Bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate

Bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate
	Black Box Warning
	Adult Indications & Dosage
	Pediatric Indications & Dosage
	Contraindications
	Warnings & Precautions
	Adverse Reactions
	Drug Interactions
	Use in Specific Populations
	Administration & Monitoring
	Overdosage
	Pharmacology
	Clinical Studies
	How Supplied
	Images
	Patient Counseling Information
	Precautions with Alcohol
	Brand Names
	Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2]

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Black Box Warning

POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

See full prescribing information for complete Boxed Warning.

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate. If appropriate, anti-hepatitis B therapy may be warranted.

Overview

Bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate 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 that is FDA approved for the treatment of HIV-1 infection in adults 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 for at least 3 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, nausea, and headache.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indication

Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults 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 for at least 3 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate.

Dosage

Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate is a three-drug fixed dose combination product containing 50 mg of bictegravir (BIC), 200 mg of emtricitabine (FTC), and 25 mg of tenofovir alafenamide (TAF). The recommended dosage of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate is one tablet taken orally once daily with or without food.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Safety and effectiveness of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate in pediatric patients less than 18 years of age have not been established.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Contraindications

Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate 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 bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate.

Warnings

POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

See full prescribing information for complete Boxed Warning.

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate. If appropriate, anti-hepatitis B therapy may be warranted.

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.
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 bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate. Patients coinfected with HIV-1 and HBV who discontinue bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate 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.

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate with certain other drugs may result in known or potentially significant drug interactions, some of which may lead to:
- Loss of therapeutic effect of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate 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 bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate therapy; review concomitant medications during bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate therapy; and monitor for the adverse reactions associated with the concomitant drugs.

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, and Guillain-Barré syndrome) 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.

New Onset or Worsening Renal Impairment

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate, there have been no cases of Fanconi syndrome or Proximal Renal Tubulopathy (PRT). In clinical trials of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate in subjects with no antiretroviral treatment history with eGFRs greater than 30 mL per minute, and in virologically suppressed subjects switched to bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate with eGFRs greater than 50 mL per minute, renal serious adverse events were encountered in less than 1% of subjects treated with bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate through Week 48. Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate is not recommended in patients with estimated creatinine clearance below 30 mL per minute.
Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents including non-steroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.
Prior to or when initiating bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate, and during treatment with bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate, 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. Discontinue bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Adverse Reactions

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 bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate was based on Week 48 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. A total of 634 subjects received one tablet of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate once daily.
The most common adverse reactions (all Grades) reported in at least 5% of subjects in the bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate group in either Trial 1489 or Trial 1490 were diarrhea, nausea, and headache. The proportion of subjects who discontinued treatment with bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate, abacavir [ABC]/dolutegravir [DTG]/ lamivudine [3TC]), or DTG + FTC/TAF, due to adverse events, regardless of severity, was 1%, 1%, and <1%, respectively. Table 1 displays the frequency of adverse reactions (all Grades) greater than or equal to 2% in the bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate group.

This image is provided by the National Library of Medicine.

Additional adverse reactions (all Grades) occurring in less than 2% of subjects administered bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate in Trials 1489 and 1490 included vomiting, flatulence, dyspepsia, abdominal pain, rash, and depression.
Suicidal ideation, suicide attempt, and depression suicidal occurred in <1% of subjects administered bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate; all events were serious and primarily occurred in subjects with a preexisting history of depression, prior suicide attempt or psychiatric illness.
The majority (87%) of adverse events associated with bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate were Grade 1.

Clinical Trials in Virologically Suppressed Adults

The safety of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate 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 bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate; and 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 bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate (Trial 1878). Overall, the safety profile in virologically suppressed adult subjects in Trials 1844 and 1878 was similar to that in subjects with no antiretroviral treatment history.

Laboratory Abnormalities

The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate in Trials 1489 and 1490 are presented in Table 2.

