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

Drug class: HIV Integrase Inhibitors

Medically reviewed by Drugs.com on Mar 10, 2025. Written by ASHP.

Warning

Fixed combination of EVG/c/FTC/TAF not indicated for treatment of chronic HBV infection. Safety and efficacy of EVG/c/FTC/TAF not established in HIV-1-infected patients coinfected with HBV.
Severe, acute exacerbations of HBV reported following discontinuance of preparations containing emtricitabine and/or the tenofovir prodrug tenofovir disoproxil fumarate (tenofovir DF; TDF) in patients coinfected with HIV and HBV; may occur with EVG/c/FTC/TAF.
Monitor hepatic function closely with both clinical and laboratory follow-up for at least several months after EVG/c/FTC/TAF discontinued in patients coinfected with HIV and HBV. If appropriate, initiation of HBV treatment may be warranted.

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 pharmacokinetic enhancer used to decrease metabolism and increase plasma concentrations of EVG; emtricitabine (FTC) and tenofovir alafenamide (TAF) are HIV nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs).

Uses for Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide

Treatment of HIV Infection

Used as a complete regimen for treatment of HIV-1 infection in adults and pediatric patients weighing ≥25 kg who have no antiretroviral treatment history or to replace the current antiretroviral regimen in patients who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to individual components.

EVG/c/FTC/TAF is a co-formulation of 2 nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs; tenofovir alafenamide fumarate and emtricitabine), an integrase strand transfer inhibitor (INSTI; elvitegravir), and a pharmacokinetic enhancer (cobicistat); consult guidelines for the most current information on the place in therapy for this regimen.

Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.

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

General

Pretreatment Screening

Test patients for HBV infection prior to initiation of EVG/c/FTC/TAF.
Assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein prior to initiation of EVG/c/FTC/TAF.
In patients with chronic kidney disease (CKD), determine serum phosphorus prior to initiation of EVG/c/FTC/TAF.

Patient Monitoring

Routinely monitor serum creatinine, estimated creatinine clearance, urine glucose, and urine protein during treatment in all patients.
Routinely monitor serum phosphorus during treatment in patients with CKD.

Dispensing and Administration Precautions

The Institute for Safe Medication Practices (ISMP) list of error-prone abbreviations, symbols, and dose designations states that the use of abbreviations for antiretroviral medications (e.g., DOR, TAF, TDF) during the medication use process should be avoided as their use has been associated with serious medication errors.

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

Antiretroviral naïve or experienced pediatric patients weighing ≥25 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

Antiretroviral naïve or experienced adults: 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): Not recommended for use.

Renal Impairment

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

Estimated Cl_cr 15–29 mL/minute or Cl_cr <15 mL/minute not receiving chronic hemodialysis: Not recommended.

Estimated Cl_cr <15 mL/minute in patients receiving chronic hemodialysis: On days of hemodialysis, administer EVG/c/FTC/TAF after completion of hemodialysis session.

Geriatric Use

No specific dosage recommendations.

Cautions for Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide

Contraindications

Concomitant use with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of EVG/c/FTC/TAF and possible resistance) include alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, lurasidone, pimozide, ergot derivatives, St. John's wort, lomitapide, lovastatin, simvastatin, sildenafil (when given for pulmonary arterial hypertension), triazolam, and orally administered midazolam.

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 (See Boxed Warning). 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

New Onset or Worsening Renal Impairment

Postmarketing cases of 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 increases in S_cr and modest decreases in estimated Cl_cr due to inhibition of tubular secretion of creatinine; glomerular function not affected.

Determine S_cr, estimated Cl_cr, urine glucose, and urine protein prior to initiation of EVG/c/FTC/TAF and routinely monitor during treatment in all patients. Measure serum phosphorous in patients with CKD.

Do not use EVG/c/FTC/TAF in patients with estimated Cl_cr 15-29 mL/minute, or in patients with end-stage renal disease (estimated Cl_cr <15 mL/minute) if not receiving chronic hemodialysis.

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.

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).

