Skip to Content

Elvitegravir and Cobicistat

Class: HIV Integrase Inhibitors
ATC Class: J05AX08
Chemical Name: 6 - [(3 - Chloro - 2 - fluorophenyl)methycypl] - 1,4 - dihydro - 1 - [(1S) - 1 - (hydroxymethyl) - 2 - methylpropyl] - 7 - methoxy - 4 - oxo - 3 - quinolinecarboxylic acid
Molecular Formula: C23H23ClFNO5C40H53N7O5S2C8H10FN3O3SC9H14N5O4P • H2O
CAS Number: 697761-98-1
Brands: Stribild

Warning(s)

  • Lactic Acidosis and Hepatomegaly with Steatosis
  • Lactic acidosis and severe hepatomegaly with steatosis, including fatalities, reported in patients receiving HIV nucleoside reverse transcriptase inhibitors (NRTIs), including tenofovir DF and emtricitabine (components of fixed combination of EVG/c/FTC/TDF), in conjunction with other antiretrovirals.1 218 221 (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

  • HBV Infection
  • Fixed combination of EVG/c/FTC/TDF not indicated for treatment of chronic HBV infection.1 Safety and efficacy of EVG/c/FTC/TDF not established in HIV-1 infected patients coinfected with HBV.1

  • Severe, acute exacerbations of HBV reported following discontinuance of emtricitabine or tenofovir DF in patients coinfected with HIV and HBV.1 218 221 Monitor hepatic function closely with both clinical and laboratory follow-up for at least several months after EVG/c/FTC/TDF discontinued in patients coinfected with HIV and HBV.1 If appropriate, initiation of HBV treatment may be warranted.1 (See HIV-infected Individuals Coinfected with HBV under Cautions.)

Introduction

Antiretroviral; fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF) (EVG/c/FTC/TDF).1 200 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 DF (TDF) are HIV nucleoside reverse transcriptase inhibitors (NRTIs).1 200

Uses for Elvitegravir and Cobicistat

Treatment of HIV Infection

Treatment of HIV-1 infection in antiretroviral-naive (have not previously received antiretroviral therapy) or antiretroviral-experienced (previously treated) adults.1 2 4 20 21 200

Fixed combination of EVG/c/FTC/TDF used alone as a complete regimen for treatment of HIV-1 infection;1 200 do not use with other antiretrovirals.1 200

For initial treatment in antiretroviral-naive adults, experts state EVG/c/FTC/TDF is a recommended INSTI-based regimen, but use only in patients with baseline estimated Clcr ≥70 mL/minute.200

For antiretroviral-experienced adults, 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).1

Postexposure Prophylaxis following Occupational Exposure to HIV

Postexposure prophylaxis of HIV infection following occupational exposure (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.199

USPHS recommends 3-drug regimen of raltegravir and emtricitabine and tenofovir DF as the preferred regimen for PEP following occupational exposures to HIV.199 EVG/c/FTC/TDF used alone is one of several alternative regimens for PEP.199

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.199 Do not delay initiation of PEP while waiting for expert consultation.199

Elvitegravir and Cobicistat Dosage and Administration

General

  • Determine estimated Clcr, urine glucose, and urine protein prior to initiation of EVG/c/FTC/TDF and routinely monitor during treatment in all patients;1 monitor serum phosphorus in those at risk for renal impairment.1 (See Renal Impairment under Cautions.)

  • Test for HBV infection prior to initiation of EVG/c/FTC/TDF.1 (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.1

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.1

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.1

Postexposure Prophylaxis following Occupational Exposure to HIV
Oral

1 tablet of EVG/c/FTC/TDF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir DF 300 mg) once daily.199

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours);199 continue for 4 weeks, if tolerated.199

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): Dosage adjustments not needed.1 200

Severe hepatic impairment (Child-Pugh class C): Do not use.1 200 (See Hepatic Impairment under Cautions.)

Renal Impairment

Estimated Clcr <70 mL/minute: Do not initiate EVG/c/FTC/TDF.1 200 (See Renal Impairment under Cautions.)

Discontinue if estimated Clcr decreases to <50 mL/minute during treatment.1 200

Geriatric Patients

Use with caution.1 (See Geriatric Use under Cautions.)

Cautions for Elvitegravir and Cobicistat

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, oral midazolam, pimozide, sildenafil used for treatment of pulmonary arterial hypertension [PAH], simvastatin, triazolam).1 (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]).1 (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

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.1 218 221 Reported mostly in women; obesity and long-term NRTI therapy also may be risk factors.1 218 221 Has been reported in patients with no known risk factors.1 218 221

Use NRTIs with caution in patients with known risk factors for liver disease.1 218 221

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).1

HIV-infected Individuals Coinfected with HBV

Test all HIV-infected patients for presence of HBV before initiating antiretroviral therapy.1 200

EVG/c/FTC/TDF not indicated for treatment of chronic HBV infection.1 Safety and efficacy of EVG/c/FTC/TDF not established in patients coinfected with HIV and HBV.1

Severe acute exacerbations of HBV reported following discontinuance of emtricitabine or tenofovir DF in HIV-infected patients with HBV infection.1 218 221 HBV exacerbations have been associated with hepatic decompensation and hepatic failure.1 218

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.1 If appropriate, initiation of HBV treatment may be warranted.1

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).1 221

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;1 15 glomerular function not affected.1 15

Determine estimated Clcr, urine glucose, and urine protein prior to and routinely monitor during EVG/c/FTC/TDF treatment in all patients.1 In addition, monitor serum phosphorus in those at risk for renal impairment.1 (See Renal Impairment under Cautions.)