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 48. In Trials 1489 and 1490, median (Q1, Q3) serum creatinine increased by 0.10 (0.03, 0.17) mg per dL from baseline to Week 48 in the bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate 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 through Week 48 in bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate clinical trials.
Changes in Bilirubin: In Trials 1489 and 1490, total bilirubin increases were observed in 12% of subjects administered bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate through Week 48. Increases were primarily Grade 1 (1.0 to 1.5 × ULN) (9%) and Grade 2 (1.5 to 2.5 × ULN) (3%). Graded bilirubin increases in the ABC/DTG/3TC, and DTG + FTC/TAF groups, were 4% and 6%, respectively. Increases were primarily Grade 1 (3% ABC/DTG/3TC and 5% DTG + FTC/TAF) or Grade 2 (1% ABC/DTG/3TC and 1% DTG + FTC/TAF). There were no discontinuations due to hepatic adverse events through Week 48 in bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate clinical studies.

Postmarketing Experience

There is limited information regarding Bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate Postmarketing Experience in the drug label.

Drug Interactions

Other Antiretroviral Medications

Because bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate 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 Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate to Affect Other Drugs

BIC inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1) in vitro. Coadministration of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate 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 Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate

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 bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate and development of resistance.
The use of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate with a drug that is a strong inhibitor of CYP3A and also an inhibitor of UGT1A1 may significantly increase the plasma concentrations of BIC (see TABLE 3).
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 bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate 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 bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate 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 bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate, the components of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate (BIC, FTC, and TAF) as individual agents, or are drug interactions that may occur with bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate.

Drugs without Clinically Significant Interactions with Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate

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

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate 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 bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Bictegravir (BIC) and tenofovir alafenamide (TAF) use in women during pregnancy has not been evaluated; however, emtricitabine (FTC) use during pregnancy has been evaluated in a limited number of women reported to the APR. Available data from the APR show no difference in the overall risk of major birth defects for FTC 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). 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%. 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.
In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate at exposures that were either not maternally toxic (rabbits) or greater than (rats and mice) those in humans at the recommended human dose (RHD). 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 bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate. 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.

Human Data

Emtricitabine: Based on prospective reports to the APR of 3,406 exposures to FTC-containing regimens during pregnancy resulting in live births (including 2,326 exposed in the first trimester and 1,080 exposed in the second/third trimester), there was no difference between FTC and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.7% to 3.0%) with first trimester exposure to FTC-containing regimens and 2.0% (95% CI: 1.3% to 3.1%) with the second/third trimester exposure to FTC-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 bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate. Spontaneous abortion, increased clinical signs [fecal changes, thin body, and cold-to-touch], 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 bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate. 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 [and lactation day 20] at tenofovir exposures of approximately 12 [19] times higher than the exposures in humans at the RHD of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate during labor and delivery.

Nursing Mothers

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.
It is not known whether bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate or all of the components of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate are present in human breast milk, affects human milk production, or has effects on the breastfed infant. Based on published data, FTC has been shown to be present in human breast milk. BIC was detected in the plasma of nursing rat pups likely due to the presence of BIC in milk, and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF (see DATA) . It is unknown if TAF is present in animal milk.
Because of the potential for 1) HIV transmission (in HIV-negative infants); 2) developing viral resistance (in HIV-positive infants); and 3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate.

Animal Data

Bictegravir: BIC was detected in the plasma of nursing rat pups in the pre/postnatal development study (post-natal day 10), likely due to the presence of BIC in milk.
Tenofovir alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is secreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11 . Tenofovir was excreted into the milk of lactating monkeys following a single subcutaneous (30 mg/kg) dose of tenofovir at concentrations up to approximately 4% of plasma concentration, resulting in exposure (AUC) of approximately 20% of plasma exposure.

Pediatric Use

Safety and effectiveness of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate in pediatric patients less than 18 years of age have not been established.

Geriatic Use

Clinical trials of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Gender

There is no FDA guidance on the use of Bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate with respect to specific gender populations.

