Emtricitabine

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 )

12.1 Mechanism of Action BIKTARVY is a fixed dose combination of antiretroviral drugs bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF) [see Microbiology (12.4) ] .

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 co

5 WARNINGS AND PRECAUTIONS Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.3 ) New onset or worsening renal impairment: Assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein when initiating BIKTARVY and during therapy as clinically appropriate in all patients. Also assess serum phosphorus in patients with chronic kidney disease. ( 5.4 ) Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.5 ) 5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus (HBV) infection before or when initiating antiretroviral therapy [see Dosage and Administration (2.1) ] . Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing FTC and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of BIKTARVY. Patients coinfected with HIV-1 and HBV who discontinue BIKTARVY should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post-treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. 5.2 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of BIKTARVY with certain other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4) , and Drug Interactions (7.5) ]: Loss of therapeutic effect of BIKTARVY and possible development of resistance. Possible clinically significant adverse reactions from greater exposures of concomitant drugs. See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during BIKTARVY therapy; review concomitant medications during BIKTARVY therapy; and monitor for the adverse reactions associated with the concomitant drugs. 5.3 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. 5.4 New Onset or Worsening Renal Impairment Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome, have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events [see Adverse Reactions (6.1 , 6.2) ]. BIKTARVY is not recommended in patients with severe renal impairment (estimated creatinine clearance of 15 to below 30 mL/min), or patients with ESRD (estimated creatinine clearance below 15 mL/min) who are not receiving chronic hemodialysis, or patients with no antiretroviral treatment history and ESRD wh

4 CONTRAINDICATIONS BIKTARVY is contraindicated to be co-administered with: dofetilide due to the potential for increased dofetilide plasma concentrations and associated serious and/or life-threatening events [see Drug Interactions (7.5) ] . rifampin due to decreased BIC plasma concentrations, which may result in the loss of therapeutic effect and development of resistance to BIKTARVY [see Drug Interactions (7.5) ] . BIKTARVY is contraindicated to be co-administered with: dofetilide. ( 4 ) rifampin. ( 4 )

10 OVERDOSAGE No data are available on overdose of BIKTARVY in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with BIKTARVY consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Hemodialysis treatment removes approximately 30% of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether FTC can be removed by peritoneal dialysis. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.