Elvitegravir, Cobicistat, Emtricitabine, And Tenofovir Disoproxil Fumarate

1 INDICATIONS AND USAGE STRIBILD ® is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older weighing at least 35 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/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 STRIBILD [see Clinical Studies (14) ] . STRIBILD is a four-drug combination of elvitegravir, an HIV integrase strand transfer inhibitor (HIV-1 INSTI), cobicistat, a CYP3A inhibitor, and emtricitabine and tenofovir disoproxil fumarate (TDF), both HIV nucleoside analog reverse transcriptase inhibitors (HIV NRTI) and is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older weighing at least 35 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/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 STRIBILD. ( 1 , 14 )

2 DOSAGE AND ADMINISTRATION Testing: Prior to initiation of STRIBILD, test patients for hepatitis B virus infection. Prior to initiation and during use of STRIBILD, on a clinically appropriate schedule, assess serum creatinine, serum phosphorous, estimated serum 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 once daily with food. ( 2.2 ) Dosage in renal impairment: Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended. Discontinue in patients with estimated creatinine clearance below 50 mL per minute. ( 2.3 ) 2.1 Testing Prior to Initiation and During Treatment with STRIBILD Prior to initiation of STRIBILD, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1) ] . Prior to initiation and during use of STRIBILD, 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 (5.2) ] . 2.2 Recommended Dosage STRIBILD is a four-drug fixed dose combination product containing 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of TDF. The recommended dosage of STRIBILD is one tablet taken orally once daily with food in adults and pediatric patients 12 years of age and older with a body weight at least 35 kg and creatinine clearance greater than or equal to 70 mL per minute [see Clinical Pharmacology (12.3) ] . 2.3 Dosage Adjustment in Patients with Renal Impairment Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended. Because STRIBILD is a fixed-dose combination tablet, STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per minute during treatment with STRIBILD, as the dose interval adjustment required for emtricitabine and tenofovir disoproxil fumarate (DF) cannot be achieved [see Warnings and Precautions (5.2) , Adverse Reactions (6.1) , Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) , and Clinical Studies (14) ] . No data are available to make dose recommendations for pediatric patients with renal impairment. 2.4 Not Recommended in Patients with Severe Hepatic Impairment STRIBILD is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]. 2.5 Not Recommended During Pregnancy STRIBILD 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) ] . STRIBILD should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with STRIBILD [see Use in Specific Populations (8.1) ] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions (5.1) ] . New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.2) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.3) ] . Bone Loss and Mineralization Defects [see Warnings and Precautions (5.5) ] . Immune Reconstitution Syndrome [see Warnings and Precautions (5.6) ] . Most common adverse drug reactions to STRIBILD (incidence greater than or equal to 10%, all grades) are nausea and diarrhea. ( 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 HIV-1 Infected Adult Subjects with No Antiretroviral Treatment History The safety assessment of STRIBILD is based on the Week-144 pooled data from 1408 subjects in two randomized, double-blind, active-controlled clinical trials, Study 102 and Study 103, in antiretroviral treatment-naïve HIV-1 infected adult subjects [see Clinical Studies (14) ]. A total of 701 subjects received STRIBILD once daily in these two studies. The proportion of subjects who discontinued treatment with STRIBILD, ATRIPLA, or ATV+RTV+TRUVADA due to adverse events, regardless of severity, was 