Bictegravir Sodium, Emtricitabine, And Tenofovir Alafenamide Fumarate

1 INDICATIONS AND USAGE BIKTARVY is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 14 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 with no known or suspected substitutions associated with resistance to bictegravir or tenofovir. BIKTARVY is a three-drug combination of bictegravir (BIC), a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI), 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 14 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 with no known or suspected substitutions associated with resistance to bictegravir or tenofovir. ( 1 )

2 DOSAGE AND ADMINISTRATION Testing: Prior to or when initiating BIKTARVY test for hepatitis B virus infection. Prior to or when initiating BIKTARVY, and during treatment, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients as clinically appropriate. In patients with chronic kidney disease, also assess serum phosphorus. ( 2.1 ) Recommended dosage in adults and pediatric patients weighing at least 25 kg: One tablet containing 50 mg BIC, 200 mg FTC, and 25 mg TAF taken once daily with or without food. ( 2.2 ) Recommended dosage in pediatric patients weighing at least 14 kg to less than 25 kg: One tablet containing 30 mg BIC, 120 mg FTC, and 15 mg TAF taken once daily with or without food. ( 2.3 ) Renal impairment: BIKTARVY is not recommended in patients with estimated creatinine clearance of 15 to below 30 mL/min, or below 15 mL/min who are not receiving chronic hemodialysis, or below 15 mL/min who have no antiretroviral treatment history. ( 2.4 ) Hepatic impairment: BIKTARVY is not recommended in patients with severe hepatic impairment. ( 2.5 ) 2.1 Testing When Initiating and During Treatment with BIKTARVY Prior to or when initiating BIKTARVY, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1) ] . Prior to or when initiating BIKTARVY, and during treatment with BIKTARVY, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients as clinically appropriate. 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 BIKTARVY is a three-drug fixed dose combination product containing bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF). The recommended dosage of BIKTARVY is one tablet containing 50 mg of BIC, 200 mg of FTC, and 25 mg of TAF taken orally once daily with or without food in: adults and pediatric patients weighing at least 25 kg with an estimated creatinine clearance greater than or equal to 30 mL/min; or virologically-suppressed adults with an estimated creatinine clearance below 15 mL/min who are receiving chronic hemodialysis. On days of hemodialysis, administer the daily dose of BIKTARVY after completion of hemodialysis treatment [see Use in Specific Populations (8.4 , 8.6) , and Clinical Pharmacology (12.3) ] . 2.3 Recommended Dosage in Pediatric Patients Weighing at Least 14 kg to Less than 25 kg The recommended dosage of BIKTARVY is one tablet containing 30 mg of BIC, 120 mg of FTC, and 15 mg of TAF taken orally once daily with or without food in: pediatric patients weighing at least 14 kg to less than 25 kg with an estimated creatinine clearance greater than or equal to 30 mL/min [see Use in Specific Populations (8.4 , 8.6) , and Clinical Pharmacology (12.3) ] . For children unable to swallow a whole tablet, the tablet can be split and each part taken separately as long as all parts are ingested within approximately 10 minutes. 2.4 Not Recommended in Patients with Severe Renal Impairment BIKTARVY is not recommended in patients with [see Dosage and Administration (2.2 , 2.3) , and Use in Specific Populations (8.6) ] : severe renal impairment (estimated creatinine clearance of 15 to below 30 mL/min); or end stage renal disease (ESRD; estimated creatinine clearance below 15 mL/min who are not receiving chronic hemodialysis; or no antiretroviral treatment history and ESRD who are receiving chronic hemodialysis. 2.5 Not Recommended in Patients with Severe Hepatic Impairment BIKTARVY 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) ].

