Elvitegravir, Cobicistat, Emtricitabine, and tenofovir Disoproxil Fumarate

Drug class: Antineoplastic Agents

Usage of Elvitegravir, Cobicistat, Emtricitabine, and tenofovir Disoproxil Fumarate

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/TDF 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/TDF is a recommended INSTI-based regimen.

For initial treatment in HIV-infected pediatric patients, experts state that EVG/c/FTC/TDF is not a preferred or alternative regimen and is recommended only for children and adolescents ≥12 years of age who weigh ≥35 kg and are in late puberty (sexual maturity rating [SMR] 4 or 5).

For antiretroviral-experienced adults and pediatric patients ≥12 years of age, manufacturer states EVG/c/FTC/TDF 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).

Postexposure Prophylaxis following Occupational Exposure to HIV

Postexposure prophylaxis of HIV infection following occupational exposure† [off-label] (PEP) in health-care personnel and others exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.

USPHS recommends 3-drug regimen of raltegravir and Emtricitabine and tenofovir DF as the preferred regimen for PEP following occupational exposures to HIV. EVG/c/FTC/TDF used alone is one of several alternative regimens for PEP.

Management of occupational exposures to HIV is complex and evolving; consult infectious disease specialist, clinician with expertise in administration of antiretrovirals, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible. Do not delay initiation of PEP while waiting for expert consultation.

Relate drugs

How to use Elvitegravir, Cobicistat, Emtricitabine, and tenofovir Disoproxil Fumarate

General

  • Determine Scr, estimated Clcr, serum phosphorus, urine Glucose, and urine protein prior to initiation of EVG/c/FTC/TDF and routinely monitor during treatment in all patients. (See Renal Impairment under Cautions.)
  • Test for HBV infection prior to initiation of EVG/c/FTC/TDF. (See HIV-infected Individuals Coinfected with HBV under Cautions.)

    • Administration

    Oral Administration

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

    Dosage

    Each fixed-combination tablet of EVG/c/FTC/TDF contains elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir DF 300 mg.

    Pediatric Patients

    Treatment of HIV Infection Oral

    Pediatric patients ≥12 years of age weighing ≥35kg: 1 tablet of EVG/c/FTC/TDF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir DF 300 mg) once daily.

    Adults

    Treatment of HIV Infection Oral

    1 tablet of EVG/c/FTC/TDF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir DF 300 mg) once daily.

    Postexposure Prophylaxis following Occupational Exposure to HIV† [off-label] Oral

    1 tablet of EVG/c/FTC/TDF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir DF 300 mg) once daily.

    Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.

    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

    Adults: Do not initiate EVG/c/FTC/TDF if estimated Clcr <70 mL/minute. Discontinue if estimated Clcr decreases to <50 mL/minute during treatment. (See Renal Impairment under Cautions.)

    Pediatric patients: Data insufficient to make dosage recommendations for those with renal impairment.

    Geriatric Patients

    Use with caution. (See Geriatric Use under Cautions.)

    Warnings

    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 which may result in decreased elvitegravir and/or cobicistat concentrations resulting in possible decreased antiretroviral efficacy and development of resistance (e.g., Carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s wort [Hypericum perforatum]). (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/TDF not indicated for treatment of chronic HBV infection. Safety and efficacy of EVG/c/FTC/TDF not established in patients coinfected with HIV and HBV.

    Severe acute exacerbations of HBV reported following discontinuance of emtricitabine or tenofovir DF in HIV-infected patients with HBV infection. HBV exacerbations have been associated with hepatic decompensation and hepatic failure.

    Closely monitor hepatic function (using both clinical and laboratory follow-up) for at least several months after EVG/c/FTC/TDF 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 DF (a component of EVG/c/FTC/TDF).

    Cobicistat (a component of EVG/c/FTC/TDF) 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/TDF and routinely monitor during treatment in all patients. (See Renal Impairment under Cautions.)

    Do not initiate EVG/c/FTC/TDF in patients with estimated Clcr <70 mL/minute; discontinue if estimated Clcr decreases to <50 mL/minute during therapy.

