Biktarvy bictegravir sodium, emtricitabine, and tenofovir alafenamide fumarate 50 mg; 200 mg; 25 mg Tablet, 30-count

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 )

5.1Severe 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.

5.2Risk 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.

5.3Immune 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.

5.4New 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…

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 .

6.1Clinical 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…

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 )

7.1Other 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.

7.2Potential 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 ).

7.3Potential 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 ).

7.4Drugs 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) ] .

7.5Established 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…