Race

There is no FDA guidance on the use of Bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate with respect to specific racial populations.

Renal Impairment

Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate is not recommended in patients with severe renal impairment (estimated creatinine clearance (CL cr) below 30 mL per minute, estimated by Cockcroft-Gault (C-G). No dosage adjustment of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate is recommended in patients with CL cr greater than or equal to 30 mL per minute.

Hepatic Impairment

No dosage adjustment of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate is not recommended for use in patients with severe hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate in patients who are immunocompromised.

Administration and Monitoring

Administration

Testing When Initiating and During Treatment with Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate

Prior to or when initiating bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate, test patients for hepatitis B virus infection.
Prior to or when initiating bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate, and during treatment with bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate, 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

Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate is a three-drug fixed dose combination product containing 50 mg of bictegravir (BIC), 200 mg of emtricitabine (FTC), and 25 mg of tenofovir alafenamide (TAF). The recommended dosage of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate is one tablet taken orally once daily with or without food.

Not Recommended in Patients with Severe Renal Impairment

Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate is not recommended in patients with estimated creatinine clearance below 30 mL per minute.

Not Recommended in Patients with Severe Hepatic Impairment

Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).

Monitoring

There is limited information regarding Bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate and IV administrations.

Overdosage

No data are available on overdose of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate 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 per minute and a dialysate flow rate of 600 mL per minute). 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%.

Pharmacology


Bictegravir
Systematic (IUPAC) name
(1S,11R,13R)-5-Hydroxy-3,6-dioxo-N-(2,4,6-trifluorobenzyl)-12-oxa-2,9-diazatetracyclo[11.2.1.0~2,11~.0~4,9~]hexadeca-4,7-diene-7-carboxamide
Identifiers
CAS number	1611493-60-7
ATC code	?
PubChem	90311989
Chemical data
Formula	Template:OrganicBox atom Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox
Mol. mass	?
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status
Routes	?


Emtricitabine
Systematic (IUPAC) name
2',3'-dideoxy-5-fluoro-3'-thiacytidine 4-amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one
Identifiers
CAS number	143491-57-0
ATC code	J05AF09
PubChem	60877
DrugBank	DB00879
Chemical data
Formula	Template:OrganicBox atom Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox
Mol. mass	247.248 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	93%
Protein binding	Very low (less than 4%)
Metabolism	Hepatic oxidation and glucuronidation CYP system not involved
Half life	10 hours
Excretion	Renal (86%) and fecal (14%)
Therapeutic considerations
Licence data	EU
Pregnancy cat.	B1(AU) B(US)
Legal status	POM(UK) [[Prescription drug\|Template:Unicode-only]](US)
Routes	Oral


Tenofovir alafenamide
Systematic (IUPAC) name
Isopropyl (2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanoate
Identifiers
CAS number	379270-37-8
ATC code	J05AF13 Combination codes: J05AR17 (WHO) J05AR18 (WHO) J05AR19 (WHO)
PubChem	9574768
DrugBank	DB09299
Chemical data
Formula	Template:OrganicBox atom Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox atom Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox
Mol. mass	476.466 g/mol
SMILES	eMolecules & PubChem
Synonyms	GS-7340
Pharmacokinetic data
Bioavailability	?
Protein binding	~80%^[1]
Metabolism	?
Half life	0.51 hours
Excretion	Feces (31.7%), urine (<1%)
Therapeutic considerations
Licence data	EU
Pregnancy cat.	?
Legal status	Template:Unicode Prescription only
Routes	Oral (tablets)

Mechanism of Action

Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate is a fixed dose combination of antiretroviral drugs bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF).