6 ADVERSE REACTIONS The following adverse 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 reactions (incidence greater than or equal to 5%, all grades) are diarrhea, nausea, and headache. ( 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 Adults with No Antiretroviral Treatment History The primary safety assessment of BIKTARVY was based on data from two randomized, double-blind, active-controlled trials, Trial 1489 and Trial 1490, that enrolled 1274 HIV-1 infected adult subjects with no antiretroviral treatment history through Week 144. After Week 144, subjects received open-label BIKTARVY in an optional extension phase for an additional 96 weeks (end of study). A total of 634 and 1025 subjects received one tablet of BIKTARVY once daily during the double-blind (Week 144) and extension phases, respectively [see Clinical Studies (14.2) ] . The most common adverse reactions (all Grades) reported in at least 5% of subjects in the BIKTARVY group in either Trial 1489 or Trial 1490 were diarrhea, nausea, and headache. The proportion of subjects who discontinued treatment through Week 144 with BIKTARVY, abacavir [ABC]/dolutegravir [DTG]/ lamivudine [3TC]), or DTG + FTC/TAF, due to adverse events, regardless of severity, was 1%, 2%, and 2%, respectively. Table 1 displays the frequency of adverse reactions (all Grades) greater than or equal to 2% in the BIKTARVY group. Table 1 Adverse Reactions Frequencies of adverse reactions are based on all adverse events attributed to trial drugs by the investigator. No adverse reactions of Grade 2 or higher occurred in > 1% of subjects treated with BIKTARVY. (All Grades) Reported in ≥ 2% of HIV-1 Infected Adults with No Antiretroviral Treatment History Receiving BIKTARVY in Trials 1489 or 1490 (Week 144 analysis) Trial 1489 Trial 1490 Adverse Reactions BIKTARVY N=314 ABC/DTG/3TC N=315 BIKTARVY N=320 DTG + FTC/TAF N=325 Diarrhea 6% 4% 3% 3% Nausea 6% 18% 3% 5% Headache 5% 5% 4% 3% Fatigue 3% 4% 2% 2% Abnormal dreams 3% 3% <1% 1% Dizziness 2% 3% 2% 1% Insomnia 2% 3% 2% <1% Abdominal distention 2% 2% 1% 2% Additional adverse reactions (all Grades) occurring in less than 2% of subjects administered BIKTARVY in Trials 1489 and 1490 included vomiting, flatulence, dyspepsia, abdominal pain, rash, and depression. Suicidal ideation, suicide attempt, and depression suicidal occurred in 2% of subjects administered BIKTARVY; these events occurred primarily in subjects with a preexisting history of depression, prior suicide attempt or psychiatric illness. The majority (84%) of adverse events associated with BIKTARVY were Grade 1. Adverse reactions in the open-label extension phases of Trials 1489 and 1490 were similar to those observed in subjects administered BIKTARVY in the Week 144 analysis. Clinical Trials in Virologically Suppressed Adults The safety of BIKTARVY in virologically-suppressed adults was based on Week 48 data from 282 subjects in a randomized, double-blind, active-controlled trial (Trial 1844) in which virologically-suppressed subjects were switched from either DTG + ABC/3TC or ABC/DTG/3TC to BIKTARVY; Week 48 data from 290 subjects in an open-label, active-controlled trial in which virologically-suppressed subjects were switched from a regimen containing atazanavir (ATV) (given with cobicistat or ritonavir) or darunavir (DRV) (given with cobicistat or ritonavir) plus either FTC/TDF or ABC/3TC, to BIKTARVY (Trial 1878); and Week 48 data from a randomized, double-blind active-controlled trial in which 284 virologically-suppressed subjects were switched from DTG plus either FTC/TAF or FTC/TDF, to BIKTARVY (Trial 