Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide (Monograph)

Drug class: HIV Integrase Inhibitors
Chemical name: 6-[(3-Chloro-2-fluorophenyl)methyl]-1,4-dihydro-1-[(1S)-1-(hydroxymethyl)-2-methylpropyl]-7-methoxy-4-oxo-3-quinolinecarboxylic acid
Molecular formula: C₂₃H₂₃ClFNO₅C₄₀H₅₃N₇O₅S₂C₈H₁₀FN₃O₃SC₂₃H₃₁O₇N₆P
CAS number: 697761-98-1

Medically reviewed by Drugs.com on Sep 29, 2022. Written by ASHP.

Introduction

Antiretroviral; fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (EVG/c/FTC/TAF). Elvitegravir (EVG) is an HIV integrase strand transfer inhibitor (INSTI) antiretroviral; cobicistat is a CYP3A inhibitor used as a pharmacokinetic enhancer to decrease metabolism and increase plasma concentrations of EVG; emtricitabine (FTC) and tenofovir alafenamide (TAF) are HIV nucleoside reverse transcriptase inhibitors (NRTIs).

Uses for Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide

Treatment of HIV Infection

Treatment of HIV-1 infection in antiretroviral-naive (have not previously received antiretroviral therapy) or antiretroviral-experienced (previously treated) adults and pediatric patients ≥12 years of age.

Fixed combination of EVG/c/FTC/TAF used alone as a complete regimen for treatment of HIV-1 infection; do not use with other antiretrovirals.

For initial treatment in antiretroviral-naive adults, experts state EVG/c/FTC/TAF is a recommended INSTI-based regimen.

For initial treatment in HIV-infected pediatric patients, experts state that EVG/c/FTC/TAF is a preferred HIV INSTI-based regimen in children and adolescents ≥12 years of age weighing ≥35 kg, including those in early puberty (sexual maturity rating [SMR] 1–3).

For antiretroviral-experienced adults and pediatric patients ≥12 years of age, manufacturer states EVG/c/FTC/TAF can be used to replace the current antiretroviral regimen in those with plasma HIV-1 RNA levels <50 copies/mL on a stable antiretroviral regimen for ≥6 months who have no history of treatment failure and are infected with HIV-1 with no known substitutions associated with resistance to the antiretroviral components of the fixed combination (i.e., elvitegravir, emtricitabine, tenofovir).

Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Dosage and Administration

General

• Determine S_cr, estimated Cl_cr, serum phosphorus, urine glucose, and urine protein prior to initiation of EVG/c/FTC/TAF and routinely monitor during treatment in all patients. (See Renal Impairment under Cautions.)

• Test for HBV infection prior to initiation of EVG/c/FTC/TAF. (See HIV-infected Individuals Coinfected with HBV under Cautions.)

Administration

Oral Administration

Administer fixed combination of EVG/c/FTC/TAF orally once daily with food.

Dosage

Each fixed-combination tablet of EVG/c/FTC/TAF contains elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg.

Tenofovir alafenamide component provided as tenofovir alafenamide fumarate; dosage expressed in terms of tenofovir alafenamide.

Pediatric Patients

Treatment of HIV Infection

Oral

Pediatric patients ≥12 years of age weighing ≥35 kg: 1 tablet of EVG/c/FTC/TAF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir alafenamide 10 mg) once daily.

Adults

Treatment of HIV Infection

Oral

1 tablet of EVG/c/FTC/TAF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir alafenamide 10 mg) once daily.

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): Dosage adjustments not needed.

Severe hepatic impairment (Child-Pugh class C): Do not use. (See Hepatic Impairment under Cautions.)

Renal Impairment

Estimated Cl_cr ≥30 mL/minute: Dosage adjustments not needed.

Estimated Cl_cr <30 mL/minute: Do not use. (See Renal Impairment under Cautions.)

Cautions for Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide

Contraindications

• Concomitant use with drugs highly dependent on CYP3A for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, cisapride, ergot alkaloids, lovastatin, lurasidone, oral midazolam, pimozide, sildenafil used for treatment of pulmonary arterial hypertension [PAH], simvastatin, triazolam). (See Specific Drugs under Interactions.)