6.0%, 7.4%, and 8.5%, respectively. Table 1 displays the frequency of adverse reactions greater than or equal to 5% of subjects in any treatment arm. Table 1 Adverse Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events attributed to study drugs. (All Grades) Reported in ≥5% of Adult Subjects in Any Treatment Arm in Studies 102 and 103 (Week-144 Analysis) STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 EYE DISORDERS Ocular icterus <1% 0% 13% GASTROINTESTINAL DISORDERS Diarrhea 12% 11% 17% Flatulence 2% <1% 8% Nausea 16% 9% 14% GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Fatigue 4% 8% 6% HEPATOBILIARY DISORDERS Jaundice 0% <1% 9% NERVOUS SYSTEM DISORDERS Somnolence 1% 7% 1% Headache 7% 4% 6% Dizziness 3% 21% 5% PSYCHIATRIC DISORDERS Insomnia 3% 9% 1% Abnormal dreams 9% 27% 4% SKIN AND SUBCUTANEOUS TISSUE DISORDERS Rash Rash event includes dermatitis, drug eruption, eczema, pruritus, pruritus generalized, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, and urticaria. 4% 15% 6% See Warnings and Precautions (5.2) for a discussion of renal adverse reactions from clinical trials experience with STRIBILD. Additional adverse reactions observed with STRIBILD included suicidal ideation and suicide attempt (0.3%), all in subjects with a preexisting history of depression or psychiatric illness. Clinical Trials in Virologically Suppressed HIV-1 Infected Adult Subjects No new adverse reactions to STRIBILD through Week 48 were identified in 584 virologically stably suppressed adult subjects switching to STRIBILD from a regimen containing a RTV-boosted protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). In a combined analysis of studies 115 and 121, the frequency of adverse reactions (all grades) was 24% in subjects switching to STRIBILD compared to 6% of subjects in either group who stayed on their baseline antiretroviral regimen, RTV-boosted PI+TRUVADA or NNRTI+TRUVADA. Common adverse reactions that occurred in greater than or equal to 2% of subjects switching to STRIBILD were nausea (4%), flatulence (2%), and headache (2%). The proportion of subjects who discontinued treatment with STRIBILD, the RTV-boosted PI, or the NNRTI due to adverse events was 2%, 3%, and 1%, respectively. Clinical Trials of the Components of STRIBILD in Adult Subjects Emtricitabine and TDF: In addition to the adverse reactions observed with STRIBILD, the following adverse reactions occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving emtricitabine or TDF with other antiretroviral agents in other clinical trials: depression, abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis. Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Laboratory Abnormalities: The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving STRIBILD in studies 102 and 103 are presented in Table 2. Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥2% of Adult Subjects Receiving STRIBILD in Studies 102 and 103 (Week-144 Analysis) Laboratory Parameter Abnormality Frequencies are based on treatment-emergent laboratory abnormalities. , For subjects with serum amylase >1.5 × upper limit of normal (ULN), lipase test was also performed. The frequency of increased lipase (Grades 3–4) occurring in STRIBILD (N=69), ATRIPLA (N=40), and ATV+RTV+TRUVADA (N=38) was 17%, 15%, and 24%, respectively. STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 AST (>5.0 × ULN) 3% 6% 6% ALT (>3.0 × ULN) 2% 5% 4% Amylase (>2.0 × ULN) 3% 3% 5% Creatine Kinase (≥10.0 × ULN) 8% 15% 11% Urine RBC (Hematuria) (>75 RBC/HPF) 4% 2% 4% In Study 103, BMD was assessed by DEXA in a nonrandom subset of 120 subjects (STRIBILD group, N=54; ATV+RTV+TRUVADA group, N=66). Mean percentage decreases in BMD from baseline to Week 144 in the STRIBILD group were comparable to that in the ATV+RTV+TRUVADA group at the lumbar spine (−1.43% versus −3.68%, respectively) and at the hip (−2.83% versus −3.77%, respectively). In studies 102 and 103, bone fractures occurred in 27 subjects (3.9%) in the STRIBILD group, 8 subjects (2.3%) in the ATRIPLA group, and 19 subjects (5.4%) in the ATV+RTV+TRUVADA group. These