4030). Overall, the safety profile in virologically-suppressed adult subjects in Trials 1844, 1878, and 4030 was similar to that in subjects with no antiretroviral treatment history [see Clinical Studies (14.3) ] . Clinical Trial in Adults with End Stage Renal Disease (ESRD) Receiving Chronic Hemodialysis The safety of FTC and TAF (components of BIKTARVY) was evaluated in a single arm, open-label trial (Trial 1825) in virologically-suppressed adults with ESRD (estimated creatinine clearance of less than 15 mL/min) on chronic hemodialysis treated with FTC+TAF in combination with elvitegravir and cobicistat as a fixed-dose combination tablet for 96 weeks (N=55). 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 65% of subjects and the most common serious adverse events were pneumonia (15%), fluid overload (7%), hyperkalemia (11%) and osteomyelitis (7%). Overall 7% of subjects permanently discontinued treatment due to an adverse event. In an extension phase of Trial 1825 in which 10 subjects switched to BIKTARVY for 48 weeks, the safety findings were similar to those in the initial phase of the open-label trial [see Use in Specific Populations (8.6) , and Clinical Studies (14.3) ] . Laboratory Abnormalities The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving BIKTARVY in Trials 1489 and 1490 are presented in Table 2. Table 2 Laboratory Abnormalities (Grades 3–4) Reported in ≥ 2% of Subjects Receiving BIKTARVY in Trials 1489 or 1490 (Week 144 analysis) Trial 1489 Trial 1490 Laboratory Parameter Abnormality Frequencies are based on treatment-emergent laboratory abnormalities. BIKTARVY N=314 ABC/DTG/3TC N=315 BIKTARVY N=320 DTG + FTC/TAF N=325 ULN = Upper limit of normal Amylase (>2.0 × ULN) 3% 4% 3% 4% ALT (>5.0 × ULN) 2% 2% 3% 1% AST (>5.0 × ULN) 5% 3% 2% 3% Creatine Kinase (≥10.0 × ULN) 8% 8% 6% 4% Neutrophils (<750 mm 3 ) 3% 4% 3% 2% LDL-cholesterol (fasted) (>190 mg/dL) 5% 5% 4% 6% Lipase (> 3.0 × ULN) Lipase test performed only in subjects with serum amylase > 1.5 × ULN. 2% 2% <1% 2% GGT (>5.0 × ULN) 2% 2% 1% 1% Changes in Serum Creatinine: BIC has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2) ] . Increases in serum creatinine occurred by Week 4 of treatment and remained stable through Week 144. In Trials 1489 and 1490, median (Q1, Q3) serum creatinine increased by 0.11 (0.03, 0.19) mg per dL from baseline to Week 144 in the BIKTARVY group and was similar to the comparator groups who received ABC/DTG/3TC, or DTG + FTC/TAF. There were no discontinuations due to renal adverse events and renal serious adverse events were encountered in less than 1% of participants treated with BIKTARVY through Week 144 in clinical trials. Changes in Bilirubin: In Trials 1489 and 1490, total bilirubin increases were observed in 17% of subjects administered BIKTARVY through Week 144. Increases were primarily Grade 1 (1.0 to 1.5 × ULN) (12%) and Grade 2 (1.5 to 2.5 × ULN) (4%). Graded bilirubin increases in the ABC/DTG/3TC, and DTG + FTC/TAF groups, were 7% and 8%, respectively. Increases were primarily Grade 1 (5% ABC/DTG/3TC and 7% DTG + FTC/TAF) or Grade 2 (2% ABC/DTG/3TC and 2% DTG + FTC/TAF). There were no discontinuations due to hepatic adverse events through Week 144 in BIKTARVY clinical studies. Clinical Trials in Pediatric Subjects The safety of BIKTARVY was evaluated in HIV-1 infected virologically-suppressed subjects between the ages of 12 to less than 18 years and weighing at least 35 kg (N=50) through Week 48 (cohort 1), in virologically-suppressed subjects between the ages of 6 to less than 12 years and weighing at least 25 kg (N=50) through