• Concomitant use with drugs that are potent inducers of CYP3A; these drugs may result in decreased elvitegravir and/or cobicistat concentrations resulting in possible decreased antiretroviral efficacy and development of resistance. (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

HIV-infected Individuals Coinfected with HBV

Test all HIV-infected patients for presence of HBV before initiating antiretroviral therapy.

EVG/c/FTC/TAF not indicated for treatment of chronic HBV infection. Safety and efficacy of EVG/c/FTC/TAF not established in patients coinfected with HIV and HBV.

Severe acute exacerbations of HBV reported following discontinuance of preparations containing emtricitabine and/or tenofovir DF in HIV-infected patients with HBV infection. HBV exacerbations have been associated with hepatic decompensation and hepatic failure. Such reactions could occur with EVG/c/FTC/TAF.

Closely monitor hepatic function (using both clinical and laboratory follow-up) for at least several months after EVG/c/FTC/TAF is discontinued in patients coinfected with HIV and HBV. If appropriate, initiation of HBV treatment may be warranted.

Other Warnings/Precautions

Renal Toxicity

Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with hypophosphatemia), reported with tenofovir prodrugs (e.g., tenofovir DF).

Cobicistat (a component of EVG/c/FTC/TAF) may cause modest increase in S_cr and modest decrease in estimated Cl_cr due to inhibition of tubular secretion of creatinine; glomerular function not affected.

Determine S_cr, estimated Cl_cr, serum phosphorus, urine glucose, and urine protein prior to initiation of EVG/c/FTC/TAF and routinely monitor during treatment in all patients. (See Renal Impairment under Cautions.)

Do not use EVG/c/FTC/TAF in patients with estimated Cl_cr <30 mL/minute.

If a confirmed increase in S_cr of >0.4 mg/dL from baseline occurs during EVG/c/FTC/TAF treatment, closely monitor for renal toxicity. Discontinue EVG/c/FTC/TAF if clinically important decreases in renal function occur or there is evidence of Fanconi syndrome.

Patients receiving a tenofovir prodrug who have impaired renal function or are receiving a nephrotoxic agent (e.g., high-dose or multiple NSAIAs) are at increased risk of developing adverse renal effects. (See Interactions.)

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving HIV NRTIs, including emtricitabine and tenofovir DF, in conjunction with other antiretrovirals.

Interrupt EVG/c/FTC/TAF treatment if there are clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (e.g., hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).

Bone Effects

Tenofovir prodrugs (tenofovir alafenamide, tenofovir DF) have been associated with decreases in bone mineral density (BMD). BMD declines reported in adults receiving tenofovir alafenamide have been smaller than those reported in adults receiving tenofovir DF. In addition, BMD increases reported when some adults were switched from a regimen containing tenofovir DF to a regimen containing tenofovir alafenamide.

Long-term clinical importance of BMD changes reported with tenofovir prodrugs unknown.

Use of Fixed Combinations

Consider cautions, precautions, and contraindications associated with each component of EVG/c/FTC/TAF. Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug in the fixed combination.

EVG/c/FTC/TAF is used alone as a complete regimen for treatment of HIV-1 infection; do not use in conjunction with other antiretrovirals. (See Specific Drugs under Interactions.)

Do not use EVG/c/FTC/TAF concomitantly with any preparation that contains any of its components (elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide). In addition, do not use EVG/c/FTC/TAF concomitantly with any preparation containing tenofovir DF, lamivudine, adefovir dipivoxil, or ritonavir.

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) also reported in the setting of immune reconstitution; time to onset is more variable and can occur many months after initiation of antiretroviral therapy.

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].

Prospective pregnancy data from the Antiretroviral Pregnancy Registry insufficient to date to adequately assess risk of birth defects or miscarriage if EVG/c/FTC/TAF used in pregnant women. Registry data available through January 2016 show no birth defects reported for elvitegravir or cobicistat and no difference in overall risk of major birth defects for emtricitabine compared with the background rate of major birth defects in the US.

In animal studies, no evidence of adverse developmental effects when components of EVG/c/FTC/TAF administered separately during organogenesis at elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide exposures up to 23, 3.8, 108, and 53 times higher, respectively, than human exposures at the recommended daily dosage.

