BIKTARVY ® (bictegravir, emtricitabine, and tenofovir alafenamide)

BIKTARVY ® (bictegravir, emtricitabine, and tenofovir alafenamide)

BIKTARVY ® (bictegravir, emtricitabine, and tenofovir alafenamide)

BIKTARVY (bictegravir, emtricitabine, and tenofovir alafenamide) is a fixed dose combination tablet containing bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF) for oral administration.

  • BIC is an integrase strand transfer inhibitor (INSTI).
  • FTC, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI).
  • TAF, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosph

BIKTARVY tablets are available in two dose strengths:

  • 50 mg/200 mg/25 mg tablet containing 50 mg of BIC (equivalent to 52.5 mg of bictegravir sodium), 200 mg of FTC, and 25 mg of TAF (equivalent to 28 mg of tenofovir alafenamide fumarate).
  • 30 mg/120 mg/15 mg tablet containing 30 mg of BIC (equivalent to 31.5 mg of bictegravir sodium), 120 mg of FTC, and 15 mg of TAF (equivalent to 16.8 mg of tenofovir alafenamide fumarate).

Both dose strengths of BIKTARVY tablets include the following inactive ingredients: croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. The tablets for both dose strengths are film-coated with a coating material containing iron oxide black, iron oxide red, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

Bictegravir: The chemical name of bictegravir sodium is 2,5-Methanopyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, 2,3,4,5,7,9,13,13a-octahydro-8-hydroxy-7,9-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-,sodium salt (1:1), (2R,5S,13aR)-.

Bictegravir sodium has a molecular formula of C21H17F3N3 NaO5 and a molecular weight of 471.4

Emtricitabine: The chemical name of FTC is 4-amino-5-fluoro-1-(2R-hydroxymethyl-1,3 oxathiolan-5S-yl)-(1H)-pyrimidin-2-one.

FTC is the (-)enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5 position. FTC has a molecular formula of C8H10FN3O3S and a molecular weight of 247.2

Tenofovir alafenamide: The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1 methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2E)-2-butenedioate (2:1).

Tenofovir alafenamide fumarate has an empirical formula of C21H29O5N6 P•1⁄2(C4H4O4 ) and a formula weight of 534.5

INDICATIONS AND USAGE

BIKTARVY is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing at least 14 kg who have no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of BIKTARVY.

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.

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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.

DOSAGE AND ADMINISTRATION

  • 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 15mL/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:

  • ediatric 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)

CONTRAINDICATIONS

BIKTARVY is contraindicated to be co-administered with:

  • dofetilide due to the potential for increased dofetilide plasma concentrations and associated serious and/or life-threatening events
  • ifampin due to decreased BIC plasma concentrations, which may result in the loss of therapeutic effect and development of resistance to BIKTARVY

WARNINGS AND PRECAUTIONS

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 BIKTARVY. Patients coinfected 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.

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of BIKTARVY with certain other drugs may result in known or potentially significant drug interactions, some of which may lead to

  • Loss of therapeutic effect of BIKTARVY and possible development of resistance.
  • Possible clinically significant adverse reactions from greater exposures of 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, 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.

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 BIKTARVY, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with BIKTARVY 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).

Drug Interactions

Drug Name  Effect on Concentration bClinical Comment
Antiarrhythmics:dofetilideDofetilideCoadministration is contraindicated due to the potential for serious and/or life-threatening events associated with dofetilide therapy
Anticonvulsants:carbamazepine coxcarbazepinephenobarbitalphenytoin↓ BIC
↓  TAF
Coadministration with alternative anticonvulsants should be considered.
Antimycobacterials:rifabutin crifampin c,drifapentine↓ BIC
↓  TAF
Coadministration with rifampin is contraindicated due tothe effect of rifampin on the BIC component ofBIKTARVY Coadministration with rifabutin or rifapentine is not recommended.
Herbal Products:St. John’s wort e↓ BIC
↓  TAF
Coadministration with St. John’s wort is notrecommended.
Medications or oralsupplementscontaining polyvalentcations (e.g., Mg, Al,Ca, Fe):Calcium or ironsupplements cCation-containingantacids or laxatives cSucralfateBuffered medications↓  BICAntacids containing Al/Mg:BIKTARVY can be taken at least 2 hours before or 6hours after taking antacids containing Al/Mg. Routine administration of BIKTARVY together with, or 2 hours after, antacids containing Al/Mg is notrecommended. 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 fastingconditions together with, or 2 hours after, supplements or antacids containing calcium or iron is not recommended.
MetforminMetforminRefer to the prescribing information of metformin for assessing the benefit and risk of concomitant use of BIKTARVY and metformin.
  • Table is not all inclusive.
  • ↑ = Increase, ↓ = Decrease.
  • Drug-drug interaction study was conducted with either BIKTARVY or its components as individual agents.
  • Strong inducer of CYP3A and P-gp, and inducer of UGT1A1.
  • The induction potency of St. John’s wort may vary widely based on preparation.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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)

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.

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.

Lactation: 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 BIKTARVY or all of the components of BIKTARVY 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. It is unknown if TAF is present in animal milk.

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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 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 history of treatment failure and no known substitutions associated with resistance to the individual components of BIKTARVY.

OVERDOSAGE

No data are available on overdose of BIKTARVY in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with BIKTARVY consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.

Hemodialysis treatment removes approximately 30% of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether FTC can be removed by peritoneal dialysis.

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.

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