Bictegravir, Emtricitabine, and Tenofovir Alafenamide

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Biktarvy: Bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg

Pharmacology

Mechanism of Action

Bictegravir, an integrase inhibitor, inhibits HIV integrase by binding to the integrase-active site and blocking the strand transfer step of DNA integration. Emtricitabine is a cytosine analogue and tenofovir alafenamide is converted intracellularly to tenofovir (adenosine nucleotide analog) and subsequently phosphorylated by cellular kinases to the active moiety, tenofovir diphosphate. Emtricitabine and tenofovir alafenamide interfere with HIV viral RNA-dependent DNA polymerase activities resulting in inhibition of viral replication.

Pharmacokinetics/Pharmacodynamics

Metabolism

Bictegravir: By CYP3A enzymes and hepatic glucuronidation mediated by UGT1A1

Emtricitabine: Not significantly metabolized

Tenofovir alafenamide: Converted intracellulary by hydrolysis (non-CYP enzymes) to tenofovir then phosphorylated by cellular kinases to the active moiety, tenofovir diphosphate; minimal extent by CYP3A

Excretion

Bictegravir: Feces (60.3%), urine (35%); Emtricitabine: Feces (13.7%), urine (70%); Tenofovir alafenamide: Feces (31.7%), urine (<1%)

Time to Peak

Bictegravir: 2 to 4 hours; Emtricitabine: 1.5 to 2 hours; Tenofovir alafenamide: 0.5 to 2 hours

Half-Life Elimination

Bictegravir: 17.3 hours; Emtricitabine: 10.4 hours; Tenofovir alafenamide: 0.51 hours (active metabolite, tenofovir diphosphate: 150 to 180 hours [intracellular])

Protein Binding

Bictegravir: >99%; Emtricitabine <4%; Tenofovir alafenamide ~80%

Use: Labeled Indications

HIV-1 infection, treatment: Treatment of HIV-1 infection (as a complete regimen) in adults and pediatric patients ≥25 kg as initial therapy in those with no antiretroviral treatment history; or to replace a stable antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) with no history of treatment failure and no known substitutions associated with resistance to the individual components.

Contraindications

Coadministration with dofetilide, rifampin

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to bictegravir, emtricitabine, tenofovir alafenamide, or any component of the formulation; coadministration with St John’s wort

Dosage and Administration

Dosing: Adult

HIV-1 infection, treatment: Oral: One tablet once daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

HIV-1 infection, treatment: Note: Products are a fixed-dose combination; use not recommended in other weight groups. Gene mutation and antiretroviral resistance patterns should be evaluated (refer to https://www.iasusa.org for more information) when necessary.

Pediatric patients weighing ≥25 kg: Oral: Biktarvy (bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg per tablet): One tablet once daily; in clinical trials, the youngest patients were 6 years of age (HHS [pediatric] 2018)

Administration

Oral: Administer with or without food.

Storage

Store below 30°C (86°F); dispense in original container.

Drug Interactions

Acyclovir-Valacyclovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Acyclovir-Valacyclovir. Monitor therapy

Adefovir: May diminish the therapeutic effect of Tenofovir Products. Adefovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Adefovir. Avoid combination

Aminoglycosides: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Aminoglycosides. Monitor therapy

Cabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib. Monitor therapy

Calcium Salts: May decrease the serum concentration of Bictegravir. Management: Bictegravir, emtricitabine, and tenofovir alafenamide can be administered with calcium salts under fed conditions, but coadministration with or 2 hours after a calcium salt is not recommended under fasting conditions. Consider therapy modification

CarBAMazepine: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Cidofovir: May increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Cidofovir. Monitor therapy

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Avoid combination

Cobicistat: May enhance the adverse/toxic effect of Tenofovir Products. More specifically, cobicistat may impair proper tenofovir monitoring and dosing. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Bictegravir. Management: Rifampin is specifically contraindicated, and the use of carbamazepine, phenytoin, or phenobarbital is not recommended when alternatives are acceptable Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Bictegravir. Monitor therapy

Diclofenac (Systemic): May enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to this combination whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Dofetilide: Bictegravir may increase the serum concentration of Dofetilide. Avoid combination

Fosphenytoin-Phenytoin: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Ganciclovir-Valganciclovir: Tenofovir Products may increase the serum concentration of Ganciclovir-Valganciclovir. Ganciclovir-Valganciclovir may increase the serum concentration of Tenofovir Products. Monitor therapy

Iron Preparations: May decrease the serum concentration of Bictegravir. Management: Bictegravir, emtricitabine, and tenofovir alafenamide can be administered with iron preparations under fed conditions, but coadministration with or 2 hours after an iron preparation is not recommended under fasting conditions. Exceptions: Ferric Carboxymaltose; Ferric Derisomaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification

LamiVUDine: May enhance the adverse/toxic effect of Emtricitabine. Avoid combination

MetFORMIN: Bictegravir may increase the serum concentration of MetFORMIN. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

OXcarbazepine: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

PHENobarbital: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Polyvalent Cation Containing Products: May decrease the serum concentration of Bictegravir. Management: Administer bictegravir under fasting conditions at least 2 hours before or 6 hours after polyvalent cation containing products. Coadministration of bictegravir with or 2 hours after most polyvalent cation products is not recommended. Exceptions: Calcium Acetate; Calcium Carbonate; Calcium Chloride; Calcium Citrate; Calcium Glubionate; Calcium Gluconate; Calcium Lactate; Ferric Citrate; Ferric Maltol; Ferrous Fumarate; Ferrous Gluconate; Ferrous Sulfate; Iron Acetyltransferrin; Polycarbophil; Polysaccharide-Iron Complex; Shark Derivatives; Sodium Feredetate. Consider therapy modification