Do not initiate EVG/c/FTC/TDF in patients with estimated Clcr <70 mL/minute;1 discontinue if estimated Clcr decreases to <50 mL/minute during therapy.1

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.1

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.1 (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).1 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.1 Consider alternatives to NSAIAs in patients at risk for renal dysfunction.1

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).1 221 Effects of tenofovir-associated changes in BMD on long-term bone health and future fracture risk unknown.1 221

Osteomalacia associated with proximal renal tubulopathy, which may contribute to fractures, reported in patients receiving tenofovir DF.1 221 Arthralgia and muscle pain or weakness also reported in cases of proximal renal tubulopathy.1 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.1

Consider BMD monitoring in those with history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.1 Effect of calcium and vitamin D supplementation not studied, but may be beneficial for all patients.1 If bone abnormalities suspected, obtain appropriate consultation.1

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.1 (See Contraindications and see Interactions.)

Consider potential drug interactions prior to and during therapy.1 Review drugs used concomitantly with EVG/c/FTC/TDF;1 monitor patient for adverse reactions associated with these drugs.1 (See Interactions.)

Use of Fixed Combinations

Consider cautions, precautions, and contraindications associated with each component of EVG/c/FTC/TDF.1 218 221 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.1 218 221

EVG/c/FTC/TDF is used alone as a complete regimen for treatment of HIV-1 infection;1 200 do not use in conjunction with other antiretrovirals.1 200 (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).1 In addition, do not use EVG/c/FTC/TDF concomitantly with any preparation containing lamivudine, adefovir dipivoxil, or ritonavir.1

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance.1

Mechanism and long-term consequences of fat redistribution unknown; causal relationship not established.1

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]);1 this may necessitate further evaluation and treatment.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) also reported in the setting of immune reconstitution;1 time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1

Specific Populations

Pregnancy

Category B.1

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202

Experts state safety and pharmacokinetic data specific to pregnant women insufficient to recommend routine use of EVG/c/FTC/TDF for initial treatment in antiretroviral-naive pregnant women.202

Lactation

Elvitegravir and cobicistat components of EVG/c/FTC/TDF distributed into milk in rats;1 not known whether these drugs distributed into human milk.1 Emtricitabine and tenofovir DF components of EVG/c/FTC/TDF distributed into human milk.1

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202

Pediatric Use

Safety and efficacy of EVG/c/FTC/TDF not established in pediatric patients <18 years of age.1

Experts state EVG/c/FTC/TDF can be considered for initial treatment in antiretroviral-naive HIV-infected adolescents ≥12 years of age weighing ≥35 kg if they are in late puberty (sexual maturity rating [SMR] 4 or 5); however, these experts state that the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (EVG/c/FTC/TAF) is preferred in adolescents ≥12 years of age weighing ≥35 kg.201

Geriatric Use

Insufficient experience in adults ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Hepatic Impairment

Moderate hepatic impairment (Child-Pugh class B): No clinically important effect on pharmacokinetics of elvitegravir, cobicistat, or tenofovir;1 not expected to affect emtricitabine pharmacokinetics.1

Severe hepatic impairment (Child-Pugh class C): EVG/c/FTC/TDF not recommended;1 data not available to date regarding pharmacokinetics or safety in such patients.1

Renal Impairment

Determine estimated Clcr, urine glucose, and urine protein prior to and routinely monitor during EVG/c/FTC/TDF treatment in all patients.1 Also monitor serum phosphorus in those at risk for renal impairment.1

Do not initiate EVG/c/FTC/TDF in patients with estimated Clcr <70 mL/minute.1 200

Discontinue if estimated Clcr decreases to <50 mL/minute during treatment.1 200

Common Adverse Effects

Nausea, diarrhea, abnormal dreams, headache.1

Interactions for Elvitegravir and Cobicistat

Elvitegravir: Substrate of CYP3A;1 weak inducer and weak inhibitor of CYP3A.24 Induces CYP2C9.1 Does not inhibit CYP1A, 2A6, 2C9, 2C19, 2D6, or 2E1 in vitro.24 Inhibits organic anion transport polypeptides (OATP) 1B1 and 1B3.1 24

Cobicistat: Substrate and inhibitor of CYP3A and 2D6;1 also inhibits CYP3A and 2D6.1 24 Inhibits p-glycoprotein (P-gp) transport, breast cancer resistance protein (BCRP), and OATP1B1 and 1B3.1

Emtricitabine: Not a substrate of CYP enzymes;218 does not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 3A4.218

Tenofovir DF and tenofovir: Not substrates of CYP enzymes;221 tenofovir does not inhibit CYP3A4, 2D6, 2C9, or 2E1, but may have a slight inhibitory effect on CYP1A.221

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.1

Consider potential interactions associated with each drug in the fixed combination.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A or 2D6 substrates: Potential increased plasma concentrations of such substrates.1

CYP3A inducers: Potential decreased plasma concentrations of elvitegravir and cobicistat;1 possible decreased antiretroviral efficacy and development of resistance.1