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.

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, autoimmune hepatitis) 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].

Use of EVG/c/FTC/TAF not recommended during pregnancy due to substantially lower elvitegravir and cobicistat exposures in the second and third trimesters.

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 the breast-fed infant.

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.

Pediatric Use

Safety and efficacy of EVG/c/FTC/TAF not established in pediatric patients weighing <25 kg.

Safety and efficacy of EVG/c/FTC/TAF in HIV-1-infected, treatment-naïve pediatric patients 6 to <12 years of age weighing >25 kg 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 18 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

Mild to moderate renal impairment (estimated Cl_cr 30–69 mL/minute) and ESRD (estimated Cl_cr <15 mL/minute) receiving chronic hemodialysis: Pharmacokinetics of elvitegravir, cobicistat, and tenofovir alafenamide similar to those in healthy subjects; increased emtricitabine and tenofovir exposures in patients with renal impairment not considered clinically relevant.

Severe renal impairment (estimated Cl_cr 15-29 mL/minute) or ESRD (estimated Cl_cr <15 mL/minute) not receiving chronic hemodialysis: Not recommended for use.

Common Adverse Effects

Most common adverse effect (≥10%): nausea.

Drug Interactions

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 are 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 are 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

Drug	Interaction	Comments
Alfuzosin	Possible increased alfuzosin concentrations; may result in hypotension	Concomitant use contraindicated
Aminoglycosides (e.g., gentamicin)	Competition for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the aminoglycoside; may increase risk of adverse effects
Antacids, aluminum-, calcium-, and/or magnesium-containing	Decreased elvitegravir concentrations when administered simultaneously	Give EVG/c/FTC/TAF at least 2 hours before or at least 2 hours after antacids
Antiarrhythmic agents (e.g., amiodarone, disopyramide, dronedarone, flecainide, lidocaine [systemic], mexiletine, propafenone, quinidine)	Amiodarone, disopyramide, dronedarone, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine: Possible increased antiarrhythmic agent concentrations	Amiodarone, disopyramide, dronedarone, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine: Use concomitantly with caution;
Anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban, warfarin)	Apixaban, dabigatran, edoxaban, rivaroxaban: Increased anticoagulant concentrations expected Warfarin: Effect on warfarin pharmacokinetics not known	Apixaban: Consult apixaban prescribing information for dosing instructions on the concomitant use with strong CYP3A and P-gp inhibitors Dabigatran, edoxaban: Dosing recommendations for dabigatran and edoxaban dependent on underlying renal function and the indication for anticoagulant use. Consult the prescribing information for the anticoagulant in use for dosing recommendations with concomitant P-gp inhibitor use Rivaroxaban: Avoid concomitant use with EVG/c/FTC/TAF Warfarin: Monitor INR
Anticonvulsants (carbamazepine, ethosuximide, oxcarbazepine, phenobarbital, phenytoin)	Carbamazepine, phenobarbital, phenytoin: Possible decreased elvitegravir, cobicistat, and tenofovir alafenamide concentrations with possible decreased antiretroviral efficacy and development of resistance Ethosuximide: Possible increased ethosuximide concentrations; possible decreased elvitegravir, cobicistat, and tenofovir alafenamide concentrations Oxcarbazepine: Possible decreased elvitegravir, cobicistat, and tenofovir alafenamide concentrations	Carbamazepine, phenobarbital, phenytoin: Concomitant use contraindicated Ethosuximide: Clinical monitoring recommended Oxcarbazepine: Consider alternative anticonvulsant
Antidepressants, tricyclics (amitriptyline, desipramine, doxepin, imipramine, nortriptyline)	Possible increased tricyclic antidepressant concentrations and AUC Desipramine: Increased desipramine concentrations when used concomitantly with cobicistat	Initiate tricyclic antidepressant using lowest initial dosage and carefully titrate dosage according to clinical response
Antifungals, azoles	Itraconazole: Possible increased itraconazole, elvitegravir, and cobicistat concentrations Ketoconazole: Increased ketoconazole, elvitegravir, and cobicistat concentrations Voriconazole: Possible increased voriconazole, elvitegravir, and cobicistat concentrations	Itraconazole: Do not exceed itraconazole dosage of 200 mg daily Ketoconazole: Do not exceed ketoconazole dosage of 200 mg daily Voriconazole: Avoid concomitant use unless benefits outweigh risks