Week 24 (cohort 2), and in virologically suppressed subjects at least 2 years of age and weighing at least 14 to less than 25 kg (N=22) through Week 24 (cohort 3) in an open label clinical trial (Trial 1474) [see Clinical Studies (14.4) ] . No new adverse reactions or laboratory abnormalities were identified compared to those observed in adults. Adverse reactions were reported in 11% of pediatric subjects. The majority (76%) of adverse reactions were Grade 1. No Grade 3 or 4 adverse reactions were reported. The adverse reaction reported by more than one subject (regardless of severity) was abdominal discomfort (n=2). One subject (1%) had Grade 2 adverse reactions of insomnia and anxiety that led to discontinuation of BIKTARVY. The other adverse reactions that occurred in single subjects were similar to those seen in adults. 6.2 Postmarketing Experience The following events have been identified during post approval use of BIKTARVY or products containing TAF. 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. Renal and Urinary Disorders Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome Skin and Subcutaneous Tissue Disorders Angioedema, Stevens-Johnson syndrome/toxic epidermal necrolysis, and urticaria Investigations Weight increased

12.3 Pharmacokinetics The pharmacokinetic (PK) properties of BIKTARVY components are provided in Table 4. The multiple dose PK parameters of BIKTARVY components (based on population pharmacokinetic analysis) are provided in Table 5. Table 4 Pharmacokinetic Properties of the Components of BIKTARVY Bictegravir (BIC) Emtricitabine (FTC) Tenofovir Alafenamide (TAF) PBMCs=peripheral blood mononuclear cells; CES1=carboxylesterase 1 Absorption T max (h) Values reflect administration of BIKTARVY with or without food. 2.0–4.0 1.5–2.0 0.5–2.0 Effect of high-fat meal (relative to fasting) Values refer to geometric mean ratio [high-fat meal/ fasting] in PK parameters and (90% confidence interval). High fat meal is approximately 800 kcal, 50% fat. AUC ratio 1.24 (1.16, 1.33) 0.96 (0.93, 0.99) 1.63 (1.43, 1.85) C max ratio 1.13 (1.06, 1.20) 0.86 (0.78, 0.93) 0.92 (0.73, 1.14) Distribution % bound to human plasma proteins >99 <4 ~80 Blood-to-plasma ratio 0.64 0.6 1.0 Elimination t 1/2 (h) t 1/2 values refer to median (Q1, Q3) terminal plasma half-life. Note that the active metabolite of TAF, tenofovir diphosphate, has a half-life of 150–180 hours within PBMCs. 17.3 (14.8, 20.7) 10.4 (9.0, 12.0) 0.51 (0.45, 0.62) Metabolism Metabolic pathway(s) CYP3A UGT1A1 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. (PBMCs) CES1 (hepatocytes) Excretion Major route of elimination Metabolism Glomerular filtration and active tubular secretion Metabolism % of dose excreted in urine Dosing in mass balance studies: single dose administration of [ 14 C] BIC; single dose administration of [ 14 C] FTC after multiple dosing of FTC for ten days; single dose administration of [ 14 C] TAF. 35 70 <1 % of dose excreted in feces 60.3 13.7 31.7 Table 5 Multiple Dose PK Parameters of BIC, FTC, and TAF Following Oral Administration of BIKTARVY in HIV-Infected Adults Parameter Mean (CV%) Bictegravir Emtricitabine Tenofovir Alafenamide CV=Coefficient of Variation; NA=Not Applicable C max (microgram per mL) 6.15 (22.9) 2.13 (34.7) 0.121 (15.4) AUC tau (microgram∙h per mL) 102 (26.9) 12.3 (29.2) 0.142 (17.3) C trough (microgram per mL) 2.61 (35.2) 0.096 (37.4) NA Specific Populations Patients with Renal Impairment No clinically relevant differences in the pharmacokinetics of BIC, TAF, or its metabolite tenofovir were observed between subjects with severe renal