CYP3A inhibitors: Potential increased plasma concentrations of cobicistat.1

Drugs Affected by P-glycoprotein Transport

P-gp substrates: Potential increased plasma concentrations of such substrates.1

Drugs Affected by Breast Cancer Resistance Protein

BCRP substrates: Potential increased plasma concentrations of such substrates.1

Drugs Affected by Organic Anion Transport Polypeptides

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

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.1

Specific Drugs

Drug

Interaction

Comments

Alfuzosin

Possible increased alfuzosin concentrations;1 may result in hypotension1

Concomitant use contraindicated1

Aminoglycosides (e.g., gentamicin)

Competition for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the concomitant aminoglycoside;1 may increase risk of adverse effects1

Antacids, aluminum-, calcium-, or magnesium-containing

Decreased elvitegravir concentrations and AUC when administered simultaneously1 9

Give antacids at least 2 hours before or after EVG/c/FTC/TDF1 200

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

Possible increased antiarrhythmic agent concentrations1 200

Use concomitantly with caution;200 monitor antiarrhythmic agent concentrations if possible1 200

Anticoagulants (apixaban, dabigatran, rivaroxaban, ticagrelor, vorapaxar, warfarin)

Apixaban, rivaroxaban, ticagrelor, vorapaxar: Increased anticoagulant concentrations expected200

Dabigatran: Possible increased dabigatran concentrations200

Warfarin: Possible altered warfarin concentrations1 200

Apixaban, rivaroxaban, ticagrelor, vorapaxar: Avoid concomitant use with EVG/c/FTC/TDF200

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/minute200

Warfarin: Monitor INR and adjust warfarin dosage accordingly1 200

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

Carbamazepine, phenobarbital, phenytoin: Possible increased anticonvulsant concentrations;1 200 possible decreased elvitegravir and cobicistat concentrations with possible decreased antiretroviral efficacy and development of resistance1 200

Ethosuximide: Possible increased ethosuximide concentrations1

Oxcarbazepine: Possible decreased elvitegravir and cobicistat concentrations1

Carbamazepine, phenobarbital, phenytoin: Concomitant use contraindicated1

Ethosuximide: If used concomitantly with EVG/c/FTC/TDF, monitor clinically for ethosuximide-associated adverse effects1

Oxcarbazepine: Consider alternative anticonvulsant1 200

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

Possible increased tricyclic antidepressant concentrations and AUC1 200

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 concentrations1 200

Antifungals, azoles

Itraconazole: Increased itraconazole concentrations expected;1 200 possible increased elvitegravir and cobicistat concentrations1 200

Ketoconazole: Increased ketoconazole, elvitegravir, and cobicistat concentrations1

Posaconazole: Possible increased posaconazole, elvitegravir, and cobicistat concentrations200

Voriconazole: Possible increased voriconazole, elvitegravir, and cobicistat concentrations1 200

Itraconazole: Do not exceed itraconazole dosage of 200 mg daily;1 experts state use itraconazole dosage >200 mg daily only if itraconazole concentrations monitored200

Ketoconazole: Do not exceed ketoconazole dosage of 200 mg daily1

Posaconazole: Monitor posaconazole concentrations200

Voriconazole: Avoid concomitant use unless benefits outweigh risks;1 200 if used concomitantly, experts state consider monitoring voriconazole concentrations and adjust voriconazole dosage accordingly200

Antimycobacterials (rifabutin, rifampin, rifapentine)

Rifabutin: Decreased elvitegravir concentrations and AUC and increased rifabutin metabolite concentrations and AUC when used with cobicistat-boosted elvitegravir1

Rifampin: Possible decreased elvitegravir and cobicistat concentrations with possible decreased antiretroviral efficacy and development of resistance1

Rifapentine: Possible decreased elvitegravir and cobicistat concentrations with possible decreased antiretroviral efficacy and development of resistance1

Rifabutin: Concomitant use not recommended1 200

Rifampin: Concomitant use contraindicated1

Rifapentine: Concomitant use not recommended1 200

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

Perphenazine, risperidone, thioridazine: Possible increased antipsychotic agent concentrations1

Pimozide: Possible increased pimozide concentrations resulting in serious and/or life-threatening reactions (e.g., cardiac arrhythmias)1

Quetiapine: Increased quetiapine concentrations expected200

Perphenazine, risperidone, thioridazine: Decreased antipsychotic dosage may be needed;1 200 if initiated in patients receiving EVG/c/FTC/TDF, use low initial dosage of the antipsychotic200

Pimozide: Concomitant use contraindicated1

Quetiapine: Consider alternative antiretroviral;1 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;1 200 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 effects200

Avanafil

Data not available200

Concomitant use not recommended200

β-Adrenergic blocking agents (metoprolol, timolol)

Metoprolol, timolol: Possible increased β-blocking agent concentrations1

Metoprolol, timolol: Monitor clinically;1 reduced β-blocking agent dosage may be needed;1 200 consider alternative agent not metabolized by CYP isoenzymes (e.g., atenolol, labetalol, nadolol, sotalol)200

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

Midazolam or triazolam: Increased benzodiazepine concentrations;1 200 potential for serious and/or life-threatening adverse effects (e.g., prolonged or increased sedation or respiratory depression)1 200

Clonazepam, clorazepate, diazepam, estazolam, flurazepam: Possible increased benzodiazepine concentrations1

Oral midazolam or triazolam: Concomitant use contraindicated1

Parenteral midazolam: Use only in monitored setting where respiratory depression and/or prolonged sedation can be managed;1 200 consider reduced midazolam dosage, particularly if >1 dose will be used1 200

