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Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide

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, 2020. Written by ASHP.

Warning

    HBV Infection
  • 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. (See HIV-infected Individuals Coinfected with HBV under Cautions.)

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 Scr, estimated Clcr, 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 Clcr ≥30 mL/minute: Dosage adjustments not needed.

Estimated Clcr <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 Scr and modest decrease in estimated Clcr due to inhibition of tubular secretion of creatinine; glomerular function not affected.

Determine Scr, estimated Clcr, 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 Clcr <30 mL/minute.

If a confirmed increase in Scr 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 Scr, estimated Clcr, serum phosphorus, urine glucose, and urine protein prior to and routinely monitor during EVG/c/FTC/TAF treatment in all patients.

Estimated Clcr <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

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 and AUC 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; monitor antiarrhythmic agent concentrations if possible

Anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban, warfarin)

Apixaban, edoxaban, rivaroxaban: Increased anticoagulant concentrations expected

Dabigatran: Possible increased dabigatran concentrations

Warfarin: Effect on warfarin pharmacokinetics not known, but warfarin concentrations may be affected

Apixaban, edoxaban, rivaroxaban: Avoid concomitant use with EVG/c/FTC/TAF

Dabigatran: Some experts state dosage adjustments not needed if used with EVG/c/FTC/TAF in patients with Clcr >50 mL/minute; do not use concomitantly in those with Clcr <50 mL/minute

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

Isavuconazonium (prodrug of isavuconazole): Possible increased isavuconazole, elvitegravir, and cobicistat concentrations

Itraconazole: Possible increased itraconazole, elvitegravir, and cobicistat concentrations

Ketoconazole: Increased ketoconazole, elvitegravir, and cobicistat concentrations

Posaconazole: Possible increased posaconazole, elvitegravir, and cobicistat concentrations

Voriconazole: Possible increased voriconazole, elvitegravir, and cobicistat concentrations

Isavuconazonium: Monitor for virologic efficacy; consider monitoring isavuconazole concentrations

Itraconazole: Do not exceed itraconazole dosage of 200 mg daily

Ketoconazole: Do not exceed ketoconazole dosage of 200 mg daily

Posaconazole: Monitor posaconazole concentrations

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 (ticagrelor, vorapaxar)

Ticagrelor or vorapaxar: Increased antiplatelet agent concentrations expected

Ticagrelor or vorapaxar: 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

Avanafil

Data not available

Concomitant use not recommended

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., clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, triazolam)

Diazepam: Possible increased diazepam concentrations

Lorazepam: Clinically important effects on lorazepam concentrations not expected

Midazolam or triazolam: Increased benzodiazepine concentrations; potential for serious and/or life-threatening adverse effects (e.g., prolonged or increased sedation or respiratory depression)

Clonazepam, clorazepate, estazolam, flurazepam: Possible increased benzodiazepine concentrations

Diazepam: Use concomitantly only in monitored setting where respiratory depression and/or prolonged sedation can be managed; experts state consider alternatives to diazepam (e.g., lorazepam, oxazepam, temazepam)

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

Clonazepam, clorazepate, estazolam, flurazepam: Experts recommend low initial benzodiazepine dosage with close monitoring

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

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

If patient receiving EVG/c/FTC/TAF is switched from transmucosal buprenorphine to subdermal implant, monitor to ensure buprenorphine effect is adequate and not excessive

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

Possible decreased elvitegravir concentrations

Give EVG/c/FTC/TAF at least 2 hours before or at least 6 hours after oral calcium supplements; monitor for antiretroviral efficacy

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 (dexamethasone, fluticasone)

Dexamethasone (systemic): Possible decreased elvitegravir and cobicistat concentrations

Fluticasone (orally inhaled, intranasal): Possible increased fluticasone concentrations

Methylprednisolone, prednisolone, or triamcinolone (intra-articular or other local injections): Increased corticosteroid concentrations; may result in adrenal insufficiency or Cushing's syndrome

Dexamethasone (systemic): Consider alternative corticosteroid

Fluticasone (orally inhaled, intranasal): Consider alternative corticosteroid, particularly for long-term use

Methylprednisolone, prednisolone, or triamcinolone (intra-articular or other local injections): Do not use concomitantly with EVG/c/FTC/TAF

Daclatasvir

Possible increased daclatasvir concentrations

If used concomitantly with EVG/c/FTC/TAF, use daclatasvir dosage of 30 mg once daily

