Biktarvy

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: with no antiretroviral treatment history, or with an antiretroviral treatment history and not virologically suppressed, with no known or suspected substitutions associated with resistance to the integrase strand inhibitor class, emtricitabine, or tenofovir, 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 [see Dosage and Administration (2.4) , and Use in Specific Populations (8.1) ]. 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: with no antiretroviral treatment history or with an antiretroviral treatment history and not virologically suppressed, with no known or suspected substitutions associated with resistance to the integrase strand inhibitor class, emtricitabine, or tenofovir, 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, or virologically-suppressed adults with estimated creatinine clearance below 15 mL/min receiving chronic hemodialysis: 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 ) Recommended dosage in pregnant individuals who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no known substitutions associated with resistance to the individual components of BIKTARVY: One tablet containing 50 mg BIC, 200 mg FTC, and 25 mg TAF taken orally once daily with or without food. ( 2.4 ) 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. ( 2.5 ) Hepatic impairment: BIKTARVY is not recommended in patients with severe hepatic impairment. ( 2.6 ) 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 [see Dosage and Administration (2.4) ] : 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 Recommended Dosage in Pregnant Individuals The recommended dosage of BIKTARVY in pregnant individuals 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 pregnant individuals who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no known substitutions associated with resistance t…

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 with HIV-1 and HBV Patients with HIV-1 should be tested for the presence of chronic hepatitis B virus (HBV) 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 with HIV-1 and HBV who have discontinued products containing FTC and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of BIKTARVY. Patients 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 who are receiving chronic hemodialysis [see Dosage an…

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 )

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…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals 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 Available data from observational studies and the APR with BIC, FTC and TAF use during pregnancy have not established a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Reports of pregnant individuals treated with products containing BIC, FTC, or TAF 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 BIC, 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%. BIKTARVY safety has also been evaluated in an open-label trial that demonstrated safety findings that were consistent with other trials in adults (see Data ). 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 BIKTARVY was evaluated in an open-label clinical trial of 33 virologically-suppressed (HIV-1 RNA < 50 copies/mL) pregnant adults with HIV-1 and no known substitutions associated with resistance to BIC, FTC, or TAF. Pregnant adults were administered BIKTARVY (containing 50 mg of BIC, 200 mg of FTC and 25 mg of TAF) once daily from the second or third trimester through postpartum. Exposures of BIC, FTC, and TAF were lower during pregnancy as compared to postpartum [see Clinical Pharmacology (12.3) ] . All 32 adult participants who completed the study maintained viral suppression during pregnancy, at delivery, and through Week 18 postpartum. The median CD4+ cell count at baseline was 558 cells/µL, and the median change in CD4+ cell count from baseline to Week 12 postpartum was 159 cells/μL. All 29 neonate participants had negative/nondetectable HIV-1 PCR results at birth and/or at 4 to 8 weeks post-birth. The safety findings in this trial were consistent with other trials in adults. BIKTARVY was only studied in pregnant individuals who were virologically-suppressed, and lower plasma exposures of BIKTARVY were observed during pregnancy compared to post-partum. Therefore, BIKTARVY is recommended in pregnant individuals who are virologically-suppressed on a stable antiretroviral regimen with no known substitutions associated with resistance to any of the individual components of BIKTARVY. Bictegravir (BIC): Based on prospective reports to the APR of over 500 exposures to a BIC-containing regimen during pregnancy resulting in live births (including 423 exposed in the first trimester and 113 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.3% (95% CI: 2.5% to 6.6%) and 1.8% (0.2%, 6.2%) following first and second/third trimester exposure, respectively, to a BIC-containing regimen. Emtricitabine (FTC): Based on prospective reports to the APR of over …

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 adult participants with HIV-1 and no antiretroviral treatment history through Week 144. After Week 144, participants received open-label BIKTARVY in an optional extension phase for an additional 96 weeks (end of study). A total of 634 and 1025 participants 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 participants in the BIKTARVY group in either Trial 1489 or Trial 1490 were diarrhea, nausea, and headache. The proportion of participants 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 participants treated with BIKTARVY. (All Grades) Reported in ≥ 2% of Adults with HIV-1 and 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 participants 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 participants administered BIKTARVY; these events occurred primarily in participants 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 participants administered BIKTARVY in the Week 144 analysis. Clinical Trials in Adults with Virologically-Suppressed HIV-1 The safety of BIKTARVY in virologically-suppressed adults was based on Week 48 data from 282 participants in a randomized, double-blind, active-controlled trial (Trial 1844) in which virologically-suppressed participants were switched from either DTG + ABC/3TC or ABC/DTG/3TC to BIKTARVY; Week 48 data from 290 participants in an open-label, active-controlled trial in which virological…