Structure

Bictegravir sodium has a molecular formula of C₂₁H₁₇F₃N₃NaO₅ and a molecular weight of 471.4 and has the following structural formula:

Emtricitabine has a molecular formula of C₈H₁₀FN₃O₃S and a molecular weight of 247.2 and has the following structural formula:

Tenofovir alafenamide fumarate has an empirical formula of C₂₁H₂₉O₅N₆P∙½(C₄H₄O₄) and a formula weight of 534.5 and has the following structural formula:

Pharmacodynamics

Cardiac Electrophysiology

In a thorough QT/QTc trial in 48 healthy subjects, BIC at doses 1.5 and 6 times the recommended dose did not affect the QT/QTc interval and did not prolong the PR interval. In a thorough QT/QTc trial in 48 healthy subjects, TAF at the recommended dose or at a dose 5 times the recommended dose, did not affect the QT/QTc interval and did not prolong the PR interval. The effect of FTC on the QT interval is not known.

Effects on Serum Creatinine

Mean change from baseline in serum creatinine in healthy subjects who received BIC 75 mg (1.5 times the approved recommended dosage) once daily with food for 14 days was 0.1 mg per dL on Days 7 and 14 compared to placebo. BIC did not have a significant effect on the estimated creatinine clearance or on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol).

Pharmacokinetics

The pharmacokinetic (PK) properties of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate components are provided in Table 4. The multiple dose PK parameters of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate components (based on population pharmacokinetic analysis) are provided in Table 5.

Specific Populations

Patients with Renal Impairment

No clinically relevant differences in the pharmacokinetics of BIC, TAF, or its metabolite tenofovir were observed between subjects with severe renal impairment (CLcr 15 to 29 mL per minute estimated by Cockcroft-Gault method) and healthy subjects.

Patients with Hepatic Impairment

Bictegravir: Clinically relevant changes in the pharmacokinetics of BIC were not observed in subjects with moderate (Child-Pugh Class B) hepatic impairment.
Emtricitabine: The pharmacokinetics of FTC has not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of hepatic impairment should be limited.
Tenofovir Alafenamide: Clinically relevant changes in the pharmacokinetics of TAF or its metabolite tenofovir were not observed in subjects with mild or moderate (Child-Pugh Class A and B) hepatic impairment.

Hepatitis B and/or Hepatitis C Virus Coinfection

The pharmacokinetics of BIC, FTC, and TAF have not been evaluated in subjects coinfected with hepatitis B and/or C virus.

Geriatric Patients

The pharmacokinetics of BIC, FTC, and TAF have not been fully evaluated in the elderly (65 years of age and older). Population pharmacokinetics analysis of HIV-infected subjects in Phase 3 trials of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate showed that age did not have a clinically relevant effect on exposures of BIC and TAF up to 74 years of age.

Race and Gender

No clinically relevant changes in the pharmacokinetics of BIC, FTC, and TAF were observed based on gender or race.

Drug Interaction Studies

As bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate is a complete regimen for the treatment of HIV-1 infection, comprehensive information regarding potential drug-drug interactions with other antiretroviral agents is not provided.
BIC is a substrate of CYP3A and UGT1A1.
BIC is an inhibitor of OCT2 and MATE1. At clinically relevant concentrations, BIC is not an inhibitor of hepatic transporters OATP1B1, OATP1B3, OCT1, BSEP, renal transporters OAT1 and OAT3, or CYP (including CYP3A) or UGT1A1 enzymes.
TAF is a substrate of P-gp and BCRP.
At clinically relevant concentrations, TAF is not an inhibitor of drug transporters P-gp, BCRP, hepatic transporters OATP1B1, OATP1B3, OCT1, BSEP, renal transporters OAT1, OAT3, OCT2, MATE1, or CYP (including CYP3A) or UGT1A1 enzymes.
Drug interaction studies were conducted with bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate or its components. Tables 6 and 7 summarize the pharmacokinetic effects of other drugs on BIC and TAF, respectively. Table 8 summarizes the pharmacokinetic effects of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate or its components on other drugs.