Dasabuvir

Fixed combination of dasabuvir, ombitasvir, paritaprevir, and ritonavir (dasabuvir/ombitasvir/paritaprevir/ritonavir): Data not available regarding concomitant use with EVG/c/FTC/TAF

Dasabuvir/ombitasvir/paritaprevir/ritonavir: Concomitant use with EVG/c/FTC/TAF not recommended

Digoxin

Increased digoxin concentrations

Use concomitantly with caution; monitor digoxin concentrations

Elbasvir and grazoprevir

Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): Possible increased elbasvir and grazoprevir concentrations

Elbasvir/grazoprevir: Concomitant use not recommended

Eplerenone

Increased eplerenone concentrations expected

Some experts state concomitant use contraindicated

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: Decreased ethinyl estradiol concentrations and AUC and increased norgestimate concentrations and AUC; possible effects of increased norgestimate unknown but may include increased risk of insulin resistance, dyslipidemia, acne, venous thrombosis

Oral contraceptives containing progestin other than 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 progestins other than norgestimate: Consider alternative nonhormonal methods of contraception

Other hormonal contraceptives (e.g., transdermal systems, vaginal ring, injections): Consider alternative nonhormonal methods of contraception

Flibanserin

Increased flibanserin concentrations expected

Experts state concomitant use contraindicated

Histamine H2-receptor antagonists (e.g., famotidine)

Famotidine: No clinically important effect on elvitegravir concentrations or AUC

Histamine H2-receptor antagonists: Clinically important interactions with EVG/c/FTC/TAF 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

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; monitor for EVG/c/FTC/TAF-associated adverse effects; some experts state initiate immunosuppressive agent using decreased dosage and monitor for toxicities; consultation with a specialist may be necessary

Everolimus, sirolimus, tacrolimus: Monitor immunosuppressive agent concentrations; some experts state initiate immunosuppressive agent using decreased dosage and monitor for toxicities; consultation with a specialist may be necessary

Iron preparations

Possible decreased elvitegravir concentrations

Give EVG/c/FTC/TAF at least 2 hours before or at least 6 hours after iron preparations; monitor for antiretroviral efficacy

Ivabradine

Increased ivabradine concentrations expected

Some experts state concomitant use contraindicated

Laxatives containing polyvalent cations

Possible decreased elvitegravir concentrations

Give EVG/c/FTC/TAF at least 2 hours before or at least 6 hours after laxatives containing polyvalent cations; monitor for antiretroviral efficacy

Ledipasvir and sofosbuvir

Fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir): Clinically important pharmacokinetic interactions not expected

Ledipasvir/sofosbuvir: Dosage adjustments not needed

Macrolides (clarithromycin)

Clarithromycin: Possible increased macrolide and/or cobicistat concentrations

Clarithromycin: Dosage modification not needed in patients with Clcr ≥60 mL/minute; reduce clarithromycin dosage by 50% in those with Clcr 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

Give EVG/c/FTC/TAF at least 2 hours before or at least 6 hours after multivitamins; monitor for antiretroviral efficacy

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

Ombitasvir

Dasabuvir/ombitasvir/paritaprevir/ritonavir: Data not available regarding concomitant use with EVG/c/FTC/TAF

Dasabuvir/ombitasvir/paritaprevir/ritonavir: Concomitant use with EVG/c/FTC/TAF not recommended

Paritaprevir

Dasabuvir/ombitasvir/paritaprevir/ritonavir: Data not available regarding concomitant use with EVG/c/FTC/TAF

Dasabuvir/ombitasvir/paritaprevir/ritonavir: Concomitant use with EVG/c/FTC/TAF not recommended

Proton-pump inhibitors (e.g., omeprazole)

Omeprazole: No clinically important effect on elvitegravir concentrations or AUC

Proton-pump inhibitors: Clinically important interactions with EVG/c/FTC/TAF not expected

Ranolazine

Experts state do not use concomitantly

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

Simeprevir

Increased simeprevir concentrations expected

Concomitant use not recommended

Sofosbuvir

Clinically important pharmacokinetic interactions not expected

Dosage adjustments not needed

Sofosbuvir and velpatasvir

Fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir): No clinically important pharmacokinetic interactions

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

Possible decreased elvitegravir concentrations

Give EVG/c/FTC/TAF at least 2 hours before or at least 6 hours after sucralfate; monitor for antiretroviral efficacy

Suvorexant

Increased suvorexant concentrations expected

Experts state concomitant use not recommended

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

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. (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.

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

AHFS DI Essentials™. © Copyright 2021, Selected Revisions October 9, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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