Experts state data insufficient to recommend routine use of EVG/c/FTC/TAF for initial treatment in pregnant women.

Lactation

Elvitegravir and cobicistat distributed into milk in rats. Tenofovir distributed into milk in animals following administration of tenofovir DF. Not known whether elvitegravir, cobicistat, or tenofovir alafenamide distributed into human milk. Emtricitabine is distributed into human milk.

Not known whether EVG/c/FTC/TAF affects human milk production or affects the breast-fed infant.

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.

Pediatric Use

Safety and efficacy of EVG/c/FTC/TAF not established in pediatric patients <12 years of age or in those weighing <35 kg.

Experts state that EVG/c/FTC/TAF is a preferred antiretroviral regimen in children and adolescents ≥12 years of age weighing ≥35 kg, including those in early puberty (SMR 1–3).

Clinical trial data indicate safety and efficacy of EVG/c/FTC/TAF in HIV-1-infected, treatment-naive pediatric patients 12 to <18 years of age is similar to that reported in adults.

Geriatric Use

No differences in safety or efficacy of EVG/c/FTC/TAF observed between individuals ≥65 years of age and individuals 12 to <65 years of age.

Hepatic Impairment

Mild hepatic impairment (Child-Pugh class A): No clinically important effects on pharmacokinetics of tenofovir alafenamide.

Moderate hepatic impairment (Child-Pugh class B): No clinically important effects on pharmacokinetics of elvitegravir, cobicistat, or tenofovir alafenamide; not expected to affect pharmacokinetics of emtricitabine.

Severe hepatic impairment (Child-Pugh class C): EVG/c/FTC/TAF not recommended; data not available to date regarding pharmacokinetics or safety in such patients.

Renal Impairment

Determine S_cr, estimated Cl_cr, serum phosphorus, urine glucose, and urine protein prior to and routinely monitor during EVG/c/FTC/TAF treatment in all patients.

Estimated Cl_cr <30 mL/minute: Do not use EVG/c/FTC/TAF; safety not established.

Common Adverse Effects

Nausea, diarrhea, fatigue, headache.

Interactions for Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide

Elvitegravir: Substrate of CYP3A; weak inducer and weak inhibitor of CYP3A. Induces CYP2C9. Does not inhibit CYP1A, 2A6, 2C9, 2C19, 2D6, or 2E1. Inhibits organic anion transport polypeptides (OATP)1B1 and 1B3.

Cobicistat: Substrate and inhibitor of CYP3A and 2D6. Inhibits p-glycoprotein (P-gp) transport, breast cancer resistance protein (BCRP), and OATP1B1 and 1B3.

Emtricitabine: Not a substrate of CYP enzymes; does not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 3A4.

Tenofovir alafenamide: Weak inhibitor of CYP3A in vitro, but does not inhibit or induce CYP3A in vivo. Does not inhibit or induce CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6. Substrate of P-gp, BCRP, and OATP1B1 and 1B3.

The following interactions are based on studies using elvitegravir, elvitegravir administered with cobicistat (cobicistat-boosted elvitegravir), elvitegravir administered with low-dose ritonavir (ritonavir-boosted elvitegravir), cobicistat, or EVG/c/FTC/TAF or are predicted to occur.

Consider potential interactions associated with each drug in the fixed combination.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A or 2D6 substrates: Potential increased plasma concentrations of such substrates.

CYP3A inducers: Potential decreased plasma concentrations of elvitegravir, cobicistat, and/or tenofovir alafenamide; possible decreased antiretroviral efficacy and development of resistance.

CYP3A inhibitors: Potential increased plasma concentrations of cobicistat.

Drugs Affected by P-glycoprotein Transport

P-gp substrates: Potential increased concentrations of such substrates.

P-gp inhibitors: Potential increased tenofovir alafenamide concentrations. Cobicistat (a P-gp inhibitor) increases tenofovir alafenamide plasma concentrations when the drugs administered as EVG/c/FTC/TAF; further increases not expected if an additional P-gp inhibitor used with EVG/c/FTC/TAF.