Antimycobacterials (rifabutin, rifampin, rifapentine)	Rifabutin: Decreased elvitegravir concentrations and AUC and increased rifabutin metabolite concentrations and AUC when used with cobicistat-boosted elvitegravir; possible decreased tenofovir alafenamide concentrations; possible decreased antiretroviral efficacy and development of resistance Rifampin: Possible decreased elvitegravir, cobicistat, and tenofovir alafenamide concentrations with possible decreased antiretroviral efficacy and development of resistance Rifapentine: Possible decreased elvitegravir, cobicistat, and tenofovir alafenamide concentrations with possible decreased antiretroviral efficacy and development of resistance	Rifabutin: Concomitant use not recommended Rifampin: Concomitant use contraindicated Rifapentine: Concomitant use not recommended
Antiplatelet agents (clopidogrel, prasugrel, ticagrelor)	Clopidogrel: Decreased clopidogrel active metabolite concentrations Prasugrel: Clinically relevant interactions not expected Ticagrelor: Increased antiplatelet agent concentrations expected	Ticagrelor or clopidogrel: Avoid concomitant use
Antipsychotics (e.g., lurasidone, perphenazine, pimozide, quetiapine, risperidone, thioridazine)	Lurasidone: Possible serious and/or life-threatening reactions Perphenazine, risperidone, thioridazine: Possible increased antipsychotic concentrations Pimozide: Possible increased pimozide concentrations resulting in serious and/or life-threatening reactions (e.g., cardiac arrhythmias) Quetiapine: Increased quetiapine concentrations expected	Lurasidone: Concomitant use contraindicated Perphenazine, risperidone, thioridazine: Decreased antipsychotic dosage may be needed Pimozide: Concomitant use contraindicated Quetiapine: Consider alternative antiretroviral; if EVG/c/FTC/TAF necessary in patient receiving stable quetiapine dosage, reduce quetiapine dosage to one-sixth of original dosage and monitor for quetiapine-associated adverse effects
β-Adrenergic blocking agents (metoprolol, timolol)	Metoprolol, timolol: Possible increased β-blocking agent concentrations	Metoprolol, timolol: Monitor clinically; reduced β-blocker dosage may be needed
Benzodiazepines (e.g., clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam)	Diazepam: Possible increased diazepam concentrations Midazolam or triazolam: Increased benzodiazepine concentrations; potential for serious and/or life-threatening adverse effects (e.g., prolonged or increased sedation or respiratory depression) Clorazepate, estazolam, flurazepam: Possible increased benzodiazepine concentrations	Diazepam: Use concomitantly only in monitored setting where respiratory depression and/or prolonged sedation can be managed; Oral midazolam or triazolam: Concomitant use contraindicated Parenteral midazolam: Use concomitantly only in monitored setting where respiratory depression and/or prolonged sedation can be managed; consider reduced midazolam dosage, particularly if >1 dose will be used
Bosentan	Possible increased bosentan concentrations	In patient already receiving EVG/c/FTC/TAF for ≥10 days, initiate bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability In patient already receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating EVG/c/FTC/TAF; after ≥10 days of EVG/c/FTC/TAF, resume bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability
Buffered medications containing polyvalent cations	Decreased elvitegravir concentrations when administered simultaneously	Give EVG/c/FTC/TAF at least 2 hours before or at least 2 hours after buffered medications
Buprenorphine/naloxone	Increased buprenorphine and norbuprenorphine concentrations and AUCs; decreased naloxone concentrations and AUC	Monitor closely for sedation and adverse cognitive effects; dosage adjustments not needed
Bupropion	Possible increased bupropion concentrations	Carefully titrate antidepressant dosage based on clinical response
Buspirone	Possible increased buspirone concentrations	Monitor clinically; reduced buspirone dosage may be needed
Calcium-channel blocking agents (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil)	Possible increased calcium-channel blocking agent concentrations	Use concomitantly with caution; monitor clinically
Calcium supplements	Decreased elvitegravir concentrations when administered simultaneously	Give EVG/c/FTC/TAF at least 2 hours before or at least 2 hours after oral calcium supplements
Cisapride	Possible increased cisapride concentrations; potential for serious and/or life-threatening reactions (e.g., cardiac arrhythmias)	Concomitant use contraindicated
Cobicistat	Increased elvitegravir concentrations and AUC as the result of cobicistat inhibition of CYP3A; acts as a pharmacokinetic enhancer (cobicistat-boosted elvitegravir); used to therapeutic advantage in fixed-combination EVG/c/FTC/TAF Increased tenofovir alafenamide concentrations and AUC as the result of cobicistat inhibition of P-gp, BCRP, and OATP1B1 and 1B3 Does not antagonize antiretroviral effects of elvitegravir, tenofovir, or emtricitabine	Component of fixed-combination EVG/c/FTC/TAF