Clonazepam, clorazepate, diazepam, estazolam, flurazepam: Monitor clinically;1 reduced benzodiazepine dosage may be needed;1 if initiated in patient receiving EVG/c/FTC/TDF, use low initial dosage200

Diazepam: Consider alternative benzodiazepine (e.g., lorazepam, oxazepam, temazepam)200

Bosentan

Possible increased bosentan concentrations1

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 tolerability1 200

In patient already receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating EVG/c/FTC/TDF;1 200 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 tolerability1 200

Buprenorphine/naloxone

Increased buprenorphine and norbuprenorphine concentrations and AUCs;1 200 decreased naloxone concentrations and AUC

Monitor closely for sedation and adverse cognitive effects;1 200 dosage adjustments not needed200

Bupropion

Possible increased or decreased bupropion concentrations1 200

Carefully titrate antidepressant dosage based on clinical response1 200

Buspirone

Possible increased buspirone concentrations1

Monitor clinically;1 reduced buspirone dosage may be needed;1 200 if initiated in patient receiving EVG/c/FTC/TDF, use low initial dosage200

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

Possible increased calcium-channel blocking agent concentrations1

Use concomitantly with caution;1 200 titrate dosage of calcium-channel blocking agent;200 monitor for efficacy and adverse effects1 200

Calcium supplements

Possible decreased elvitegravir concentrations200

Administer EVG/c/FTC/TDF at least 2 hours before or 6 hours after oral calcium supplements;200 monitor for antiretroviral efficacy200

Cisapride

Possible increased cisapride concentrations;1 potential for serious and/or life-threatening reactions (e.g., cardiac arrhythmias)1

Concomitant use contraindicated1

Cobicistat

Increased elvitegravir concentrations and AUC as the result of cobicistat inhibition of CYP3A;1 200 acts as a pharmacokinetic enhancer (cobicistat-boosted elvitegravir);1 8 9 200 used to therapeutic advantage in fixed combination EVG/c/FTC/TDF1 8 9 200

Slightly increased emtricitabine concentrations and AUC and slightly increased tenofovir concentrations;8 not considered clinically important8

Does not antagonize antiretroviral effects of elvitegravir, tenofovir, or emtricitabine1

Component of fixed combination EVG/c/FTC/TDF1

Colchicine

Increased colchicine concentrations expected1 200

Patients with renal or hepatic impairment: Concomitant use not recommended1 200

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 later1 200

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 daily1 200

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)1 200

Corticosteroids (dexamethasone, fluticasone, methylprednisolone, prednisolone, triamcinolone)

Fluticasone (orally inhaled, intranasal): Increased fluticasone concentrations; may result in decreased cortisol concentrations and adrenal insufficiency, including Cushing's syndrome1 200

Methylprednisolone, prednisolone, triamcinolone (intra-articular, epidural, intraorbital, other local injections): Increased corticosteroid concentrations;200 may result in adrenal insufficiency, including Cushing's syndrome200

Dexamethasone (systemic): Possible decreased elvitegravir and cobicistat concentrations with possible decreased antiretroviral efficacy and development of resistance1 200

Fluticasone (orally inhaled, intranasal): Consider alternative corticosteroid (e.g., beclomethasone), particularly for long-term use1 200

Methylprednisolone, prednisolone, triamcinolone (intra-articular, epidural, intraorbital, other local injections): Do not use concomitantly200

Dexamethasone (systemic): Consider alternative corticosteroid;1 200 if used concomitantly, use caution and monitor virologic response200

Daclatasvir

Possible increased daclatasvir concentrations178

If used concomitantly with EVG/c/FTC/TDF, use daclatasvir dosage of 30 mg once daily178

Dasabuvir

Fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) copackaged with dasabuvir: Data not available regarding concomitant use with EVG/c/FTC/TDF200

Ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir: Concomitant use with EVG/c/FTC/TDF not recommended200

Digoxin

Possible increased digoxin concentrations

Use concomitantly with caution;200 monitor digoxin concentrations if possible1 200

Elbasvir and grazoprevir

Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): Possible increased elbasvir and grazoprevir concentrations177

Elbasvir/grazoprevir: Concomitant use not recommended177

Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)

Potential for serious and/or life-threatening adverse effects (e.g., peripheral vasospasm, ischemia of extremities)1

Concomitant use contraindicated1

Estrogens/progestins

Oral contraceptives containing ethinyl estradiol and norgestimate: Decreased ethinyl estradiol concentrations and AUC and increased norgestimate concentrations and AUC;1 7 200 possible effects of increased norgestimate unknown but may include increased risk of insulin resistance, dyslipidemia, acne, venous thrombosis1 200

Oral contraceptives containing progestin other than norgestimate: Not studied1

Other hormonal contraceptives (e.g., patch, vaginal ring, injections): Not studied1

Oral contraceptives containing ethinyl estradiol and norgestimate: Consider risks/benefits of concomitant use, particularly in women at risk of norgestimate-associated adverse effects1 200

Oral contraceptives containing progestins other than norgestimate: Consider alternative nonhormonal methods of contraception1 200

Other hormonal contraceptives (e.g., patch, vaginal ring, injections): Consider alternative nonhormonal methods of contraception1 200

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

Famotidine: No clinically important effect on elvitegravir concentrations or AUC1

Histamine H2-receptor antagonists: Clinically important interactions with EVG/c/FTC/TDF not expected1 200

