Biktarvy Drug Information

Testing

When Initiating and During Treatment with BIKTARVY Prior to or when initiating BIKTARVY, test patients for hepatitis B virus infection . 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.

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 .

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 . 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.

Not Recommended in Patients with Severe Renal Impairment

BIKTARVY is not recommended in patients with : 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.

Not Recommended in Patients with Severe Hepatic Impairment

BIKTARVY is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).

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 . 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 /dolutegravir / lamivudine ), 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 . 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 . 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 . 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 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) . 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.

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

Other Antiretroviral Medications

Because BIKTARVY is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended . 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.

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 ).

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 . 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 . 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 ).

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 .

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 . 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 . 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 considered. Antimycobacterials: rifabutin rifampin, Strong inducer of CYP3Aand P-gp, and inducer of UGT1A1. rifapentine ↓ BIC ↓ TAF Coadministration with rifampin is contraindicated due to the effect of rifampin on the BIC component of BIKTARVY . Coadministration with rifabutin or rifapentine is not recommended. Herbal Products: St.

John's wort The induction potency of St. John's wort may vary widely based on preparation. ↓ BIC ↓ TAF Coadministration with St. John's wort is not recommended.

Medications or oral supplements containing polyvalent cations (e.g., Mg, Al, Ca, Fe): Calcium or iron supplements Cation-containing antacids or laxatives Sucralfate Buffered medications ↓ BIC Antacids containing Al/Mg: BIKTARVY can be taken at least 2 hours before or 6 hours after taking antacids containing Al/Mg. Routine administration of BIKTARVY together with, or 2 hours after, antacids containing Al/Mg is not recommended. Supplements or Antacids containing Calcium or Iron: BIKTARVY and supplements or antacids containing calcium or iron can be taken together with food.

Routine administration of BIKTARVY under fasting conditions together with, or 2 hours after, supplements or antacids containing calcium or iron is not recommended. Metformin ↑ Metformin Refer to the prescribing information of metformin for assessing the benefit and risk of concomitant use of BIKTARVY and metformin.

Drugs without Clinically Significant Interactions with

BIKTARVY Based on drug interaction studies conducted with BIKTARVY or the components of BIKTARVY, no clinically significant drug interactions have been observed when BIKTARVY is combined with the following drugs: ethinyl estradiol, ledipasvir/sofosbuvir, midazolam, norgestimate, sertraline, sofosbuvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir.

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% (95% CI: 1.9% to 3.7%) following first and second/third trimester exposure, respectively, to FTC-containing regimens. Tenofovir Alafenamide (TAF): Based on prospective reports to the APR of over 660 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 520 exposed in the first trimester and over 130 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.2% (95% CI: 2.6% to 6.3%) and 3.0% (95% CI: 0.8% to 7.5%) following first and second/third trimester exposure, respectively, to TAF-containing regimens. Animal Data Bictegravir: BIC was administered orally to pregnant rats (5, 30, or 300 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) on gestation days 7 through 17, and 7 through 19, respectively.

No adverse embryo-fetal effects were observed in rats and rabbits at BIC exposures (AUC) of up to approximately 36 (rats) and 0.6 (rabbits) times the exposure in humans at the RHD of BIKTARVY. Spontaneous abortion, increased clinical signs, and decreased body weight were observed at a maternally toxic dose in rabbits (1000 mg/kg/day; approximately 1.4 times higher than human exposure at the RHD). In a pre/postnatal development study, BIC was administered orally to pregnant rats (up to 300 mg/kg/day) from gestation days 6 to lactation/post-partum day 24. No significant adverse effects were observed in the offspring exposed daily from before birth ( in utero ) through lactation at maternal and pup exposures (AUC) of approximately 30 and 11 times higher, respectively, than human exposures at the RHD. Emtricitabine: FTC was administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures approximately 60 times higher and in rabbits at approximately 108 times higher than human exposures at the RHD. In a pre/postnatal development study with FTC, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth ( in utero ) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the RHD. Tenofovir alafenamide: TAF was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures of approximately 2 (rats) and 78 (rabbits) times higher than the exposure in humans at the recommended daily dose of BIKTARVY. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 55 (rats) and 86 (rabbits) times higher than human tenofovir exposures at the RHD. Since TAF is rapidly converted to tenofovir and lower tenofovir exposures in rats and mice were observed after TAF administration compared to TDF administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation; no adverse effects were observed in the offspring on gestation day 7 at tenofovir exposures of approximately 12 times higher than the exposures in humans at the RHD of BIKTARVY.

Pediatric Use The safety and effectiveness of BIKTARVY have been established as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in 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 resistance to bictegravir or tenofovir . Use of BIKTARVY in pediatric patients weighing at least 14 kg is supported by the following: trials in adults an open-label trial in three age-based cohorts of virologically-suppressed pediatric subjects Cohort 1: 12 to less than 18 years of age and weighing at least 35 kg receiving BIKTARVY through Week 48 (N=50), Cohort 2: 6 to less than 12 years of age and weighing at least 25 kg receiving BIKTARVY through Week 24 (N=50), and Cohort 3: at least 2 years of age and weighing at least 14 to less than 25 kg through Week 24 (N=22). No pediatric subjects 2 years of age were enrolled; of the 6 pediatric subjects who were 3 years of age at enrollment, 3 subjects weighed between 14 to less than 15 kg. The safety and efficacy of BIKTARVY in these pediatric subjects were similar to that in adults, and there was no clinically significant change in exposure for the components of BIKTARVY . Safety and effectiveness of BIKTARVY in pediatric patients weighing less than 14 kg have not been established.

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 . rifampin due to decreased BIC plasma concentrations, which may result in the loss of therapeutic effect and development of resistance to BIKTARVY . BIKTARVY is contraindicated to be co-administered with: dofetilide. rifampin.

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%.