Colchicine	Increased colchicine concentrations expected	Patients with renal or hepatic impairment: Concomitant use not recommended Colchicine for treatment of gout flares: In those receiving EVG/c/FTC/TAF, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later Colchicine for prophylaxis of gout flares: In those receiving EVG/c/FTC/TAF, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 mg once daily Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving EVG/c/FTC/TAF, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)
Corticosteroids (betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, mometasone, triamcinolone)	Corticosteroids whose exposures are substantially affected by potent CYP3A inhibitors: Increased corticosteroid concentrations; may result in adrenal insufficiency or Cushing's syndrome Dexamethasone (systemic): Possible decreased elvitegravir and cobicistat concentrations	Corticosteroids via all routes whose exposures are substantially affected by potent CYP3A4 inhibitors: Consider alternative corticosteroid (e.g., beclomethasone, prednisone, prednisolone), particularly for long-term use Dexamethasone (systemic): Consider alternative corticosteroid
Digoxin	Increased digoxin concentrations	Use concomitantly with caution; monitor digoxin concentrations
Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)	Potential for serious and/or life-threatening adverse effects (e.g., peripheral vasospasm, ischemia of extremities)	Concomitant use contraindicated
Estrogens/progestins	Oral contraceptives containing ethinyl estradiol and norgestimate or drosperinone: Decreased ethinyl estradiol concentrations and AUC and increased progestin concentrations and AUC; possible effects of increased norgestimate unknown but may include increased risk of insulin resistance, dyslipidemia, acne, venous thrombosis Oral contraceptives containing levonorgestrel: Potential increased concentrations of levonorgestrel Oral contraceptives containing progestin other than drosperinone, levonorgestrel, or norgestimate: Not studied Other hormonal contraceptives (e.g., transdermal systems, vaginal ring, injections): Not studied	Oral contraceptives containing ethinyl estradiol and norgestimate: Consider risks/benefits of concomitant use, particularly in women at risk of norgestimate-associated adverse effects Oral contraceptives containing ethinyl estradiol and drospirenone: Clinical monitoring for hyperkalemia recommended Oral contraceptives containing progestins other than drosperinone, levonorgestrel, norgestimate: Consider alternative nonhormonal methods of contraception Oral contraceptives containing estrogen: Consider additional or alternative non-hormonal forms of contraception Other hormonal contraceptives (e.g., transdermal systems, vaginal ring, injections): Consider alternative nonhormonal methods of contraception
Famotidine	Clinically important interactions with EVG/c/FTC/TAF not expected
Fentanyl	Possible increased fentanyl concentrations	Carefully monitor for therapeutic and adverse events with concomitant fentanyl use
HCV antiretrovirals (ledipasvir, sofosbuvir, and voxilaprevir; sofosbuvir; sofosbuvir and velpatasvir; sofosbuvir, velpatasvir, and voxilaprevir)	Ledipasvir, sofosbuvir, and voxilaprevir: Clinically important pharmacokinetic interactions not expected Sofosbuvir: Clinically important pharmacokinetic interactions not expected Sofosbuvir, velpatasvir, and voxilaprevir: Clinically important pharmacokinetic interactions not expected
HIV INSTIs		Elvitegravir: Component of fixed-combination EVG/c/FTC/TAF; do not use concomitantly
HIV NRTIs		Emtricitabine, tenofovir alafenamide: Components of EVG/c/FTC/TAF; do not use any preparation containing emtricitabine or tenofovir alafenamide concomitantly with EVG/c/FTC/TAF Tenofovir DF: Do not use any preparation containing tenofovir DF concomitantly with EVG/c/FTC/TAF Other HIV NRTIs (including lamivudine): Do not use concomitantly with EVG/c/FTC/TAF
HIV protease inhibitors (PIs)		Ritonavir: Do not use ritonavir or any ritonavir-containing preparation concomitantly with EVG/c/FTC/TAF
HMG-CoA reductase inhibitors (statins)	Atorvastatin: Possible increased atorvastatin concentrations Lovastatin, simvastatin: Possible increased statin concentrations may lead to serious adverse effects, including myopathy and rhabdomyolysis Rosuvastatin: Increased rosuvastatin concentrations and AUC; no clinically important effect on elvitegravir pharmacokinetics	Atorvastatin: Initiate using lowest atorvastatin dosage and titrate carefully; monitor for atorvastatin-associated adverse effects Do not exceed a dosage of atorvastatin 20 mg daily Lovastatin, simvastatin: Concomitant use contraindicated