Dosage adjustment not needed if EVG/c/FTC/TDF used concomitantly with a histamine H2-receptor antagonist200

HIV entry and fusion inhibitors (maraviroc)

Maraviroc: Increased maraviroc concentrations and AUC10

Do not use concomitantly with EVG/c/FTC/TDF200

HIV integrase inhibitors (INSTIs)

Dolutegravir, elvitegravir, raltegravir: Do not use concomitantly with EVG/c/FTC/TDF1 200

HIV nonnucleoside reverse transcriptase inhibitor antiretrovirals (NNRTIs)

Efavirenz, etravirine, nevirapine, rilpivirine: Possible altered elvitegravir, cobicistat, and/or NNRTI concentrations200

Efavirenz, etravirine, nevirapine, rilpivirine: Do not use concomitantly with EVG/c/FTC/TDF 1 200

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/TDF1 200

Other NRTIs (including lamivudine): Do not use concomitantly with EVG/c/FTC/TDF1 200

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 inhibitor200

Ritonavir: Has an effect on CYP3A similar to that reported with cobicistat1 200

HIV PIs (with or without low-dose ritonavir or cobicistat): Do not use concomitantly with EVG/c/FTC/TDF1 200

Ritonavir: Do not use ritonavir or any ritonavir-containing preparation concomitantly with EVG/c/FTC/TDF1

HMG-CoA reductase inhibitors (statins)

Atorvastatin, lovastatin, simvastatin: Increased concentrations of the antilipemic agent;1 200 increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis1 200

Pitavastatin, pravastatin: Data not available regarding concomitant use with EVG/c/FTC/TDF200

Rosuvastatin: Increased rosuvastatin concentrations and AUC;1 no clinically important effect on elvitegravir pharmacokinetics1

Atorvastatin: Initiate using lowest atorvastatin dosage and titrate slowly; monitor for atorvastatin-associated adverse effects1 200

Lovastatin: Concomitant use contraindicated1

Rosuvastatin: Some experts recommend slowly titrating rosuvastatin dosage;200 use lowest possible rosuvastatin dose200

Simvastatin: Concomitant use contraindicated1

Immunosuppressive agents (cyclosporine, everolimus, sirolimus, tacrolimus)

Cyclosporine, everolimus, sirolimus, tacrolimus: Possible increased immunosuppressive agent concentrations1 200

Cyclosporine, sirolimus, tacrolimus: Monitor immunosuppressive agent concentrations and associated toxicities1

Cyclosporine, everolimus, sirolimus, tacrolimus: Some experts recommend initiating immunosuppressive agent using a reduced dosage and monitoring for toxicities;200 consultation with specialist may be needed200

Iron preparations

Possible decreased elvitegravir concentrations200

Administer EVG/c/FTC/TDF at least 2 hours before or 6 hours after iron preparations;200 monitor for antiretroviral efficacy200

Laxatives containing polyvalent cations

Possible decreased elvitegravir concentrations200

Administer EVG/c/FTC/TDF at least 2 hours before or 6 hours after laxatives containing polyvalent cations;200 monitor for antiretroviral efficacy200

Ledipasvir

Fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir): Increased ledipasvir concentrations and increased tenofovir concentrations expected;1 200 safety of increased tenofovir concentrations in patients receiving ledipasvir/sofosbuvir and EVG/c/FTC/TDF not established1

Ledipasvir/sofosbuvir: Do not use concomitantly1 200

Macrolides (clarithromycin)

Clarithromycin: Possible increased clarithromycin and/or cobicistat concentrations1

Clarithromycin: Dosage modification not needed in patients with Clcr ≥60 mL/minute;1 reduce clarithromycin dosage by 50% in those with Clcr 50–60 mL/minute;1 200 do not use concomitantly with EVG/c/FTC/TDF if Clcr <50 mL/minute1 200

Methadone

Clinically important pharmacokinetic interactions not expected1 200

Dosage adjustments not needed200

Multivitamins

Possible decreased elvitegravir concentrations200

Administer EVG/c/FTC/TDF at least 2 hours before or 6 hours after multivitamins;200 monitor for antiretroviral efficacy200

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 effects1

In patients at risk for renal dysfunction, consider alternatives to NSAIAs1

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 effects1

Entecavir, famciclovir: Clinically important interaction not expected1

Ribavirin: Clinically important interaction not expected1

Adefovir: Do not use concomitantly with EVG/c/FTC/TDF1 200

Ombitasvir

Ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir: Data not available regarding concomitant use with EVG/c/FTC/TDF200

Ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir: Concomitant use with EVG/c/FTC/TDF not recommended200

Paritaprevir

Ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir: Data not available regarding concomitant use with EVG/c/FTC/TDF200

Ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir: Concomitant use with EVG/c/FTC/TDF not recommended200

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

Omeprazole: No clinically important effect on elvitegravir concentrations or AUC1

Proton-pump inhibitors: Clinically important interactions with EVG/c/FTC/TDF not expected1 200

Dosage adjustments not needed if EVG/c/FTC/TDF used concomitantly with a proton-pump inhibitor200

Salmeterol

Possible increased salmeterol concentrations;1 may increase risk of QT prolongation, palpitations, or sinus tachycardia1

Concomitant use with EVG/c/FTC/TDF not recommended1 200

Selective serotonin-reuptake inhibitors (SSRIs)

Citalopram, escitalopram, fluoxetine, paroxetine, sertraline: Possible increased SSRI concentrations1 200

