02 (0.92,1.12) R-Methadone 80–120 daily 150 once daily 150 once daily N/A N/A 11 1.01 (0.91,1.13) 1.07 (0.96,1.19) 1.10 (0.95,1.28) S-Methadone 0.96 (0.87,1.06) 1.00 (0.89,1.12) 1.02 (0.89,1.17) Sertraline 50 single dose 150 once daily 150 once daily 200 once daily 10 once daily 19 1.14 (0.94,1.38) 0.93 (0.77,1.13) N/A Rifabutin 150 once every other day 150 once daily 150 once daily N/A N/A 12 1.09 (0.98,1.20) Comparison based on rifabutin 300 mg once daily. 0.92 (0.83,1.03) 0.94 (0.85,1.04) 25-O-desacetyl-rifabutin 12 4.84 (4.09,5.74) 6.25 (5.08,7.69) 4.94 (4.04,6.04) Rosuvastatin 10 single dose 150 once daily 150 once daily N/A N/A 10 1.89 (1.48,2.42) 1.38 (1.14,1.67) NC Sofosbuvir 400 once daily 150 once daily 150 once daily 200 once daily 10 once daily 24 1.23 (1.07,1.42) 1.37 (1.24,1.52) N/A GS-331007 1.29 (1.25,1.33) 1.48 (1.43,1.53) 1.58 (1.52,1.65) Velpatasvir 100 once daily 1.30 (1.17,1.45) 1.50 (1.35,1.66) 1.60 (1.44,1.78) Sofosbuvir 400 once daily 150 once daily 150 once daily 200 once daily 10 once daily 29 1.27 (1.09,1.48) 1.22 (1.12,1.32) NC GS-331007 1.28 (1.25,1.32) 1.43 (1.39,1.47) NC Velpatasvir 100 once daily 0.96 (0.89,1.04) 1.16 (1.06,1.27) 1.46 (1.30,1.64) Voxilaprevir 100 + 100 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. once daily 1.92 (1.63,2.26) 2.71 (2.30,3.19) 4.50 (3.68,5.50)