Biktarvy

Indications and Usage ( 1 ) 02/2024

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) ].

3 DOSAGE FORMS AND STRENGTHS BIKTARVY tablets are available in two dose strengths: 50 mg/200 mg/25 mg tablets: 50 mg of bictegravir (BIC) (equivalent to 52.5 mg of bictegravir sodium), 200 mg of emtricitabine (FTC), and 25 mg of tenofovir alafenamide (TAF) (equivalent to 28 mg of tenofovir alafenamide fumarate). These tablets are purplish brown, capsule-shaped, film-coated, and debossed with "GSI" on one side and "9883" on the other side. 30 mg/120 mg/15 mg tablets: 30 mg of BIC (equivalent to 31.5 mg of bictegravir sodium), 120 mg of FTC, and 15 mg of TAF (equivalent to 16.8 mg of tenofovir alafenamide fumarate). These tablets are pink, capsule-shaped, film-coated, and debossed with "GSI" on one side and "B" on the other side. Tablets: 50 mg of BIC, 200 mg of FTC, and 25 mg of TAF. ( 3 ) Tablets: 30 mg of BIC, 120 mg of FTC, and 15 mg of TAF. ( 3 )

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 )

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% 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 (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% 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 × U …

7 DRUG INTERACTIONS Because BIKTARVY is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. ( 7.1 ) Consult the Full Prescribing Information prior to and during treatment for important drug interactions. ( 4 , 5.2 , 7 , 12.3 ) 7.1 Other Antiretroviral Medications Because BIKTARVY is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended [see Indications and Usage (1) ] . Comprehensive information regarding potential drug-drug interactions with other antiretroviral medications is not provided because the safety and efficacy of concomitant HIV-1 antiretroviral therapy is unknown. 7.2 Potential for BIKTARVY to Affect Other Drugs BIC inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1) in vitro . Coadministration of BIKTARVY with drugs that are substrates of OCT2 and MATE1 (e.g., dofetilide) may increase their plasma concentrations (see Table 3 ). 7.3 Potential Effect of Other Drugs on One or More Components of BIKTARVY BIC is a substrate of CYP3A and UGT1A1. A drug that is a strong inducer of CYP3A and also an inducer of UGT1A1 can substantially decrease the plasma concentrations of BIC which may lead to loss of therapeutic effect of BIKTARVY and development of resistance [see Clinical Pharmacology (12.3) ] . The use of BIKTARVY with a drug that is a strong inhibitor of CYP3A and also an inhibitor of UGT1A1 may significantly increase the plasma concentrations of BIC. TAF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Co-administration of drugs that inhibit P-gp and BCRP may increase the absorption and plasma concentrations of TAF [see Clinical Pharmacology (12.3) ] . Co-administration of drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of BIKTARVY and development of resistance (see Table 3 ). 7.4 Drugs Affecting Renal Function Because FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of BIKTARVY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.4) ] . 7.5 Established and Potentially Significant Drug Interactions Table 3 provides a listing of established or potentially clinically significant drug interactions with recommended prevention or management strategies. The drug interactions described are based on studies conducted with either BIKTARVY, the components of BIKTARVY (BIC, FTC, and TAF) as individual agents, or are drug interactions that may occur with BIKTARVY [see Contraindications (4) , Warnings and Precautions (5.2) , and Clinical Pharmacology (12.3) ] . Table 3 Established and Potentially Significant Table is not all inclusive. Drug Interactions: Alteration in Regimen May be Recommended Concomitant Drug Class: Drug Name Effect on Concentration ↑ = Increase, ↓ = Decrease. Clinical Comment Antiarrhythmics: dofetilide ↑ Dofetilide Coadministration is contraindicated due to the potential for serious and/or life-threatening events associated with dofetilide therapy [see Contraindications (4) ] . Anticonvulsants: carbamazepine Drug-drug interaction study was conducted with either BIKTARVY or its components as individual agents. oxcarbazepine phenobarbital phenytoin ↓ BIC ↓ TAF Coadministration with alternative anticonvulsants should be considere …