    If a cOnfirmed increase in Scr of >0.4 mg/dL from baseline occurs during EVG/c/FTC/TDF treatment, closely monitor for renal toxicity.

    Because persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy, promptly evaluate renal function in patients at risk for renal dysfunction who present with such symptoms. (See Bone Effects under Cautions.)

    Avoid EVG/c/FTC/TDF in patients who are receiving or have recently received a nephrotoxic drug (e.g., high-dose or multiple NSAIAs). Acute renal failure reported after initiation of high-dose or multiple NSAIAs in HIV-infected patients at risk for renal dysfunction who appeared stable while receiving tenofovir DF; hospitalization and renal replacement therapy required in some patients. Consider alternatives to NSAIAs in patients at risk for renal dysfunction.

    Lactic Acidosis and Severe Hepatomegaly with Steatosis

    Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) reported in patients receiving NRTIs, including emtricitabine and tenofovir DF (components of EVG/c/FTC/TDF), in conjunction with other antiretrovirals.

    Interrupt EVG/c/FTC/TDF 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

    Decreases in bone mineral density (BMD) from baseline at lumbar spine and hip, increases in several biochemical markers of bone metabolism, and increased serum parathyroid hormone and 1,25 vitamin D levels reported in patients receiving tenofovir DF (a component of EVG/c/FTC/TDF). Bone effects reported in pediatric patients are similar to those reported in adults. Effects of tenofovir-associated changes in BMD on long-term bone health and future fracture risk unknown.

    Osteomalacia associated with proximal renal tubulopathy, which may contribute to fractures, reported in patients receiving tenofovir DF. Arthralgia and muscle pain or weakness also reported in cases of proximal renal tubulopathy. Consider hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving preparations containing tenofovir DF.

    Consider BMD monitoring in adult and pediatric patients with history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Effect of calcium and vitamin D supplementation not studied, but may be beneficial for all patients. If bone abnormalities suspected, obtain appropriate consultation.

    Interactions

    Concomitant use with certain drugs may result in decreased antiretroviral plasma concentrations leading to loss of therapeutic effect and possible development of resistance; concomitant use with certain other drugs may result in increased antiretroviral plasma concentrations and/or increased plasma concentrations of the concomitant drugs leading to clinically important adverse reactions. (See Contraindications and see Interactions.)

    Consider potential drug interactions prior to and during therapy. Review drugs used concomitantly with EVG/c/FTC/TDF; monitor patient for adverse reactions associated with these drugs. (See Interactions.)

    Use of Fixed Combinations

    Consider cautions, precautions, and contraindications associated with each component of EVG/c/FTC/TDF. 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/TDF 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/TDF concomitantly with any preparation that contains any of its components (elvitegravir, cobicistat, emtricitabine, tenofovir DF). In addition, do not use EVG/c/FTC/TDF concomitantly with any preparation containing 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/TDF 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 or tenofovir DF 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/TDF administered during the period of organogenesis at elvitegravir, cobicistat, emtricitabine, and tenofovir DF exposures up to 23, 4.3, 120, and 19 times higher, respectively, than human exposures at the recommended daily dosage.

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

    Lactation

    Elvitegravir and cobicistat distributed into milk in rats; not known whether these drugs distributed into human milk. Emtricitabine and tenofovir DF are distributed into human milk.

    Not known whether EVG/c/FTC/TDF 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/TDF not established in pediatric patients <12 years of age or in those weighing <35 kg.

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

    Bone effects reported when tenofovir DF is used in pediatric and adolescent patients are similar to those reported in adults. In clinical studies, total body BMD gain in tenofovir DF-treated pediatric patients was less than that reported in control groups; skeletal growth appeared to be unaffected. Effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk unknown.