impairment (estimated creatinine clearance of 15 to less than 30 mL/min, by Cockcroft-Gault method) and healthy subjects in Phase 1 studies. In a separate Phase 1 study of FTC alone, FTC exposures were increased in subjects with severe renal impairment. The pharmacokinetics of BIC, FTC and TAF were evaluated in a subset of HIV-1 infected virologically-suppressed subjects with ESRD (estimated creatinine clearance less than 15 mL/min, by Cockcroft-Gault method) receiving chronic hemodialysis in Trial 1825. The pharmacokinetics of TAF were similar between healthy subjects and subjects with ESRD receiving chronic hemodialysis; increases in FTC and tenofovir exposures in subjects with ESRD were not considered clinically relevant. Median (minimum, maximum) BIC C trough values in subjects (n=7) with ESRD who received BIKTARVY were 846 ng/mL (288, 1810) compared to 2540 ng/mL (757, 6499) in subjects (N=584) with normal renal function. Despite significantly lower BIC C trough values in the virologically-suppressed ESRD population, virologic suppression was maintained [see Use in Specific Populations (8.6) , and Clinical Studies (14.3) ] . Patients with Hepatic Impairment Bictegravir: Clinically relevant changes in the pharmacokinetics of BIC were not observed in subjects with moderate (Child-Pugh Class B) hepatic impairment. Emtricitabine: The pharmacokinetics of FTC has not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited. Tenofovir Alafenamide: Clinically relevant changes in the pharmacokinetics of TAF or its metabolite tenofovir were not observed in subjects with mild or moderate (Child-Pugh Class A and B) hepatic impairment [see Use in Specific Populations (8.7) ] . Hepatitis B and/or Hepatitis C Virus Coinfection The pharmacokinetics of BIC, FTC, and TAF have not been evaluated in subjects coinfected with hepatitis B and/or C virus. Geriatric Patients The pharmacokinetics of BIC, FTC, and TAF have not been fully evaluated in the elderly (65 years of age and older). Population pharmacokinetics analysis of HIV-infected subjects in Phase 3 trials of BIKTARVY showed that age did not have a clinically relevant effect on exposures of BIC and TAF up to 74 years of age [see Use in Specific Populations (8.5) ] . Pediatric Patients Mean BIC C trough was lower in 50 pediatric patients aged 12 to less than 18 years and weighing at least 35 kg who received BIKTARVY in Trial 1474 relative to adults following administration of BIKTARVY, but was not considered clinically significant based on exposure-response relationships; exposures of FTC and TAF in these pediatric patients were similar to those in adults (Table 6). Table 6 Multiple Dose PK Parameters of BIC, FTC, and TAF Following Oral Administration of BIKTARVY in HIV-Infected Pediatric Subjects Aged 12 to less than 18 years Parameter Mean (CV%) Bictegravir From Population PK analysis of cohort 1 of Trial 1474 (n=50 for BIC; n=49 for TAF). Emtricitabine From Intensive PK analysis of cohort 1 of Trial 1474 (n=24). Tenofovir Alafenamide CV=Coefficient of Variation; NA=Not Applicable C max (microgram per mL) 6.24 (27.1) 2.69 (34.0) 0.133 (70.2) AUC tau (microgram∙h per mL) 89.1 (31.0) 13.6 (21.7) 0.196 (50.3) C trough (microgram per mL) 1.78 (44.4) 0.064 (25.0) NA Mean BIC C max , and exposures of FTC and TAF (AUC tau and C max ) achieved in 50 pediatric patients between the ages of 6 to less than 12 years and weighing at least 25 kg, and in 22 pediatric patients at least 2 years of age and weighing at least 14 to less than 25 kg who received BIKTARVY in Trial 1474 were higher than exposures in adults; however, the