P-gp inducers: Decreased absorption and decreased plasma concentrations of tenofovir alafenamide expected.

Drugs Affected by Breast Cancer Resistance Protein

BCRP substrates: Potential increased concentrations of such substrates.

BCRP inhibitors: Potential increased tenofovir alafenamide concentrations. Cobicistat (a BCRP inhibitor) increases tenofovir alafenamide plasma concentrations when the drugs administered as EVG/c/FTC/TAF; further increases not expected if an additional BCRP inhibitor used with EVG/c/FTC/TAF.

Drugs Affected by Organic Anion Transport Polypeptides

OATP1B1 or 1B3 substrates: Potential increased concentrations of such substrates.

Drugs Affecting Renal Function

Drugs that reduce renal function or compete for active tubular secretion: Potential increased concentrations of emtricitabine, tenofovir, and/or concomitant drug.

Specific Drugs

Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Pharmacokinetics

Absorption

Bioavailability

Following an oral dose of EVG/c/FTC/TAF with food, peak plasma concentrations of elvitegravir and cobicistat occur at 4 and 3 hours, respectively, and peak plasma concentrations of emtricitabine and tenofovir occur at 3 and 1 hours, respectively.

Cobicistat component of EVG/c/FTC/TAF increases plasma concentrations of elvitegravir and tenofovir alafenamide. (See Specific Drugs under Interactions.)

Food

Relative to fasting, administration of EVG/c/FTC/TAF with high-fat meal (approximately 800 kcal, 50% fat) increases mean systemic exposures of elvitegravir by 87%; changes in mean systemic exposures of cobicistat, emtricitabine, and tenofovir alafenamide not clinically important.

Distribution

Extent

Elvitegravir, cobicistat, tenofovir: Distributed into milk in rats; not known whether distributed into human milk.

Emtricitabine: Distributed into human milk.

Plasma Protein Binding

Elvitegravir: Approximately 99%.

Cobicistat: Approximately 98%.

Emtricitabine: <4%.

Tenofovir alafenamide: Approximately 80%.

Elimination

Metabolism

Elvitegravir: Metabolized principally by CYP3A; also undergoes glucuronidation via UGT1A1/3. Cobicistat, a CYP3A inhibitor, is included in fixed-combination EVG/c/FTC/TAF to inhibit metabolism of and increase plasma concentrations of elvitegravir.

Cobicistat: Metabolized principally by CYP3A and, to a lesser extent, by CYP2D6.

Emtricitabine: Converted intracellularly to active 5′-triphosphate metabolite; not substantially metabolized further.

Tenofovir alafenamide: Prodrug of tenofovir; hydrolyzed intracellularly by cathepsin A to form tenofovir and subsequently metabolized to active metabolite (tenofovir diphosphate). In vitro, also converted to tenofovir by carboxylesterase 1 in hepatocytes.

Elimination Route

Elvitegravir: 94.8% in feces, 6.7% in urine. Unlikely to be removed by hemodialysis or peritoneal dialysis.

Cobicistat: 86.2% in feces, 8.2% in urine. Unlikely to be removed by hemodialysis or peritoneal dialysis.

Emtricitabine: 70% in urine (glomerular filtration and active tubular secretion), 13.7% in feces. Removed by hemodialysis (approximately 30% of a dose over 3 hours); not known whether removed by peritoneal dialysis.

Tenofovir alafenamide: 31.7% in feces, <1% in urine. Removed by hemodialysis.

Half-life

Elvitegravir: 12.9 hours.

Cobicistat: 3.5 hours.

Emtricitabine: 10 hours.

Tenofovir alafenamide: 0.51 hours; active metabolite (tenofovir diphosphate) half-life within peripheral blood mononuclear cells is 150–180 hours.

Special Populations

Mild hepatic impairment (Child-Pugh class A): No clinically important effects on pharmacokinetics of tenofovir alafenamide.

Moderate hepatic impairment (Child-Pugh class B): No clinically important effects on pharmacokinetics of elvitegravir, cobicistat, or tenofovir alafenamide. Pharmacokinetics of emtricitabine unlikely to be affected.