Primidone: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Rifabutin: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Rifabutin: May decrease the serum concentration of Bictegravir. Avoid combination

RifAMPin: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

RifAMPin: May decrease the serum concentration of Bictegravir. Avoid combination

Rifapentine: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Rifapentine: May decrease the serum concentration of Bictegravir. Avoid combination

Sofosbuvir: May increase the serum concentration of Tenofovir Alafenamide. Monitor therapy

St John's Wort: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

St John's Wort: May decrease the serum concentration of Bictegravir. Avoid combination

Tipranavir: May decrease the serum concentration of Tenofovir Alafenamide. Avoid combination

Adverse Reactions

Also see individual agents.

>10%: Hepatic: Increased serum bilirubin (12%)

1% to 10%:

Cardiovascular: Increased serum creatine kinase (4%)

Central nervous system: Headache (4% to 5%), abnormal dreams (≤3%), fatigue (2% to 3%), dizziness (2%), insomnia (2%), depression (<2%)

Dermatologic: Skin rash (<2%)

Endocrine & metabolic: Increased LDL cholesterol (2% to 3%)

Gastrointestinal: Diarrhea (3% to 6%), nausea (3% to 5%), increased serum amylase (2%), abdominal pain (<2%), dyspepsia (<2%), flatulence (<2%), vomiting (<2%)

Hematologic & oncologic: Decreased neutrophils (2%)

Hepatic: Increased serum alanine aminotransferase (1% to 2%), increased serum aspartate aminotransferase (1% to 2%)

Frequency not defined: Renal: Increased serum creatinine

<1%, postmarketing, and/or case reports: Angioedema, suicidal ideation, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome, resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome, autoimmune hepatitis) later in therapy; further evaluation and treatment may be required.
• Lactic acidosis/hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported with the use of nucleoside analogs, alone or in combination with other antiretrovirals. Suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (marked transaminase elevation may/may not accompany hepatomegaly and steatosis).
• Renal toxicity: Cases of acute renal failure and/or Fanconi syndrome have been reported with use of tenofovir prodrugs; patients with preexisting renal impairment and those taking nephrotoxic agents (including NSAIDs) are at increased risk. Assess serum creatinine, estimated CrCl, urine protein, and urine glucose prior to initiation of therapy and during therapy; in patients with chronic kidney disease, also assess serum phosphorus. Discontinue therapy in patients that develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

Disease-related concerns:

• Chronic hepatitis B: [US Boxed Warning]: Severe acute exacerbations of HBV have been reported in patients coinfected with HIV-1 and HBV following discontinuation of antiretroviral therapy. Closely monitor hepatic function with clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue bictegravir/emtricitabine/tenofovir alafenamide therapy. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced hepatic disease or cirrhosis (post-treatment exacerbation of hepatitis may lead to hepatic decompensation or liver failure). All patients with HIV should be tested for HBV prior to initiation of treatment.
• Hepatic impairment: Use is not recommended in patients with severe hepatic impairment (Child-Pugh class C).
• Renal impairment: Use is not recommended in patients with CrCl <30 mL/minute.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions for more detailed information.

Monitoring Parameters

CD4 count, HIV RNA plasma levels; serum creatinine, urine glucose, urine protein (prior to initiation and as clinically indicated during therapy); serum phosphorus in patients with chronic kidney disease; hepatic function tests, bone density (patients with a history of bone fracture or have risk factors for bone loss); testing for HBV is recommended prior to the initiation of antiretroviral therapy. If used as therapy replacement in virologically suppressed patients meeting criteria, additional HIV-1 RNA and regimen tolerability monitoring is recommended to assess potential virologic failure or rebound. Patients with HIV and HBV coinfection should be monitored for several months following therapy discontinuation.

Pregnancy

Pregnancy Considerations

It is not known if bictegravir crosses the placenta. Data collected by the antiretroviral registry related to the use of bictegravir in pregnancy is insufficient to evaluate teratogenicity. Refer to the emtricitabine and tenofovir alafenamide monographs for additional information specific to these components.

The Health and Human Services (HHS) perinatal HIV guidelines note data are insufficient to recommend this fixed-dose combination for pregnant females living with HIV who are antiretroviral-naive, who have had antiretroviral therapy (ART) in the past but are restarting, who require a new ART regimen (due to poor tolerance or poor virologic response of current regimen), who are not yet pregnant but are trying to conceive, or who become pregnant during therapy. Pharmacokinetic studies of bictegravir are not available to make dosing recommendations for pregnant females.

In general, ART is recommended for all pregnant females living with HIV to keep the viral load below the limit of detection and reduce the risk of perinatal transmission. Therapy should be individualized following a discussion of the potential risks and benefits of treatment during pregnancy. Monitoring of pregnant females is more frequent than in nonpregnant adults. ART should be continued postpartum for all females living with HIV and can be modified after delivery.

Health care providers are encouraged to enroll pregnant females exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (800-258-4263 or http://www.APRegistry.com). Health care providers caring pregnant females living with HIV and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2019).

Patient Education

What is this drug used for?

• It is used to treat HIV infection.

Frequently reported side effects of this drug

• Diarrhea
• Nausea
• Headache

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Lactic acidosis like fast breathing, fast heartbeat, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps.
• Infection
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.