Fluvoxamine: Possible increased or decreased elvitegravir concentrations200

Citalopram, escitalopram, fluoxetine, paroxetine, sertraline: Initiate SSRI using lowest dose and carefully titrate dosage based on antidepressant response1 200

Fluvoxamine: Some experts state consider alternative to fluvoxamine or alternative to EVG/c/FTC/TDF200

Sildenafil

Increased sildenafil concentrations and increased risk of sildenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1

Sildenafil for treatment of PAH: Concomitant use with EVG/c/FTC/TDF contraindicated1

Sildenafil for treatment of erectile dysfunction: Do not exceed sildenafil dosage of 25 mg once every 48 hours;1 200 closely monitor for sildenafil-related adverse effects1 200

Simeprevir

Increased simeprevir concentrations expected200

Concomitant use not recommended200

Sofosbuvir

Clinically important pharmacokinetic interactions not expected188 200

May be used concomitantly with EVG/c/FTC/TDF200

St. John’s wort (Hypericum perforatum)

Possible decreased elvitegravir and cobicistat concentrations with possible decreased antiretroviral efficacy and development of resistance1

Concomitant use contraindicated1

Suvorexant

Increased suvorexant concentrations expected200

Concomitant use with EVG/c/FTC/TDF not recommended200

Tadalafil

Increased tadalafil concentrations and increased risk of tadalafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1

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;1 200 if tolerated, increase dosage to 40 mg once daily1 200

EVG/c/FTC/TDF in patients receiving tadalafil for PAH: Discontinue tadalafil for at least 24 hours prior to initiating EVG/c/FTC/TDF;1 200 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 daily1 200

Tadalafil for treatment of erectile dysfunction: Do not exceed tadalafil dosage of 10 mg once every 72 hours;1 closely monitor for tadalafil-related adverse effects;1 some experts recommend initiating tadalafil at a dose of 5 mg200

Trazodone

Possible increased trazodone concentrations1

If trazodone initiated in patients receiving EVG/c/FTC/TDF, use lowest initial trazodone dosage and carefully titrate dosage based on response1 200

Vardenafil

Possible increased vardenafil concentrations and increased risk of vardenafil-associated adverse effects (e.g., hypotension, syncope, visual disturbances, prolonged erection)1

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 effects1

Zolpidem

Increased zolpidem concentrations expected1 200

Monitor clinically;1 reduced zolpidem dosage may be needed;1 200 if initiated in patients receiving EVG/c/FTC/TDF, use low initial zolpidem dosage200

Elvitegravir and Cobicistat Pharmacokinetics

Absorption

Bioavailability

Following an oral dose of EVG/c/FTC/TDF 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 2 hours, respectively.1

Cobicistat component of EVG/c/FTC/TDF increases plasma concentrations of elvitegravir;1 8 200 cobicistat does not have clinically important effect on pharmacokinetics of emtricitabine or tenofovir DF.8

Food

Relative to fasting, administration of EVG/c/FTC/TDF with high-fat meal (approximately 800 kcal, 50% fat) increases mean systemic exposures of elvitegravir and tenofovir by 87 and 23%, respectively, and decreases mean systemic exposures of cobicistat and emtricitabine by 17 and 4%, respectively.1 9

Distribution

Extent

Elvitegravir and cobicistat: Distributed into milk in rats;1 not known whether distributed into human milk.1

Emtricitabine and tenofovir: Distributed into human milk.1

Plasma Protein Binding

Elvitegravir: Approximately 99%.1

Cobicistat: Approximately 98%.1

Emtricitabine: <4%.1

Tenofovir: <0.7%.1

Elimination

Metabolism

Elvitegravir: Metabolized principally by CYP3A to produce inactive M1 metabolite, also undergoes glucuronidation via UGT1A1/3 to produce inactive M4 metabolite.1 9 Cobicistat, a CYP3A inhibitor, is included in fixed combination of EVG/c/FTC/TDF to inhibit metabolism of and increase plasma concentrations of elvitegravir.1 8 200

Cobicistat: Metabolized principally by CYP3A and, to a lesser extent, by CYP2D6.1 Does not undergo glucuronidation.1

Emtricitabine: Undergoes oxidation and conjugation with glucuronic acid.1 Phosphorylated intracellularly and converted by cellular enzymes to the active emtricitabine 5′-triphosphate.1

Tenofovir DF: Prodrug of tenofovir;1 undergoes initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylation by cellular enzymes to form the active tenofovir diphosphate.1

Elimination Route

Elvitegravir: 94.8% in feces, 6.7% in urine.1 Unlikely to be removed by hemodialysis or peritoneal dialysis.1

Cobicistat: 86.2% in feces, 8.2% in urine.1 Unlikely to be removed by hemodialysis or peritoneal dialysis.1

Emtricitabine: 70% in urine (glomerular filtration and active tubular secretion), 13.7% in feces.1 Removed by hemodialysis;1 not known whether removed by peritoneal dialysis.1

Tenofovir: 70–80% in urine (glomerular filtration and active tubular secretion).1 Removed by hemodialysis.1

Half-life

Elvitegravir: 12.9 hours.1

Cobicistat: 3.5 hours.1

Emtricitabine: 10 hours.1

Tenofovir: 12–18 hours.1

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B): No clinically important effect on pharmacokinetics of elvitegravir or cobicistat.1 Pharmacokinetics of emtricitabine and tenofovir unlikely to be affected.1