Severe hepatic impairment (Child-Pugh class C): Pharmacokinetics of EVG/c/FTC/TAF not studied.

Stability

Storage

Oral

Tablets

<30°C.

Store in original container; keep tightly closed.

Actions and Spectrum

• EVG/c/FTC/TAF is a fixed-combination antiretroviral containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide.

• Elvitegravir (EVG) is an HIV integrase strand transfer inhibitor antiretroviral. Inhibits activity of HIV-1 integrase, an enzyme that integrates HIV DNA into the host cell genome. Active against HIV-1 and also has some in vitro activity against HIV type 2 (HIV-2); inactive against HBV and HCV.

• Cobicistat is a mechanism-based CYP3A inhibitor and is included in EVG/c/FTC/TAF as a pharmacokinetic enhancer to decrease elvitegravir metabolism and increase plasma concentrations of the drug (cobicistat-boosted elvitegravir). Has no antiretroviral or antiviral activity and is not active against HIV-1, HBV, or HCV. Does not antagonize the antiretroviral activity of elvitegravir, emtricitabine, or tenofovir.

• Emtricitabine (FTC) is an HIV NRTI. Inactive until converted intracellularly to an active 5′-triphosphate metabolite. After conversion, active against HIV-1 and also has some in vitro activity against HIV-2.

• Tenofovir alafenamide (TAF) is a nucleotide reverse transcriptase inhibitor antiretroviral classified as an HIV NRTI. Tenofovir alafenamide is a tenofovir prodrug that is inactive until hydrolyzed intracellularly by cathepsin A to form tenofovir and subsequently metabolized by cellular kinases to the active metabolite (tenofovir diphosphate). Compared with the tenofovir prodrug tenofovir DF (TDF), tenofovir alafenamide is more stable in blood and plasma and more efficiently converted intracellularly to tenofovir diphosphate, resulting in higher concentrations of active metabolite within HIV target cells and lower circulating concentrations of tenofovir than those reported with tenofovir DF. Active against HIV-1 and also has some in vitro activity against HIV-2; also active against HBV.

• HIV-1 resistant to elvitegravir, emtricitabine, or tenofovir have been produced in vitro and have emerged during EVG/c/FTC/TAF therapy. In clinical trials in antiretroviral-naive patients, genotypic resistance to elvitegravir, emtricitabine, and/or tenofovir was identified in HIV-1 isolates from patients who received EVG/c/FTC/TAF and were considered to be virologic treatment failures.

• Cross-resistance between elvitegravir and other HIV integrase inhibitors (e.g., dolutegravir, raltegravir) has been reported. Cross-resistance also occurs among the HIV NRTIs.

Advice to Patients

• Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician. Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.

• Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.

• Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency syndrome (AIDS) and death.

• Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others. Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.

• Importance of reading patient information provided by the manufacturer.

• Advise patients that EVG/c/FTC/TAF is a complete regimen for treatment of HIV-1 infection and should not be used in conjunction with other antiretroviral agents.

• Importance of taking EVG/c/FTC/TAF with food.

• Inform patients that testing for HBV infection recommended before antiretroviral therapy initiated. Also advise patients that severe acute exacerbations of HBV infection have been reported following discontinuance of emtricitabine and/or tenofovir DF in HIV-infected patients coinfected with HBV and may occur with EVG/c/FTC/TAF.

• Advise patients that renal impairment, including cases of acute renal failure or Fanconi syndrome, has occurred. Importance of not using EVG/c/FTC/TAF concomitantly with or shortly after nephrotoxic agents (e.g., high-dose or multiple NSAIAs).

• Advise patients that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have occurred in patients receiving HIV NRTIs, including emtricitabine and/or tenofovir DF, in conjunction with other antiretrovirals. Importance of contacting clinician if symptoms suggestive of lactic acidosis or hepatotoxicity occur.

• Advise patients that signs and symptoms of inflammation from previous infections may occur soon after initiation of antiretroviral therapy in some individuals with advanced HIV infection (AIDS). These symptoms may be due to an improvement in immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Importance of immediately informing a healthcare provider if any symptoms of infection occur.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise HIV-infected women not to breast-feed.

• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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