Immunosuppressive agents (everolimus, cyclosporine, sirolimus, tacrolimus)	Cyclosporine: Possible increased cyclosporine, elvitegravir, and cobicistat concentrations Everolimus, sirolimus, tacrolimus: Possible increased immunosuppressive agent concentrations	Cyclosporine: Monitor cyclosporine concentrations Everolimus, sirolimus, tacrolimus: Monitor immunosuppressive agent concentrations
Iron preparations	Possible decreased elvitegravir concentrations when administered simultaneously	Give EVG/c/FTC/TAF at least 2 hours before or at least 2 hours after iron preparations; monitor for antiretroviral efficacy
Laxatives containing polyvalent cations	Possible decreased elvitegravir concentrations when administered simultaneously	Give EVG/c/FTC/TAF at least 2 hours before or at least 2 hours after laxatives containing polyvalent cations
Lomitapide	Possible markedly increased transaminase levels	Concomitant use contraindicated
Macrolides (clarithromycin)	Clarithromycin: Possible increased macrolide and/or cobicistat concentrations	Clarithromycin: Dosage modification not needed in patients with Cl_cr ≥60 mL/minute; reduce clarithromycin dosage by 50% in those with Cl_cr 50–60 mL/minute
Methadone	Clinically important pharmacokinetic interactions not expected
Multivitamins or other preparations containing calcium, iron, aluminum, magnesium, or zinc	Possible decreased elvitegravir concentrations if administered simultaneously	Give EVG/c/FTC/TAF at least 2 hours before or at least 2 hours after multivitamins
NSAIAs	High-dose or multiple NSAIAs: Competition for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the concomitant NSAIA; may increase risk of adverse effects	Avoid EVG/c/FTC/TAF in patients who are receiving or have recently received a nephrotoxic drug (e.g., high-dose or multiple NSAIAs)
Nucleoside and nucleotide antivirals (acyclovir, adefovir, cidofovir, entecavir, famciclovir, ganciclovir, ribavirin, valacyclovir, valganciclovir)	Acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir: Competition for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the concomitant antiviral; may increase risk of adverse effects Entecavir, famciclovir: Clinically important interaction not expected Ribavirin: Clinically important interaction not expected	Adefovir: Do not use concomitantly with EVG/c/FTC/TAF
Proton-pump inhibitors (e.g., omeprazole)	Omeprazole: No clinically important effect on elvitegravir concentrations or AUC
Salmeterol	Possible increased salmeterol concentrations; may increase risk of QT prolongation, palpitations, or sinus tachycardia	Concomitant use with EVG/c/FTC/TAF not recommended
Selective serotonin-reuptake inhibitors (SSRIs)	SSRIs: Possible increased SSRI concentrations Sertraline: Clinically important interactions not expected	SSRIs: Carefully titrate SSRI dosage and monitor antidepressant response
Sildenafil	Increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)	Sildenafil for treatment of PAH: Concomitant use with EVG/c/FTC/TAF contraindicated Sildenafil for treatment of erectile dysfunction: Do not exceed sildenafil dosage of 25 mg once every 48 hours; closely monitor for sildenafil-related adverse effects
St. John’s wort (Hypericum perforatum)	Possible decreased elvitegravir, cobicistat, and tenofovir alafenamide concentrations with possible decreased antiretroviral efficacy and development of resistance	Concomitant use contraindicated
Sucralfate	Decreased elvitegravir concentrations when administered simultaneously	Give EVG/c/FTC/TAF at least 2 hours before or at least 2 hours after sucralfate
Tadalafil	Increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)	Tadalafil for treatment of PAH in patients who have been receiving EVG/c/FTC/TAF for ≥1 week: Use initial tadalafil dosage of 20 mg once daily; if tolerated, increase dosage to 40 mg once daily EVG/c/FTC/TAF in patients receiving tadalafil for PAH: Discontinue tadalafil for at least 24 hours prior to initiating EVG/c/FTC/TAF; after ≥1 week of the antiretroviral agent, may resume tadalafil at a dosage of 20 mg once daily, and, if tolerated, may increase dosage to 40 mg once daily Tadalafil for treatment of erectile dysfunction: Do not exceed tadalafil dosage of 10 mg once every 72 hours; closely monitor for tadalafil-related adverse effects
Tramadol	Possible increased tramadol concentrations	A dose decrease may be necessary when tramadol is used concomitantly
Trazodone	Possible increased trazodone concentrations	Carefully titrate trazodone dosage and monitor antidepressant response
Vardenafil	Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)	Vardenafil for treatment of erectile dysfunction: Do not exceed vardenafil dosage of 2.5 mg once every 72 hours; closely monitor for vardenafil-related adverse effects
Zolpidem	Possible increased zolpidem concentrations	Monitor clinically; reduced zolpidem dosage may be needed