findings were consistent with data from an earlier 144-week trial of treatment-naïve subjects receiving TDF + lamivudine + efavirenz. Proteinuria (all grades) occurred in 52% of subjects receiving STRIBILD, 41% of subjects receiving ATRIPLA, and 42% of subjects receiving ATV+RTV+TRUVADA. The cobicistat component of STRIBILD has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In studies 102 and 103, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with STRIBILD, after which levels stabilized. Table 3 displays the mean changes in serum creatinine and eGFR levels at Week 144 and the percentage of subjects with elevations in serum creatinine (all grades). Table 3 Change from Baseline in Serum Creatinine and eGFR and Incidence of Elevated Serum Creatinine (All Grades) in Studies 102 and 103 at Week 144 STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 Serum Creatinine (mg/dL) Mean change ± standard deviation 0.14 (±0.14) 0.01 (±0.12) 0.09 (±0.15) eGFR by Cockcroft-Gault (mL/minute) −14.0 (±16.6) −1.9 (±17.9) −9.8 (±19.4) Subjects with Elevations in Serum Creatinine (All Grades) (%) 12 2 6 Emtricitabine or TDF: In addition to the laboratory abnormalities observed with STRIBILD, the following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or TDF with other antiretroviral agents in other clinical trials: Grade 3 or 4 laboratory abnormalities of ALT (M: greater than 215 U per L; F: greater than 170 U per L), alkaline phosphatase (greater than 550 U per L), bilirubin (greater than 2.5 × ULN), serum glucose (less than 40 or greater than 250 mg per dL), glycosuria (greater than or equal to 3+), neutrophils (less than 750 per mm 3 ), fasting cholesterol (greater than 240 mg per dL), and fasting triglycerides (greater than 750 mg per dL). Serum Lipids: In the clinical trials of STRIBILD, a similar percentage of subjects receiving STRIBILD, ATRIPLA, and ATV+RTV+TRUVADA were on lipid-lowering agents at baseline (12%, 12%, and 13%, respectively). While receiving study drug through Week 144, an additional 11% of STRIBILD subjects were started on lipid-lowering agents, compared to 13% of ATRIPLA and 12% of ATV+RTV+TRUVADA subjects. Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 4. Table 4 Lipid Values, Mean Change from Baseline at Week 144 in Adult Subjects Receiving STRIBILD or Comparator in Studies 102 and 103 STRIBILD N=701 ATRIPLA N=352 ATV+RTV+TRUVADA N=355 Baseline Week 144 Baseline Week 144 Baseline Week 144 mg/dL Change The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 144 values. mg/dL Change mg/dL Change Total Cholesterol (fasted) 166 [N=675] +17 [N=535] 161 [N=343] +22 [N=262] 168 [N=337] +16 [N=243] HDL-cholesterol (fasted) 43 [N=675] +7 [N=535] 43 [N=343] +9 [N=262] 42 [N=335] +7 [N=242] LDL-cholesterol (fasted) 100 [N=675] +15 [N=535] 97 [N=343] +19 [N=262] 101 [N=337] +18 [N=242] Triglycerides (fasted) 122 [N=675] +12 [N=535] 121 [N=343] +5 [N=262] 132 [N=337] +22 [N=242] Clinical Trials in Pediatric Subjects The safety of STRIBILD in 50 HIV-1 infected, treatment-naïve pediatric subjects aged 12 to less than 18 years and weighing at least 35 kg was evaluated through 48 weeks in an open-label clinical trial (Study 112) [see Clinical Studies (14.4) ]. In this study, the safety profile of STRIBILD was similar to that in adults. Twenty-two subjects (44%) had treatment-emergent proteinuria (Grades 1–2). One subject met laboratory criteria for proximal renal tubulopathy, evidenced by sustained proteinuria and normoglycemic glycosuria beginning at Week 32. The subject continued to receive STRIBILD and was ultimately lost to follow-up. Among the 50 pediatric subjects receiving STRIBILD for 48 weeks, mean BMD increased from baseline to Week 48, +0.68% at the lumbar spine and +0.77% for total body less head. Mean changes from baseline BMD Z-scores (height-age adjusted) to Week 48 were −0.09 for lumbar spine and −0.12 for total body less head. At Week 48, 7 STRIBILD subjects had significant (greater than or equal to 4%) lumbar spine BMD loss and 2 had significant total body less head BMD loss. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TDF. Because postmarketing reactions 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. No additional postmarketing adverse reactions specific for emtricitabine have been identified. Immune System Disorders allergic reaction, including angioedema Metabolism and Nutrition Disorders lactic acidosis, hypokalemia, hypophosphatemia Respiratory, Thoracic, and Mediastinal Disorders dyspnea Gastrointestinal Disorders pancreatitis, increased amylase, abdominal pain Hepatobiliary Disorders hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT) Skin and Subcutaneous Tissue Disorders rash Musculoskeletal and Connective Tissue Disorders rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy Renal and Urinary Disorders acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria General Disorders and Administration Site Conditions asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

12.3 Pharmacokinetics The pharmacokinetic properties of the components of STRIBILD are provided in Table 6. The multiple dose pharmacokinetic parameters of elvitegravir, cobicistat, emtricitabine, and tenofovir are provided in Table 7. Table 6 Pharmacokinetic Properties of the Components of STRIBILD Elvitegravir Cobicistat Emtricitabine Tenofovir NC=Not Calculated Absorption T max (h) 4 3 3 2 Effect of light meal (relative to fasting) Values refer to mean systemic exposure (90% confidence interval). STRIBILD light meal=~373 kcal, 20% fat; STRIBILD high fat meal=~800 kcal, 50% fat. Increase = ↑; Decrease = ↓ ↑34% (↑19, ↑51) ↑3% (↓10, ↑17) ↓5% (↓9, 0) ↑24% (↑18, ↑30) Effect of high fat meal (relative to fasting) ↑87% (↑66, ↑110) ↓17% (↓27, ↓5) ↓4% (↓8, 0) ↑23% (↑17, ↑29) Distribution % Bound to human plasma proteins ~99 ~98 <4 <0.7 Source of protein binding data Ex vivo In vitro In vitro In vitro Blood-to-plasma ratio 0.73 0.5 0.6 NC Metabolism Metabolism CYP3A (major) UGT1A1/3 (minor) CYP3A (major) CYP2D6 (minor) Not significantly metabolized Elimination Major route of elimination Metabolism Glomerular filtration and active tubular secretion T 1/2 (h) t 1/2 values refer to median terminal plasma half-life. 12.9 3.5 10 12–18 % Of dose excreted in urine Dosing in mass balance studies: elvitegravir (single dose administration of [ 14 C] elvitegravir, coadministered with 100 mg RTV); 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); mass balance study not conducted for tenofovir. 6.7 8.2 70 70–80 % Of dose excreted in feces 94.8 86.2 13.7 NC Table 7 Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Exposure Following Oral Administration of STRIBILD in HIV-Infected Subjects Parameter Mean ± SD [range, min:max] Elvitegravir From Population Pharmacokinetic analysis, N=419. Cobicistat From Intensive Pharmacokinetic analysis, N=61–62, except cobicistat C trough N=53. Emtricitabine Tenofovir SD=Standard Deviation C max (microgram per mL) 1.7 ± 0.4 [0.4:3.7] 1.1 ± 0.4 [0.1:2.1] 1.9 ± 0.5 [0.6:3.6] 0.45 ± 0.2 [0.2:1.2] AUC tau (microgram∙hour per mL) 23.0 ± 7.5 [4.4:69.8] 8.3 ± 3.8 [0.5:18.3] 12.7 ± 4.5 [5.2:34.1] 4.4 ± 2.2 [2.1:18.2] C trough (microgram per mL) 0.45 ± 0.26 [0.05:2.34] 0.05 ± 0.13 [0.01:0.92] 0.14 ± 0.25 [0.04:1.94] 0.10 ± 0.08 [0.04:0.58] Specific Populations Geriatric Patients The pharmacokinetics of elvitegravir, cobicistat, emtricitabine, and tenofovir have not been fully evaluated in elderly (65 years of age and older) patients [see Use in Specific Populations (8.5) ]. Pediatric Patients Exposures (AUC) of elvitegravir and tenofovir in 14 pediatric subjects aged 12 to less than 18 years who received STRIBILD in Study 112 were increased by 30% and 37%, respectively, compared with exposures achieved in adults following administration of STRIBILD, but were deemed acceptable based on the overall safety profile of these agents and exposure-safety assessments. The other components of STRIBILD had similar exposures in adolescents compared with adults [see Use in Specific Populations (8.4) ]. Emtricitabine has been studied in pediatric subjects from 3 months to 17 years of age. TDF has been studied in pediatric subjects from 2 years to less than 18 years of age. The pharmacokinetics of elvitegravir or cobicistat in pediatric subjects less than 12 years of age have not been established [see Use in Specific Populations (8.4) ]. Race, Gender No clinically significant differences in pharmacokinetics of STRIBILD have been identified based on race or gender. Patients with Renal Impairment Elvitegravir and Cobicistat: A study of the pharmacokinetics of cobicistat+elvitegravir was performed in healthy subjects and subjects with severe renal impairment (estimated creatinine clearance less than 30 mL per minute). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment. Emtricitabine and TDF: The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with estimated creatinine clearance below 50 mL per minute or with end-stage renal disease requiring dialysis (ESRD) (Table 8) [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6) ]. Table 8 Pharmacokinetic Parameters of Emtricitabine 200 mg, single dose of emtricitabine and Tenofovir 300 mg, single dose of TDF in Adults with Varying Degrees of Renal Function Parameter Mean ± SD Creatinine Clearance (mL/min) >80 50–80 30–49 <30 ESRD ESRD subjects requiring dialysis SD=Standard Deviation Emtricitabine N=6 N=6 N=6 N=5 N=5 AUC inf (microgram∙hr per mL) 11.8 ± 2.9 19.9 ± 1.2 25.1 ± 5.7 33.7± 2.1 53.2 ± 9.9 C max (microgram per mL) 2.2 ± 0.6 3.8 ± 0.9 3.2 ± 0.6 2.8 ± 0.7 2.8 ± 0.5 Tenofovir N=3 N=10 N=8 N=11 N=9 AUC inf (microgram∙hr per mL) 2.18 ± 0.26 3.06 ± 0.93 6.01 ± 2.50 15.98 ± 7.22 44.90 ± 12.96 C max (microgram per mL) 0.34 ± 0.03 0.33 ± 0.06 0.37 ± 0.16 0.60 ± 0.19 1.06 ± 0.25 Patients with Hepatic Impairment Elvitegravir and Cobicistat: A study of the pharmacokinetics of cobicistat+elvitegravir 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. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of elvitegravir or cobicistat has not been studied [see Use in Specific Populations (8.7) ]. Emtricitabine: The pharmacokinetics of emtricitabine have 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 DF: The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD have been studied in healthy subjects with moderate to severe hepatic impairment (Child-Pugh Class C). No clinically relevant differences in tenofovir pharmacokinetics were observed between subjects with hepatic impairment and healthy subjects. Hepatitis B and/or Hepatitis C Virus Coinfection 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 cobicistat-boosted elvitegravir. 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 TDF: The pharmacokinetics of emtricitabine and TDF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus. Assessment of Drug Interactions [see Contraindications (4) and Drug Interactions (7) ] The drug-drug interaction studies described were conducted with STRIBILD, elvitegravir (coadministered with cobicistat or RTV), or cobicistat administered alone. As STRIBILD is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral medications, information regarding drug-drug interactions with other antiretroviral agents is not provided . The effects of coadministered drugs on the exposure of elvitegravir, emtricitabine, and tenofovir are shown in Table 9, Table 10, and Table 11 respectively. The effects of elvitegravir plus cobicistat, or cobicistat, or emtricitabine on the exposure of coadministered drugs are shown in Table 12. For information regarding clinical recommendations, [see Drug Interactions (7) ] . Table 9 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 Elvitegravir Dose (mg) Cobicistat or RTV Booster 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 RTV 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 mg single dose 150 once daily Study conducted with GENVOYA ® (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide). 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 mg 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, 0.04) Famotidine 40 mg 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 mg 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 mg twice daily 150 once daily RTV 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 mg once daily 150 once daily Cobicistat 150 once daily Percent change of cobicistat PK parameters (90% CI) was 1.25 (1.18 to 1.32) for C max , 1.59 (1.49 to 1.70) for AUC, and 4.25 (3.47 to 5.22) for C min . 