8 USE IN SPECIFIC POPULATIONS Pediatrics: Not recommended for patients weighing less than 14 kg. ( 8.4 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to BIKTARVY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary There are insufficient human data on the use of BIKTARVY during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Dolutegravir, another integrase inhibitor, has been associated with neural tube defects (NTDs) (see Data ) . Discuss the benefit-risk of using BIKTARVY with individuals of childbearing potential, particularly if pregnancy is being planned. BIKTARVY use during pregnancy has been evaluated in a limited number of women reported to the APR; consequently, there are insufficient BIC data from the APR to adequately assess the risk of major birth defects. Reports of pregnant individuals treated with other drug products containing TAF or FTC contribute to APR's overall risk assessment for these components. Available data from the APR show no statistically significant difference in the overall risk of major birth defects for FTC or TAF compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data ) . The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15–20%. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of BIKTARVY at exposures that were either not maternally toxic (rabbits) or greater than (rats and mice) those in humans at the recommended human dose (RHD) ( see Data ). During organogenesis, systemic exposures (AUC) to BIC were approximately 36 (rats) and 0.6 times (rabbits), to FTC were approximately 60 (mice) and 108 times (rabbits), and to TAF were approximately 2 (rats) and 78 times (rabbits) the exposure at the RHD of BIKTARVY. In rat pre/postnatal development studies, maternal systemic exposures (AUC) were 30 times (BIC), 60 times (FTC), and 19 times (TDF) the exposures of each component in humans at the RHD. Data Human Data Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of BIKTARVY are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation. Bictegravir (BIC): Data from an observational study in Botswana showed that dolutegravir, another integrase inhibitor, was associated with increased risk of neural tube defects when administered at the time of conception and in early pregnancy. Data available to date from other sources including the APR, clinical trials, and postmarketing data are insufficient to address this risk with BIC. There are an insufficient number of reports to the APR to adequately assess the risk of major birth defects associated with BIC exposure. The APR has received prospective reports of 3 birth defects among 100 (3.0%) first trimester exposures to BIC-containing regimens during pregnancy resulting in live births. No birth defects were reported among 40 exposures during the second/third trimester. Emtricitabine (FTC): Based on prospective reports to the APR of over 5,400 exposures to FTC-containing regimens during pregnancy resulting in live births (including over 3,900 exposed in the first trimester and over 1,500 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.6% (95% CI: 2.2% to 3.2%) and 2.7 …

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) ] .

11 DESCRIPTION BIKTARVY (bictegravir, emtricitabine, and tenofovir alafenamide) is a fixed dose combination tablet containing bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF) for oral administration. BIC is an integrase strand transfer inhibitor (INSTI). FTC, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI). TAF, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. BIKTARVY tablets are available in two dose strengths: 50 mg/200 mg/25 mg tablet containing 50 mg of BIC (equivalent to 52.5 mg of bictegravir sodium), 200 mg of FTC, and 25 mg of TAF (equivalent to 28 mg of tenofovir alafenamide fumarate). 30 mg/120 mg/15 mg tablet containing 30 mg of BIC (equivalent to 31.5 mg of bictegravir sodium), 120 mg of FTC, and 15 mg of TAF (equivalent to 16.8 mg of tenofovir alafenamide fumarate). Both dose strengths of BIKTARVY tablets include the following inactive ingredients: croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets for both dose strengths are film-coated with a coating material containing iron oxide black, iron oxide red, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Bictegravir: The chemical name of bictegravir sodium is 2,5-Methanopyrido[1',2':4,5]pyrazino[2,1- b ][1,3]oxazepine-10-carboxamide, 2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo- N -[(2,4,6-trifluorophenyl)methyl]-, sodium salt (1:1), (2 R ,5 S ,13a R )-. Bictegravir sodium has a molecular formula of C 21 H 17 F 3 N 3 NaO 5 and a molecular weight of 471.4 and has the following structural formula: Bictegravir sodium is an off-white to yellow solid with a solubility of 0.1 mg per mL in water at 20 °C. Chemical Structure Emtricitabine: The chemical name of FTC is 4-amino-5-fluoro-1-(2 R -hydroxymethyl-1,3-oxathiolan-5 S -yl)-(1H)-pyrimidin-2-one. FTC is the (-)enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position. FTC has a molecular formula of C 8 H 10 FN 3 O 3 S and a molecular weight of 247.2 and has the following structural formula: FTC is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25 °C. Chemical Structure Tenofovir alafenamide: The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N -[( S )-[[(1 R )-2-(6-amino-9 H -purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2 E )-2-butenedioate (2:1). Tenofovir alafenamide fumarate has an empirical formula of C 21 H 29 O 5 N 6 P∙1⁄2(C 4 H 4 O 4 ) and a formula weight of 534.5 and has the following structural formula: Tenofovir alafenamide fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20 °C. Chemical Structure

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%.

16 HOW SUPPLIED/STORAGE AND HANDLING Product: 50090-6247 NDC: 50090-6247-0 30 TABLET in a BOTTLE, PLASTIC