increases were not considered clinically significant as the safety profiles were similar in adult and pediatric patients (Tables 7 and 8) [see Use in Specific Populations (8.4) ] . Table 7 Multiple Dose PK Parameters of BIC, FTC, and TAF Following Oral Administration of BIKTARVY in HIV-Infected Pediatric Subjects Aged 6 to less than 12 years Parameter Mean (CV%) Bictegravir From Population PK analysis of cohort 2 of Trial 1474 (n=50 for BIC; n=47 for TAF). Emtricitabine From Intensive PK analysis of cohort 2 of Trial 1474 (n=25 except n=24 for C trough ). Tenofovir Alafenamide CV=Coefficient of Variation; NA=Not Applicable C max (microgram per mL) 9.46 (24.3) 3.89 (31.0) 0.205 (44.6) AUC tau (microgram∙h per mL) 128 (27.8) 17.6 (36.9) 0.278 (40.3) C trough (microgram per mL) 2.36 (39.0) 0.227 (323) NA Table 8 Multiple Dose PK Parameters of BIC, FTC, and TAF Following Oral Administration of BIKTARVY in HIV-Infected Pediatric Subjects at Least 2 Years of Age Cohort 3 of Trial 1474 enrolled pediatric subjects from 3 to 9 years of age. and Weighing at Least 14 to Less than 25 kg Parameter Mean (CV%) Bictegravir From Population PK analysis of cohort 3 of Trial 1474 (n=22). Emtricitabine From Intensive PK analysis of cohort 3 of Trial 1474 (n=12 except n=11 for C trough for FTC). Tenofovir Alafenamide CV=Coefficient of Variation; NA=Not Applicable C max (microgram per mL) 9.15 (44.8) 3.85 (34.7) 0.414 (31.0) AUC tau (microgram∙h per mL) 126 (42.4) 15.0 (21.9) 0.305 (42.6) C trough (microgram per mL) 2.43 (40.1) 0.210 (243) NA Race and Gender No clinically relevant changes in the pharmacokinetics of BIC, FTC, and TAF were observed based on gender or race. Drug Interaction Studies As BIKTARVY is a complete regimen for the treatment of HIV-1 infection, comprehensive information regarding potential drug-drug interactions with other antiretroviral agents is not provided. BIC is a substrate of CYP3A and UGT1A1. BIC is an inhibitor of OCT2 and MATE1. At clinically relevant concentrations, BIC is not an inhibitor of hepatic transporters OATP1B1, OATP1B3, OCT1, BSEP, renal transporters OAT1 and OAT3, or CYP (including CYP3A) or UGT1A1 enzymes. TAF is a substrate of P-gp and BCRP. At clinically relevant concentrations, TAF is not an inhibitor of drug transporters P-gp, BCRP, hepatic transporters OATP1B1, OATP1B3, OCT1, BSEP, renal transporters OAT1, OAT3, OCT2, MATE1, or CYP (including CYP3A) or UGT1A1 enzymes. Drug interaction studies were conducted with BIKTARVY or its components. Tables 9 and 10 summarize the pharmacokinetic effects of other drugs on BIC and TAF, respectively. Table 11 summarizes the pharmacokinetic effects of BIKTARVY or its components on other drugs. Effect of Other Drugs on BIKTARVY Components Table 9 Effect of Other Drugs on BIC All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) BIC (mg) Mean Ratio of BIC Pharmacokinetic Parameters (90% CI); No effect = 1.00 C max AUC C min NA= Not Applicable Ledipasvir/Sofosbuvir (fed) 90/400 once daily 75 once daily 0.98 (0.94, 1.03) 1.00 (0.97, 1.03) 1.04 (0.99, 1.09) Rifabutin (fasted) 300 once daily 75 once daily 0.80 (0.67, 0.97) 0.62 (0.53, 0.72) 0.44 (0.37, 0.52) Rifampin (fed) 600 once daily 75 single dose 0.72 (0.67, 0.78) 0.25 (0.22, 0.27) NA Sofosbuvir/ velpatasvir/ voxilaprevir (fed) 400/100/100+100 voxilaprevir Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. once daily 50 once daily 0.98 (0.94, 1.01) 1.07 (1.03, 1.10) 1.10 (1.05, 1.17) Voriconazole (fasted) 300 twice daily 75 single dose 1.09 (0.96, 1.23) 1.61 (1.41, 1.84) NA Maximum strength antacid (simultaneous administration, fasted) 