Effect of Other Drugs on Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate Components

Effect of Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate Components on Other Drugs

Microbiology

Mechanism of Action

Bictegravir: BIC inhibits the strand transfer activity of HIV-1 integrase (integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of linear HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the virus.
Emtricitabine: FTC, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, Ɛ, and mitochondrial DNA polymerase γ.
Tenofovir Alafenamide: TAF is a phosphonamidate prodrug of tenofovir (2′-deoxyadenosine monophosphate analog). Plasma exposure to TAF allows for permeation into cells and then TAF is intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is subsequently phosphorylated by cellular kinases to the active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV-1 replication through incorporation into viral DNA by the HIV reverse transcriptase, which results in DNA chain-termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.

Antiviral Activity in Cell Culture

The triple combination of BIC, FTC, and TAF was not antagonistic with respect to antiviral activity in cell culture.
Bictegravir: The antiviral activity of BIC against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes. In MT-4 cells (human lymphoblastoid T-cell line) acutely infected with HIV-1 IIIB, the mean 50% effective concentration (EC 50) was 2.4±0.4 nM, and the protein-adjusted EC 95 value was 361 nM (0.162 micrograms per mL). BIC displayed antiviral activity in activated PBMCs against clinical isolates of HIV-1 representing groups M, N, and O, including subtypes A, B, C, D, E, F, and G, with a median EC 50 value of 0.55 nM (range <0.05 to 1.71 nM). The EC 50 value against a single HIV-2 isolate was 1.1 nM.
Emtricitabine: The antiviral activity of FTC against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, the MAGI-CCR5 cell line, and PBMCs. In PBMCs acutely infected with HIV-1 subtypes A, B, C, D, E, F, and G, the median EC 50 value for FTC was 9.5 nM (range 1 to 30 nM) and against HIV-2 was 7 nM.
Tenofovir Alafenamide: The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells and CD4-T lymphocytes. The EC 50 values for TAF ranged from 2.0 to 14.7 nM. TAF displayed antiviral activity in cell culture against all HIV-1 groups (M, N, O), including subtypes A, B, C, D, E, F, and G (EC 50 values ranged from 0.1 to 12 nM) and strain specific activity against HIV-2 (EC 50 values ranged from 0.9 to 2.6 nM).

Resistance In Cell Culture

Bictegravir: HIV-1 isolates with reduced susceptibility to BIC have been selected in cell culture. In one selection with BIC, a virus pool emerged expressing amino acid substitutions M50I and R263K in the HIV-1 integrase. M50I, R263K, and M50I+R263K substitutions, when introduced into a wild-type virus by site-directed mutagenesis, conferred 1.3-, 2.2-, and 2.9-fold reduced susceptibility to BIC, respectively. In a second selection, emergence of amino acid substitutions T66I and S153F was detected, and 0.4-, 1.9-, and 0.5-fold reductions in BIC susceptibility were observed with T66I, S153F, and T66I+S153F, respectively. In addition, S24G and E157K substitutions emerged during the selection process.
Emtricitabine: HIV-1 isolates with reduced susceptibility to FTC were selected in cell culture and in subjects treated with FTC. Reduced susceptibility to FTC was associated with M184V or I substitutions in HIV-1 RT.
Tenofovir Alafenamide: HIV-1 isolates with reduced susceptibility to TAF were selected in cell culture. HIV-1 isolates selected by TAF expressed a K65R substitution in HIV-1 RT, sometimes in the presence of S68N or L429I substitutions; in addition, a K70E substitution in HIV-1 RT was observed.

In Clinical Trials

In Subjects with No Antiretroviral Treatment History: Pooled genotypic resistance analyses were performed on paired baseline and on-treatment HIV-1 isolates from subjects receiving bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate through Week 48 in Trials 1489 and 1490 who had HIV-1 RNA greater than or equal to 200 copies/mL at the time of confirmed virologic failure, Week 48, or early study drug discontinuation. No specific amino acid substitutions emerged consistently in the 8 treatment failure subjects with evaluable genotypic resistance data and failed to establish an association with genotypic BIC resistance. There were no treatment-emergent NRTI resistance-associated substitutions detected in the 8 evaluated treatment failure isolates. Phenotypic resistance analyses of failure isolates found fold-changes in drug susceptibility below the biological or clinical cutoffs for BIC, FTC, and TFV, compared to wild-type reference HIV-1.
In Virologically Suppressed Subjects: In 2 switch trials, Trials 1844 and 1878, of virologically suppressed HIV-1 infected subjects (n=572), only one subject with virologic rebound in the resistance analysis population had IN genotypic and phenotypic data, and 2 rebounders had RT genotypic and phenotypic data. No subjects had HIV-1 with treatment-emergent genotypic or phenotypic resistance to BIC, FTC, or TAF.