    Experts state EVG/c/FTC/TDF recommended for initial treatment only in antiretroviral-naive HIV-infected children and adolescents ≥12 years of age weighing ≥35 kg in late puberty (SMR 4 or 5). These experts state that the fixed combination of elvitegravir, cobicistat, emtricitabine, and Tenofovir alafenamide (EVG/c/FTC/TAF) is preferred in children and adolescents ≥12 years of age weighing ≥35 kg.

    Geriatric Use

    Insufficient experience in adults ≥65 years of age to determine whether geriatric patients respond differently than younger adults.

    Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

    Hepatic Impairment

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

    Severe hepatic impairment (Child-Pugh class C): EVG/c/FTC/TDF 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/TDF treatment in all patients.

    Adults: Do not initiate EVG/c/FTC/TDF in patients with estimated Clcr <70 mL/minute. Discontinue if estimated Clcr decreases to <50 mL/minute during treatment.

    Pediatric patients: Data insufficient to make dosage recommendations for those with renal impairment.

    Common Adverse Effects

    Nausea, diarrhea, abnormal dreams, headache.

    What other drugs will affect Elvitegravir, Cobicistat, Emtricitabine, and tenofovir Disoproxil Fumarate

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

    Cobicistat: Substrate and inhibitor of CYP3A and 2D6; also inhibits 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 DF and tenofovir: Not substrates of CYP enzymes; tenofovir does not inhibit CYP3A4, 2D6, 2C9, or 2E1, but may have a slight inhibitory effect on CYP1A.

    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/TDF 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 and cobicistat; 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 plasma concentrations of such substrates.

    Drugs Affected by Breast Cancer Resistance Protein

    BCRP substrates: Potential increased plasma concentrations of such substrates.

    Drugs Affected by Organic Anion Transport Polypeptides

    OATP1B1 or 1B3 substrates: Potential increased plasma 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 concomitant 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/TDF at least 2 hours before or at least 2 hours after antacids

    Antiarrhythmic agents (amiodarone, disopyramide, dronedarone, Flecainide, lidocaine [systemic], mexiletine, propafenone, quinidine)

    Possible increased antiarrhythmic agent concentrations

    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: Possible altered warfarin concentrations

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

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

    Warfarin: Monitor INR and adjust warfarin dosage accordingly

    Anticonvulsants (carbamazepine, ethosuximide, oxcarbazepine, phenobarbital, phenytoin)

    Carbamazepine, phenobarbital, phenytoin: Possible increased anticonvulsant concentrations; possible decreased elvitegravir and cobicistat concentrations with possible decreased antiretroviral efficacy and development of resistance

    Ethosuximide: Possible increased ethosuximide concentrations

    Oxcarbazepine: Possible decreased elvitegravir and cobicistat concentrations

    Carbamazepine, phenobarbital, phenytoin: Concomitant use contraindicated

    Ethosuximide: If used concomitantly with EVG/c/FTC/TDF, monitor clinically for ethosuximide-associated adverse effects

    Oxcarbazepine: Consider alternative anticonvulsant

    Antidepressants, tricyclics (amitriptyline, Desipramine, doxepin, imipramine, nortriptyline)

    Possible increased tricyclic antidepressant concentrations and AUC

    If tricyclic antidepressant initiated in patients receiving EVG/c/FTC/TDF, use lowest initial antidepressant dosage and carefully titrate dosage based on clinical response and/or antidepressant concentrations

    Antifungals, azoles

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

    Itraconazole: Increased itraconazole concentrations expected; possible increased 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; experts state use itraconazole dosage >200 mg daily only if itraconazole concentrations monitored

    Ketoconazole: Do not exceed ketoconazole dosage of 200 mg daily

    Posaconazole: Monitor posaconazole concentrations

    Voriconazole: Avoid concomitant use unless benefits outweigh risks; if used concomitantly, experts state consider monitoring voriconazole concentrations and adjust voriconazole dosage accordingly

    Antiplatelet agents (ticagrelor, vorapaxar)

    Ticagrelor or vorapaxar: Increased antiplatelet concentrations expected

    Ticagrelor or vorapaxar: Avoid concomitant use

    Antimycobacterials (rifabutin, rifampin, rifapentine)