20 mL Maximum strength antacid contained 80 mg aluminum hydroxide, 80 mg magnesium hydroxide, and 8 mg simethicone, per mL. single dose (oral) 50 single dose 0.20 (0.16, 0.24) 0.21 (0.18, 0.26) NA Maximum strength antacid (2 h after BIKTARVY fasted) 20 mL single dose (oral) 50 single dose 0.93 (0.88, 1.00) 0.87 (0.81, 0.93) NA Maximum strength antacid (2 h before BIKTARVY fasted) 20 mL single dose (oral) 50 single dose 0.42 (0.33, 0.52) 0.48 (0.38, 0.59) NA Maximum strength antacid (simultaneous administration, fed Reference treatment administered under fasted conditions. ) 20 mL single dose (oral) 50 single dose 0.51 (0.43, 0.62) 0.53 (0.44, 0.64) NA Calcium carbonate (simultaneous administration, fasted) 1200 single dose 50 single dose 0.58 (0.51, 0.67) 0.67 (0.57, 0.78) NA Calcium carbonate (simultaneous administration, fed ) 1200 single dose 50 single dose 0.90 (0.78, 1.03) 1.03 (0.89, 1.20) NA Ferrous fumarate (simultaneous administration, fasted) 324 single dose 50 single dose 0.29 (0.26, 0.33) 0.37 (0.33, 0.42) NA Ferrous fumarate (simultaneous administration, fed ) 324 single dose 50 single dose 0.75 (0.65, 0.87) 0.84 (0.74, 0.95) NA Table 10 Effect of Other Drugs on TAF All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) Tenofovir Alafenamide (mg) Mean Ratio of Tenofovir Alafenamide Pharmacokinetic Parameters (90% CI); No effect = 1.00 C max AUC C min NA= Not Applicable Carbamazepine 300 twice daily 25 single dose Study conducted with emtricitabine/tenofovir alafenamide. 0.43 (0.36, 0.51) 0.46 (0.40, 0.54) NA Ledipasvir/sofosbuvir 90/400 once daily 25 once daily 1.17 (1.00, 1.38) 1.27 (1.19, 1.34) NA 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 25 once daily 1.28 (1.09, 1.51) 1.57 (1.44, 1.71) NA Effect of BIKTARVY Components on Other Drugs Table 11 Effect of Components of BIKTARVY on Other Drugs All interaction studies conducted in healthy volunteers. Coadministered Drug Dose of Coadministered Drug (mg) BIC (mg) TAF (mg) Mean Ratio of Coadministered Drug Pharmacokinetic Parameters (90% CI); No effect = 1.00 C max AUC C min NA= Not Applicable Ledipasvir 90/400 once daily 75 once daily 25 once daily 0.85 (0.81, 0.90) 0.87 (0.83, 0.92) 0.90 (0.84, 0.96) Sofosbuvir 1.11 (1.00, 1.24) 1.07 (1.01, 1.13) NA GS-331007 The predominant circulating nucleoside metabolite of sofosbuvir. 1.10 (1.07, 1.13) 1.11 (1.08, 1.14) 1.02 (0.99, 1.06) Metformin 500 twice daily 50 once daily 25 once daily 1.28 (1.21, 1.36) 1.39 (1.31, 1.48) 1.36 (1.21, 1.53) Midazolam 2 single dose 50 once daily 25 once daily 1.03 (0.87, 1.23) 1.15 (1.00, 1.31) NA Norelgestromin norgestimate 0.180/0.215/0.250 once daily /ethinyl estradiol 0.025 once daily 75 once daily - 1.23 (1.14, 1.32) 1.08 (1.05, 1.10) 1.10 (1.05, 1.15) Norgestrel 1.15 (1.10, 1.21) 1.13 (1.07, 1.19) 1.14 (1.06, 1.22) Ethinyl estradiol 1.15 (1.03, 1.27) 1.04 (0.99, 1.10) 1.05 (0.95, 1.14) Norelgestromin norgestimate 0.180/0.215/0.250 once daily / ethinyl estradiol 0.025 once daily - 25 once daily Study conducted with emtricitabine/tenofovir alafenamide. 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) Sertraline 50 single dose - 10 once daily Study conducted with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. 1.14 (0.94, 1.38) 0.93 (0.77, 1.13) NA Sofosbuvir 400/100/100+100 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. once daily 50 once daily 25 once daily 1.14 (1.04,1.25) 1.09 (1.02, 1.15) NA GS-331007 1.03 (0.99,1.06) 1.03 (1.00,1.06) 1.01 (0.98, 1.05) Velpatasvir 0.96 (0.91,1.01) 0.96 (0.90, 1.02) 0.94 (0.88, 1.01) Voxilaprevir 0.90 (0.76, 1.06) 0.91 (0.80, 1.03) 0.97 (0.88, 1.06)