29 0.88 (0.82, 0.95) 1.02 (0.95, 1.09) 1.36 (1.23, 1.49) Omeprazole 40 mg once daily given 2 hours before elvitegravir 50 once daily RTV 100 once daily 9 0.93 (0.83, 1.04) 0.99 (0.91, 1.07) 0.94 (0.85, 1.04) 20 mg 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 mg 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 mg 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 mg 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 mg 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 mg once daily 150 once daily Study conducted with STRIBILD. Cobicistat 150 once daily , Percent change of cobicistat PK parameters (90% CI) was1.11 (1.06, 1.17) for C max , 1.23 (1.17, 1.29) for AUC, and 1.71 (1.54, 1.90) for C min . 24 0.93 (0.86, 1.00) 0.93 (0.87, 0.99) 0.97 (0.91, 1.04) Sofosbuvir/Velpatasvir Voxilaprevir 400/100/100 + 100 Voxilaprevir once daily Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. 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 10 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 NC=Not calculated Famciclovir 500 single dose 200 single dose 12 0.90 (0.80, 1.01) 0.93 (0.87, 0.99) NC Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered Drug All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) TDF Dose (mg) N Mean Ratio of Tenofovir Pharmacokinetic Parameters (90%CI); No Effect=1.00 C max AUC C min Sofosbuvir/Velpatasvir 400/100 once daily 300 once daily Study conducted with STRIBILD. 24 1.36 (1.25, 1.47) 1.35 (1.29, 1.42) 1.45 (1.39, 1.51) Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Elvitegravir plus Cobicistat, Cobicistat, Emtricitabine, or STRIBILD All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) Elvitegravir Dose NA=Not Applicable (mg) Cobicistat Booster Dose (mg) FTC Dose (mg) N Mean Ratio of Coadministered Drug Pharmacokinetic Parameters NC=Not Calculated (90% CI); No Effect=1.00 C max AUC C min FTC=emtricitabine Atorvastatin 10 single dose 150 once daily Study conducted with GENVOYA. 150 once daily 200 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 NA 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 NA 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 NA 150 once daily NA 8 1.24 (1.08, 1.44) 1.65 (1.36, 2.02) NC Digoxin 0.5 single dose NA 150 once daily NA 22 1.41 (1.29, 1.55) 1.08 (1.00, 1.17) NC Famciclovir 500 single dose NA NA 200 single dose 12 0.93 (0.78, 1.11) 0.91 (0.84, 0.99) NC Ledipasvir 90/400 once daily 150 once daily 150 once daily NA 29 1.63 (1.51, 1.75) 1.78 (1.64, 1.94) 1.91 (1.76, 2.08) Sofosbuvir 1.33 (1.14, 1.56) 1.36 (1.21, 1.52) NA GS-331007 The predominant circulating nucleoside metabolite of sofosbuvir. 1.33 (1.22, 1.44) 1.44 (1.41, 1.48) 1.53 (1.47, 1.59) Naloxone 4–6 once daily 150 once daily 150 once daily NA 17 0.72 (0.61, 0.85) 0.72 (0.59, 0.87) NA Norgestimate/ ethinyl estradiol 0.180/0.215/ 0.250 norgestimate once daily 150 once daily Study conducted with STRIBILD. 150 once daily 200 once daily 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) R-Methadone 80–120 daily 150 once daily 150 once daily NA 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) Sofosbuvir 400/100 once daily 150 once daily 150 once daily 200 once daily 24 1.01 (0.85, 1.19) 1.24 (1.13, 1.37) NA GS-331007 1.13 (1.07, 1.18) 1.35 (1.30, 1.40) 1.45 (1.38, 1.52) Velpatasvir 1.05 (0.93, 1.19) 1.19 (1.07, 1.34) 1.37 (1.22, 1.54) Sofosbuvir 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 150 once daily 200 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 0.96 (0.89, 1.04) 1.16 (1.06, 1.27) 1.46 (1.30, 1.64) Voxilaprevir 1.92 (1.63, 2.26) 2.71 (2.30, 3.19) 4.50 (3.68, 5.50) Rifabutin 150 once every other day 150 once daily 150 once daily NA 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 single dose NA 10 1.89 (1.48, 2.42) 1.38 (1.14, 1.67) NC Sertraline 50 single dose 150 once daily 150 once daily 200 once daily 19 1.14 (0.94, 1.38) 0.93 (0.77, 1.13) NA