    Rifabutin: Decreased elvitegravir concentrations and AUC and increased rifabutin metabolite concentrations and AUC when used with cobicistat-boosted elvitegravir

    Rifampin: Possible decreased elvitegravir and cobicistat concentrations with possible decreased antiretroviral efficacy and development of resistance

    Rifapentine: Possible decreased elvitegravir and cobicistat concentrations with possible decreased antiretroviral efficacy and development of resistance

    Rifabutin: Concomitant use not recommended

    Rifampin: Concomitant use contraindicated

    Rifapentine: Concomitant use not recommended

    Antipsychotics (perphenazine, lurasidone, pimozide, risperidone, quetiapine, thioridazine)

    Lurasidone: Possible serious and/or life-threatening reactions

    Perphenazine, risperidone, thioridazine: Possible increased antipsychotic agent 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; if initiated in patients receiving EVG/c/FTC/TDF, use low initial dosage of the antipsychotic

    Pimozide: Concomitant use contraindicated

    Quetiapine: Consider alternative antiretroviral; if EVG/c/FTC/TDF necessary in patient receiving stable quetiapine dosage, reduce quetiapine dosage to one-sixth of original dosage and monitor for quetiapine efficacy and adverse effects; if quetiapine necessary in patient receiving EVG/c/FTC/TDF, initiate using lowest quetiapine dosage, titrate as needed, and closely monitor for quetiapine efficacy and 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-blocking agent dosage may be needed; consider alternative agent not metabolized by CYP isoenzymes (e.g., atenolol, labetalol, nadolol, sotalol)

    Benzodiazepines (clonazepam, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam)

    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, diazepam, estazolam, flurazepam: Possible increased benzodiazepine concentrations

    Oral midazolam or triazolam: Concomitant use contraindicated

    Parenteral midazolam: Use 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, diazepam, estazolam, flurazepam: Monitor clinically; reduced benzodiazepine dosage may be needed; if initiated in patient receiving EVG/c/FTC/TDF, use low initial dosage

    Diazepam: Consider alternative benzodiazepine (e.g., lorazepam, oxazepam, Temazepam)

    Bosentan

    Possible increased bosentan concentrations

    In patient already receiving EVG/c/FTC/TDF 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/TDF; after ≥10 days of EVG/c/FTC/TDF, 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/TDF is switched from transmucosal buprenorphine to subdermal implant, monitor to ensure buprenorphine effect is adequate and not excessive

    Bupropion

    Possible increased or decreased bupropion concentrations

    Carefully titrate antidepressant dosage based on clinical response

    Buspirone

    Possible increased buspirone concentrations

    Monitor clinically; reduced buspirone dosage may be needed; if initiated in patient receiving EVG/c/FTC/TDF, use low initial dosage

    Calcium-channel blocking agents (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil)

    Possible increased calcium-channel blocking agent concentrations

    Use concomitantly with caution; titrate dosage of calcium-channel blocking agent; monitor for efficacy and adverse effects

    Calcium supplements

    Possible decreased elvitegravir concentrations

    Give EVG/c/FTC/TDF 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/TDF

    Slightly increased emtricitabine concentrations and AUC and slightly increased tenofovir concentrations; not considered clinically important

    Does not antagonize antiretroviral effects of elvitegravir, tenofovir, or emtricitabine

    Component of fixed combination EVG/c/FTC/TDF

    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/TDF, 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/TDF, 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/TDF, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)

    Corticosteroids (beclomethasone, Betamethasone, buDesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, mometasone, prednisolone, prednisone, triamcinolone)

    Fluticasone (orally inhaled, intranasal) or other orally inhaled or intranasal corticosteroids whose exposures are substantially affected by potent CYP3A inhibitors (e.g., ciclesonide, mometasone): Increased corticosteroid concentrations; may result in adrenal insufficiency or Cushing's syndrome

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

    Dexamethasone or other corticosteroids that induce CYP3A (systemic): Possible decreased elvitegravir and cobicistat concentrations with possible decreased antiretroviral efficacy and development of resistance