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.

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.

Mild to moderate renal impairment (estimated Cl_cr 30–69 mL/minute): No clinically important effects on emtricitabine or tenofovir alafenamide exposures.

End-stage renal disease (estimated Cl_cr <15 mL/minute) receiving chronic hemodialysis: Pharmacokinetics of elvitegravir, cobicistat, and tenofovir alafenamide similar to those in healthy subjects; no clinically important effects on emtricitabine or tenofovir alafenamide exposures.

No clinically important effects of race or gender on pharmacokinetics of EVG/c/FTC/TAF.

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 has emerged during EVG/c/FTC/TAF therapy. In clinical trials in antiretroviral-naïve 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

Advise patients of the critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician. Importance of taking EVG/c/FTC/TAF as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.
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.
Advise patients of the 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 of reproductive potential that additional or nonhormonal methods of contraception should be used when estrogen-based contraceptives are used concomitantly with EVG/c/FTC/TDF.
Advise patients that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have occurred in patients receiving HIV NRTIs, including emtricitabine and/or tenofovir disoproxil fumarate (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.
Advise patients to inform their 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.
Advise women to inform clinicians if they are or plan to become pregnant or plan to breast-feed.
Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Fumarate
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	Elvitegravir 150 mg, Cobicistat 150 mg, Emtricitabine 200 mg, and Tenofovir Alafenamide Fumarate 10 mg (of tenofovir alafenamide)	Genvoya	Gilead