Cross-Resistance

Bictegravir: Cross-resistance has been observed among INSTIs. The susceptibility of BIC was tested against 64 clinical isolates expressing known INSTI resistance-associated substitutions listed by IAS-USA (20 with single substitutions and 44 with 2 or more substitutions). Isolates with a single INSTI-resistance substitution including E92Q, T97A, Y143C/R, Q148R, and N155H showed less than 2-fold reduced susceptibility to BIC. All isolates (n=14) with more than 2.5-fold reduced susceptibility to BIC (above the biological cutoff for BIC) contained G140A/C/S and Q148H/R/K substitutions; the majority (64.3%, 9/14) had a complex INSTI resistance pattern with an additional INSTI-resistance substitution L74M, T97A, or E138A/K. Of those evaluated isolates containing G140A/C/S and Q148H/R/K substitutions in the absence of additional INSTI-resistance substitutions, 38.5% (5/13) showed more than 2.5-fold reduction. In addition, site-directed mutant viruses with G118R (dolutegravir and raltegravir treatment-emergent substitution) and G118R+T97A had 3.4- and 2.8-fold reduced susceptibility to BIC, respectively.
BIC demonstrated equivalent antiviral activity with less than 2-fold reductions in susceptibility against HIV-1 variants expressing substitutions associated with resistance to NNRTIs, NRTIs, and PIs, compared with the wild-type virus.
Emtricitabine: Cross-resistance has been observed among NRTIs. FTC-resistant viruses with an M184V/I substitution in HIV-1 RT were cross-resistant to lamivudine. HIV-1 isolates containing the K65R RT substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by FTC.
Tenofovir Alafenamide: Cross-resistance has been observed among NRTIs. Tenofovir resistance substitutions K65R and K70E result in reduced susceptibility to abacavir, didanosine, emtricitabine, lamivudine, and tenofovir. HIV-1 with multiple thymidine analog substitutions (M41L, D67N, K70R, L210W, T215F/Y, K219Q/E/N/R), or multinucleoside resistant HIV-1 with a T69S double insertion mutation or with a Q151M substitution complex including K65R, showed reduced susceptibility to TAF in cell culture.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Bictegravir

BIC was not carcinogenic in a 6-month rasH2 transgenic mouse study at doses of up to 100 mg/kg/day in males and 300 mg/kg/day in females. A carcinogenicity study in rats is ongoing.
BIC was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.
BIC did not affect fertility, reproductive performance or embryonic viability in male and female rats at 29 times higher exposures (AUC) than in humans at the recommended dose of 50 mg BIC in bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate.

Emtricitabine

In long-term carcinogenicity studies of FTC, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (25 times the human systemic exposure at the recommended dose of 200 mg per day in bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate) or in rats at doses up to 600 mg per kg per day (30 times the human systemic exposure at the recommended dose in bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate).
FTC was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.
FTC did not affect fertility in male rats at approximately 140 times or in male and female mice at approximately 60 times higher exposures (AUC) than in humans given the recommended 200 mg daily dose in bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended 200 mg daily dose in bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate.