    Corticosteroids whose exposures substantially affected by potent CYP3A inhibitors (systemic) (e.g., betamethasone, prednisone): Increased corticosteroid concentrations; may result in adrenal insufficiency or Cushing's syndrome

    Fluticasone (orally inhaled, intranasal) or other corticosteroids whose exposures are substantially affected by potent CYP3A inhibitors (e.g., ciclesonide, mometasone): Consider alternative corticosteroid (e.g., beclomethasone), particularly for long-term use

    Methylprednisolone, prednisolone, triamcinolone (intra-articular, epidural, intraorbital, other local injections): Do not use concomitantly

    Dexamethasone (systemic): Consider alternative corticosteroid; if used concomitantly, use caution and monitor virologic response

    Other systemic corticosteroids whose exposures substantially affected by potent CYP3A inhibitors (e.g., betamethasone, budesonide, prednisone): Consider alternative corticosteroids (e.g., prednisolone), particularly for long-term use

    Daclatasvir

    Possible increased daclatasvir concentrations

    If used concomitantly with EVG/c/FTC/TDF, 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/TDF

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

    Digoxin

    Possible increased digoxin concentrations

    Use concomitantly with caution; monitor digoxin concentrations if possible

    Elbasvir and grazoprevir

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

    Elbasvir/grazoprevir: Concomitant use with EVG/c/FTC/TDF 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., patch, 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., patch, vaginal ring, injections): Consider alternative nonhormonal methods of contraception

    Flibanserin

    Increased flibanserin concentrations expected

    Some 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/TDF not expected

    Dosage adjustment not needed if EVG/c/FTC/TDF used concomitantly with a histamine H2-receptor antagonist

    HIV entry and fusion inhibitors (maraviroc)

    Maraviroc: Increased maraviroc concentrations and AUC

    Do not use concomitantly with EVG/c/FTC/TDF

    HIV integrase inhibitors (INSTIs)

    Dolutegravir, elvitegravir, raltegravir: Do not use concomitantly with EVG/c/FTC/TDF

    HIV nonnucleoside reverse transcriptase inhibitor antiretrovirals (NNRTIs)

    Efavirenz, etravirine, Nevirapine, rilpivirine: Possible altered elvitegravir, cobicistat, and/or NNRTI concentrations

    Efavirenz, etravirine, nevirapine, rilpivirine: Do not use concomitantly with EVG/c/FTC/TDF

    HIV nucleoside and nucleotide reverse transcriptase inhibitor antiretrovirals (NRTIs)

    Emtricitabine and tenofovir DF: Components of EVG/c/FTC/TDF; do not use any preparation containing emtricitabine or tenofovir DF concomitantly with EVG/c/FTC/TDF

    Other NRTIs (including lamivudine): Do not use concomitantly with EVG/c/FTC/TDF

    HIV protease inhibitors (PIs) (atazanavir, darunavir, fosamprenavir, lopinavir, ritonavir, saquinavir, tipranavir)

    HIV PIs (with or without low-dose ritonavir or cobicistat): Possible altered concentrations of elvitegravir, cobicistat, and/or the HIV protease inhibitor

    Ritonavir: Has an effect on CYP3A similar to that reported with cobicistat

    HIV PIs (with or without low-dose ritonavir or cobicistat): Do not use concomitantly with EVG/c/FTC/TDF

    Ritonavir: Do not use ritonavir or any ritonavir-containing preparation concomitantly with EVG/c/FTC/TDF

    HMG-CoA reductase inhibitors (statins)

    Atorvastatin, lovastatin, simvastatin: Increased concentrations of the antilipemic agent; increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis

    Pitavastatin, pravastatin: Data not available regarding concomitant use with EVG/c/FTC/TDF

    Rosuvastatin: Increased rosuvastatin concentrations and AUC; no clinically important effect on elvitegravir pharmacokinetics

    Atorvastatin: Initiate using lowest atorvastatin dosage and titrate slowly; monitor for atorvastatin-associated adverse effects