Severe hepatic impairment (Child-Pugh class C): Pharmacokinetics of EVG/c/FTC/TDF not studied.1

Renal impairment: No clinically important effects on pharmacokinetics of elvitegravir or cobicistat.1 Pharmacokinetics of emtricitabine and tenofovir altered (decreased clearance resulting in increased plasma concentrations and AUC).1 218 221

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Store in original container; keep tightly closed.1

Actions and Spectrum

  • EVG/c/FTC/TDF is a fixed-combination antiretroviral containing elvitegravir, cobicistat, emtricitabine, and tenofovir DF.1

  • Elvitegravir (EVG) is an HIV integrase strand transfer inhibitor antiretroviral.1 9 12 200 Inhibits activity of HIV-1 integrase, an enzyme that integrates HIV DNA into the host cell genome.1 9 12 Active against HIV-1 and also has some in vitro activity against HIV type 2 (HIV-2);1 inactive against HBV and HCV.1

  • Cobicistat is a mechanism-based CYP3A inhibitor and is included in EVG/c/FTC/TDF as a pharmacokinetic enhancer to decrease elvitegravir metabolism and increase plasma concentrations of the drug, resulting in trough concentrations of elvitegravir sufficient to allow for once-daily dosing (cobicistat-boosted elvitegravir).1 8 9 200 Has no antiretroviral or antiviral activity and is not active against HIV-1, HBV, or HCV.1 Does not antagonize the antiretroviral activity of elvitegravir, emtricitabine, or tenofovir.1

  • Emtricitabine (FTC) is an HIV NRTI.1 218 Prodrug that is inactive until converted intracellularly to an active 5′-triphosphate metabolite.1 218 Active against HIV-1 and also has some in vitro activity against HIV-2.1 218

  • Tenofovir DF (TDF) is a nucleotide reverse transcriptase inhibitor antiretroviral classified as an HIV NRTI.1 Prodrug that is inactive until it undergoes diester hydrolysis in vivo to tenofovir and is subsequently metabolized to the active metabolite (tenofovir diphosphate).1 221 Active against HIV-1 and also has some in vitro activity against HIV-2;1 221 also active against HBV.221

  • HIV-1 resistant to elvitegravir, emtricitabine, and tenofovir have been produced in vitro and have emerged during EVG/c/FTC/TDF therapy.1 12 13 17 18 19 One or more primary mutations associated with resistance to elvitegravir, emtricitabine, and/or tenofovir have been identified in HIV-1 isolates from patients who received EVG/c/FTC/TDF and were considered to be virologic treatment failures.1 17

  • Cross-resistance between elvitegravir and other HIV integrase inhibitors (e.g., dolutegravir, raltegravir) reported.1 11 12 13 16 18 22 23 Cross-resistance also occurs among the HIV NRTIs.1

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1

  • Antiretroviral therapy is not a cure for HIV infection;1 opportunistic infections and other complications associated with HIV disease may still occur.1

  • Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency syndrome (AIDS) and death.1

  • 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.200 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.1 200

  • Importance of reading patient information provided by the manufacturer.1

  • Advise patients that the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/c/FTC/TDF) is a complete regimen for treatment of HIV-1 infection and should not be used in conjunction with other antiretroviral agents.1

  • Importance of taking EVG/c/FTC/TDF with food.1

  • If a dose is missed, take the dose as soon as it is remembered and take next dose at regularly scheduled time.1 If a dose is skipped, do not take a double dose to make up for the missed dose.1

  • Advise patients that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have occurred with emtricitabine and tenofovir DF (components of EVG/c/FTC/TDF).1 Importance of contacting clinician if symptoms suggestive of lactic acidosis or hepatotoxicity (e.g., nausea, vomiting, unusual/unexpected stomach discomfort, weakness) occur.1

  • Inform patients that testing for HBV infection recommended before antiretroviral therapy initiated.1 Also advise patients that severe acute exacerbations of HBV infection have been reported following discontinuance of emtricitabine or tenofovir DF in HIV-infected patients coinfected with HBV.1

  • Advise patients that renal impairment, including cases of acute renal failure or Fanconi syndrome, has occurred.1 Importance of not using EVG/c/FTC/TDF concomitantly with or shortly after nephrotoxic agents (e.g., high-dose or multiple NSAIAs).1

  • Advise patients that decreased bone mineral density (BMD) has occurred and that assessment of BMD should be considered in those with a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.1

  • Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy;1 cause and long-term health effects unknown.1

  • 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).1 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.1 Importance of immediately informing a healthcare provider if any symptoms of infection occur.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products (e.g., St. John's wort), as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise HIV-infected women not to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 (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 Disoproxil Fumarate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

Elvitegravir 150 mg, Cobicistat 150 mg, Emtricitabine 200 mg, and Tenofovir Disoproxil Fumarate 300 mg

Stribild

Gilead

AHFS DI Essentials. © Copyright 2016, Selected Revisions August 29, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Gilead Sciences. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2016 Feb.