Tenofovir Alafenamide

Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to TDF administration, carcinogenicity studies were conducted only with TDF. Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 times (rats) those observed in humans at the recommended dose of TDF (300 mg) for HIV-1 infection. The tenofovir exposure in these studies was approximately 151 times (mice) and 51 times (rat) those observed in humans after administration of the daily recommended dose of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate. At the high dose in female mice, liver adenomas were increased at tenofovir exposures approximately 10 times (300 mg TDF) and 151 times (bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate) the exposure observed in humans. In rats, the study was negative for carcinogenic findings.
TAF was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.
There were no effects on fertility, mating performance or early embryonic development when TAF was administered to male rats at a dose equivalent to 155 times (25 mg TAF) the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 14 days prior to mating through Day 7 of gestation.

Animal Toxicology and/or Pharmacology

Minimal to slight infiltration of mononuclear cells in the posterior uvea was observed in dogs with similar severity after three and nine month administration of TAF; reversibility was seen after a three month recovery period. No eye toxicity was observed in the dog at systemic exposures of 7 (TAF) and 14 (tenofovir) times the exposure seen in humans with the recommended daily TAF dose in bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate.

Clinical Studies

Description of Clinical Trials

The efficacy and safety of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate were evaluated in the trials summarized in Table 9.

Clinical Trial Results in HIV-1 Subjects with No Antiretroviral Treatment History

In Trial 1489, subjects were randomized in a 1:1 ratio to receive either bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate (N=314) or ABC/DTG/3TC (600 mg/50 mg/300 mg) (N=315) once daily. In Trial 1490, subjects were randomized in a 1:1 ratio to receive either bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate (N=320) or DTG + FTC/TAF (50 mg + 200 mg/25 mg) (N=325) once daily.
In Trial 1489, the mean age was 34 years (range 18–71), 90% were male, 57% were White, 36% were Black, and 3% were Asian. 22% percent of patients identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.4 log 10 copies/mL (range 1.3–6.5). The mean baseline CD4+ cell count was 464 cells per mm 3 (range 0–1424) and 11% had CD4+ cell counts less than 200 cells per mm 3. 16% of subjects had baseline viral loads greater than 100,000 copies per mL.
In Trial 1490, the mean age was 37 years (range 18–77), 88% were male, 59% were White, 31% were Black, and 3% were Asian. 25% percent of patients identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.4 log 10 copies/mL (range 2.3–6.6). The mean baseline CD4+ cell count was 456 cells per mm 3 (range 2–1636) and 12% had CD4+ cell counts less than 200 cells per mm 3. 19% of subjects had baseline viral loads greater than 100,000 copies per mL.
In both trials, subjects were stratified by baseline HIV-1 RNA (less than or equal to 100,000 copies per mL, greater than 100,000 copies per mL to less than or equal to 400,000 copies per mL, or greater than 400,000 copies per mL), by CD4 count (less than 50 cells per mm 3, 50-199 cells per mm 3, or greater than or equal to 200 cells per mm 3), and by region (US or ex-US).
Treatment outcomes of Trials 1489 and 1490 through Week 48 are presented in Table 10.

Treatment outcomes were similar across subgroups by age, sex, race, baseline viral load, and baseline CD4+ cell count.
In Trials 1489 and 1490, the mean increase from baseline in CD4+ count at Week 48 was 233 and 229 cells per mm 3 in the bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate and ABC/DTG/3TC groups, respectively, and 180 and 201 cells per mm 3 in the bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate and DTG + FTC/TAF groups, respectively.

Clinical Trial Results in HIV-1 Virologically-Suppressed Subjects Who Switched to Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate

In Trial 1844, the efficacy and safety of switching from a regimen of DTG + ABC/3TC or ABC/DTG/3TC to bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate were evaluated in a randomized, double-blind trial of virologically-suppressed (HIV-1 RNA less than 50 copies per mL) HIV-1 infected adults (N=563, randomized and dosed). Subjects must have been stably suppressed (HIV-1 RNA less than 50 copies per mL) on their baseline regimen for at least 3 months prior to trial entry and had no history of treatment failure. Subjects were randomized in a 1:1 ratio to either switch to bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate at baseline (N=282), or stay on their baseline antiretroviral regimen (N=281). Subjects had a mean age of 45 years (range 20–71), 89% were male, 73% were White, and 22% were Black. 17% of subjects identified as Hispanic/Latino. The mean baseline CD4+ cell count was 723 cells per mm 3 (range 124–2444).
In Trial 1878, the efficacy and safety of switching from either ABC/3TC or FTC/TDF (200/300 mg) plus ATV or DRV (given with either cobicistat or ritonavir) to bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate were evaluated in a randomized, open-label study of virologically-suppressed HIV-1 infected adults (N=577, randomized and dosed). Subjects must have been stably suppressed on their baseline regimen for at least 6 months, must not have been previously treated with any INSTI, and had no history of treatment failure. Subjects were randomized in a 1:1 ratio to either switch to bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate (N=290) or stay on their baseline antiretroviral regimen (N=287). Subjects had a mean age of 46 years (range 20–79), 83% were male, 66% were White, and 26% were Black. 19% of subjects identified as Hispanic/Latino. The mean baseline CD4+ cell count was 663 cells per mm 3 (range 62–2582). Subjects were stratified by prior treatment regimen. At screening, 15% of subjects were receiving ABC/3TC plus ATV or DRV (given with either cobicistat or ritonavir) and 85% of subjects were receiving FTC/TDF plus ATV or DRV (given with either cobicistat or ritonavir).
Treatment outcomes of Trials 1844 and 1878 through Week 48 are presented in Table 11.

In Trial 1844, treatment outcomes between treatment groups were similar across subgroups by age, sex, race, and region. The mean change from baseline in CD4+ count at Week 48 was -31 cells per mm 3 in subjects who switched to bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate and 4 cells per mm 3 in subjects who stayed on ABC/DTG/3TC.
In Trial 1878, treatment outcomes between treatment groups were similar across subgroups by age, sex, race, and region. The mean change from baseline in CD4+ count at Week 48 was 25 cells per mm 3 in patients who switched to bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate and 0 cells per mm 3 in patients who stayed on their baseline regimen.

How Supplied

Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate tablets are purplish brown, capsule-shaped, and film-coated with "GSI" debossed on one side and "9883" on the other side. Each bottle contains 30 tablets (NDC 61958-2501-1), a silica gel desiccant, polyester coil, and is closed with a child-resistant closure. Each bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate tablet contains 50 mg of bictegravir (BIC), 200 mg of emtricitabine (FTC), and 25 mg of tenofovir alafenamide (TAF).

Storage

Store below 30 °C (86 °F).
Keep container tightly closed.
Dispense only in original container.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Post-treatment Acute Exacerbation of Hepatitis B in Patients with HBV Coinfection

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV] and HIV-1 and have discontinued products containing FTC and/or TDF, and may likewise occur with discontinuation of bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate. Advise the patient to not discontinue bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate without first informing their healthcare provider.

Drug Interactions

Bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate may interact with certain drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products including St. John's wort.

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started.

Renal Impairment

Advise patients to avoid taking bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate with concurrent or recent use of nephrotoxic agents. Renal impairment including cases of acute renal failure has been reported in association with the use of tenofovir prodrugs.

Lactic Acidosis and Severe Hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of drugs similar to bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate. Advise patients that they should stop bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.

Missed Dosage

Inform patients that it is important to take bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate on a regular dosing schedule with or without food and to avoid missing doses as it can result in development of resistance.

Pregnancy Registry

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to bictegravir sodium/emtricitabine/tenofovir alafenamide fumarate.

Lactation

Instruct women with HIV]-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.

Patient Package Insert

Precautions with Alcohol

Alcohol-Bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

Biktarvy

Look-Alike Drug Names

There is limited information regarding Bictegravir sodium, emtricitabine, tenofovir alafenamide fumarate Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

↑ "GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) Tablets, for Oral Use. Full Prescribing Information" (PDF). Gilead Sciences, Inc. Foster City, CA 94404.

[1] "GENVOYA (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) Tablets, for Oral Use. Full Prescribing Information" (PDF). Gilead Sciences, Inc. Foster City, CA 94404.

[1]