    Lovastatin: Concomitant use contraindicated

    Rosuvastatin: Some experts recommend slowly titrating rosuvastatin dosage; use lowest possible rosuvastatin dose

    Simvastatin: Concomitant use contraindicated

    Immunosuppressive agents (cyclosporine, everolimus, sirolimus, tacrolimus)

    Cyclosporine, everolimus, sirolimus, tacrolimus: Possible increased immunosuppressive agent concentrations

    Cyclosporine, sirolimus, tacrolimus: Monitor immunosuppressive agent concentrations and associated toxicities

    Cyclosporine, everolimus, sirolimus, tacrolimus: Some experts recommend initiating immunosuppressive agent using a reduced dosage and monitoring for toxicities; consultation with specialist may be needed

    Iron preparations

    Possible decreased elvitegravir concentrations

    Give EVG/c/FTC/TDF 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/TDF 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): Increased ledipasvir concentrations and increased tenofovir concentrations expected; safety of increased tenofovir concentrations in patients receiving ledipasvir/sofosbuvir and EVG/c/FTC/TDF not established

    Ledipasvir/sofosbuvir: Do not use concomitantly with EVG/c/FTC/TDF

    Macrolides (clarithromycin)

    Clarithromycin: Possible increased clarithromycin 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; do not use concomitantly with EVG/c/FTC/TDF if Clcr <50 mL/minute

    Methadone

    Clinically important pharmacokinetic interactions not expected

    Dosage adjustments not needed

    Multivitamins or other preparations containing calcium, iron, aluminum magnesium, or zinc

    Possible decreased elvitegravir concentrations

    Give EVG/c/FTC/TDF 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

    In patients at risk for renal dysfunction, consider alternatives to 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/TDF

    Ombitasvir

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

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

    Paritaprevir

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

    Dasabuvir/ombitasvir/paritaprevir/ritonavir: Concomitant use with EVG/c/FTC/TDF 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/TDF not expected

    Dosage adjustments not needed if EVG/c/FTC/TDF used concomitantly with a proton-pump inhibitor

    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/TDF not recommended

    Selective serotonin-reuptake inhibitors (SSRIs)

    Citalopram, escitalopram, fluoxetine, paroxetine, Sertraline: Possible increased SSRI concentrations

    Fluvoxamine: Possible increased or decreased elvitegravir concentrations

    Citalopram, escitalopram, fluoxetine, paroxetine, sertraline: Initiate SSRI using lowest dose and carefully titrate dosage based on antidepressant response

    Fluvoxamine: Some experts state consider alternative to fluvoxamine or alternative to EVG/c/FTC/TDF

    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/TDF 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

    May be used concomitantly without dosage adjustments

    Sofosbuvir and velpatasvir

    Fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir): Increased tenofovir exposures

    Sofosbuvir/velpatasvir: Monitor for tenofovir-associated adverse effects

    St. John’s wort (Hypericum perforatum)

    Possible decreased elvitegravir and cobicistat concentrations with possible decreased antiretroviral efficacy and development of resistance

    Concomitant use contraindicated

    Sucralfate

    Possible decreased elvitegravir concentrations

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

    Suvorexant

    Increased suvorexant concentrations expected

    Concomitant use with EVG/c/FTC/TDF 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/TDF for ≥1 week: Use initial tadalafil dosage of 20 mg once daily; if tolerated, increase dosage to 40 mg once daily

    EVG/c/FTC/TDF in patients receiving tadalafil for PAH: Discontinue tadalafil for at least 24 hours prior to initiating EVG/c/FTC/TDF; 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; some experts recommend initiating tadalafil at a dose of 5 mg

    Trazodone

    Possible increased trazodone concentrations

    If trazodone initiated in patients receiving EVG/c/FTC/TDF, use lowest initial trazodone dosage and carefully titrate dosage based on 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

    Increased zolpidem concentrations expected

    Monitor clinically; reduced zolpidem dosage may be needed; if initiated in patients receiving EVG/c/FTC/TDF, use low initial zolpidem dosage

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