2. Sax PE, DeJesus E, Mills A et al. EVG/c/FTC/TDF, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012; 379:2439-48. [PubMed 22748591]

3. Zolopa A, Sax PE, Dejesus E et al. A Randomized Double-Blind Comparison of Coformulated Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate Versus Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate for Initial Treatment of HIV-1 Infection: Analysis of Week 96 Results. J Acquir Immune Defic Syndr. 2013; 63:96-100. [PubMed 23392460]

4. DeJesus E, Rockstroh JK, Henry K et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet. 2012; 379:2429-38. [PubMed 22748590]

5. Rockstroh JK, Dejesus E, Henry K et al. A randomized, double-blind comparison of co-formulated elvitegravir/cobicistat/emtricitabine/tenofovir versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr. 2013; :483–6.

6. Ramanathan S, Kakuda TN, Mack R et al. Pharmacokinetics of elvitegravir and etravirine following coadministration of ritonavir-boosted elvitegravir and etravirine. Antivir Ther. 2008; 13:1011-7. [PubMed 19195326]

7. Tseng A, Hills-Nieminen C. Drug interactions between antiretrovirals and hormonal contraceptives. Expert Opin Drug Metab Toxicol. 2013; 9:559-72. [PubMed 23425052]

8. German P, Warren D, West S et al. Pharmacokinetics and bioavailability of an integrase and novel pharmacoenhancer-containing single-tablet fixed-dose combination regimen for the treatment of HIV. J Acquir Immune Defic Syndr. 2010; 55:323-9. [PubMed 20683270]

9. Ramanathan S, Mathias AA, German P et al. Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin Pharmacokinet. 2011; 50:229-44. [PubMed 21348537]

10. Ramanathan S, Abel S, Tweedy S et al. Pharmacokinetic interaction of ritonavir-boosted elvitegravir and maraviroc. J Acquir Immune Defic Syndr. 2010; 53:209-14. [PubMed 19851115]

11. Marinello J, Marchand C, Mott BT et al. Comparison of raltegravir and elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants. Biochemistry. 2008; 47:9345-54. [PubMed 18702518]

12. Lampiris HW. Elvitegravir: a once-daily, boosted, HIV-1 integrase inhibitor. Expert Rev Anti Infect Ther. 2012; 10:13-20. [PubMed 22149610]

13. Blanco JL, Varghese V, Rhee SY et al. HIV-1 integrase inhibitor resistance and its clinical implications. J Infect Dis. 2011; 203:1204-14. [PubMed 21459813]

14. Mathias AA, German P, Murray BP et al. Pharmacokinetics and pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity. Clin Pharmacol Ther. 2010; 87:322-9. [PubMed 20043009]

15. German P, Liu HC, Szwarcberg J et al. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. J Acquir Immune Defic Syndr. 2012; 61:32-40. [PubMed 22732469]

16. Garrido C, Villacian J, Zahonero N et al. Broad phenotypic cross-resistance to elvitegravir in HIV-infected patients failing on raltegravir-containing regimens. Antimicrob Agents Chemother. 2012; 56:2873-8. [PubMed 22450969]

17. Hatano H, Lampiris H, Fransen S et al. Evolution of integrase resistance during failure of integrase inhibitor-based antiretroviral therapy. J Acquir Immune Defic Syndr. 2010; 54:389-93. [PubMed 20300008]

18. Goethals O, Clayton R, Van Ginderen M et al. Resistance mutations in human immunodeficiency virus type 1 integrase selected with elvitegravir confer reduced susceptibility to a wide range of integrase inhibitors. J Virol. 2008; 82:10366-74. [PubMed 18715920]

19. Kobayashi M, Nakahara K, Seki T et al. Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants. Antiviral Res. 2008; 80:213-22. [PubMed 18625269]

20. Arribas JR, Pialoux G, Gathe J et al. Simplification to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial. Lancet Infect Dis. 2014; 14:581-9. [PubMed 24908551]

21. Pozniak A, Markowitz M, Mills A et al. Switching to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults with HIV (STRATEGY-NNRTI): 48 week results of a randomised, open-label, phase 3b non-inferiority trial. Lancet Infect Dis. 2014; 14:590-9. [PubMed 24908550]

22. Malet I, Thierry E, Wirden M et al. Combination of two pathways involved in raltegravir resistance confers dolutegravir resistance. J Antimicrob Chemother. 2015; 70:2870-80. [PubMed 26205139]

23. Malet I, Gimferrer Arriaga L, Artese A et al. New raltegravir resistance pathways induce broad cross-resistance to all currently used integrase inhibitors. J Antimicrob Chemother. 2014; 69:2118-22. [PubMed 24710029]

24. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203093Orig1s000. Clinical pharmacology and biopharmaceutics review(s). From FDA website.

177. Merck & Co., Inc. Zepatier (elbasvir and grazoprevir) tablets prescribing information. Whitehouse Station, NJ; 2016 Jan.

178. Bristol-Myers Squibb. Daklinza (daclatasvir) tablets prescribing information. Princeton, NJ. 2016 Apr.

188. Gilead Sciences. Sovaldi (sofosbuvir) tablet prescribing information. Foster City, CA; 2015 Aug.

199. Kuhar DT, Henderson DK, Struble KA et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol. 2013; 34:875-92. [PubMed 23917901]

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (January 28, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website.

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (March 1, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website.

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (August 6, 2015). Updates may be available at HHS AIDS Information (AIDSinfo) website.

218. Gilead Sciences. Emtriva (emtricitabine) capsules and oral solution prescribing information. Foster City, CA; 2012 Nov.

221. Gilead Sciences. Viread (tenofovir disoproxil fumarate) tablets and powder for oral use prescribing information. Foster City, CA; 2016 Feb.

Hide