Stribild

Pronunciation

Generic Name: Elvitegravir and Cobicistat
Class: Integrase Inhibitors
ATC Class: J05AX08
Chemical Name: 6 - [(3 - Chloro - 2 - fluorophenyl)methyl] - 1,4 - dihydro - 1 - [(1S) - 1 - (hydroxymethyl) - 2 - methylpropyl] - 7 - methoxy - 4 - oxo - 3 - quinolinecarboxylic acid
Molecular Formula: C23H23ClFNO5C40H53N7O5S2
CAS Number: 697761-98-1

Warning(s)

  • Lactic Acidosis and Hepatomegaly with Steatosis
  • Lactic acidosis and severe hepatomegaly with steatosis, including fatalities, reported in patients receiving NRTIs, including tenofovir and emtricitabine (components of fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate [EVG/COBI/TDF/FTC]).1 218 221 (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

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

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

Introduction

Antiretroviral; elvitegravir and cobicistat available only as fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/COBI/TDF/FTC).1 200 Elvitegravir (EVG) is an HIV integrase inhibitor antiretroviral; cobicistat (COBI) is a potent inhibitor of CYP3A that decreases metabolism and increases plasma concentrations of EVG; tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are nucleoside reverse transcriptase inhibitor (NRTI) antiretrovirals.1 200

Uses for Stribild

Treatment of HIV Infection

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

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

For initial treatment in HIV-infected adults and adolescents, EVG/COBI/TDF/FTC is an alternative (not a preferred) regimen.200

Stribild Dosage and Administration

Administration

Oral Administration

Administer fixed combination of EVG/COBI/TDF/FTC orally with food.1 (See Food under Pharmacokinetics.)

Dosage

Dosage of EVG/COBI/TDF/FTC expressed as number of tablets.1 Each tablet contains elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg.1

Adults

Treatment of HIV Infection
Oral

EVG/COBI/TDF/FTC: 1 tablet once daily.1

Special Populations

Hepatic Impairment

Dosage adjustment not necessary in patients with mild to moderate hepatic impairment (Child-Pugh Class A or B);1 200 do not use in patients with severe hepatic impairment (Child-Pugh Class C).1 200 (See Hepatic Impairment under Cautions.)

Renal Impairment

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

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

Cautions for Stribild

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., 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 tenofovir and emtricitabine (components of EVG/COBI/TDF/FTC), 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/COBI/TDF/FTC 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

Individuals with HBV Infection

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

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

Severe acute exacerbations of HBV reported following discontinuance of tenofovir or emtricitabine 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/COBI/TDF/FTC 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, a component of EVG/COBI/TDF/FTC.1 221

Cobicistat, a component of EVG/COBI/TDF/FTC, may cause modest increase in Scr and decrease in estimated Clcr due to inhibition of tubular secretion of creatinine; glomerular function not affected.1 15

Determine estimated Clcr, urine glucose, and urine protein prior to initiating EVG/COBI/TDF/FTC and monitor regularly during therapy.1 In addition, monitor serum phosphorous in patients at risk for renal impairment.1

Do not initiate EVG/COBI/TDF/FTC in patients with estimated Clcr <70 mL/minute; 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/COBI/TDF/FTC treatment, closely monitor for renal toxicity.1

Avoid EVG/COBI/TDF/FTC in patients who are receiving or have recently received a nephrotoxic drug.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, a component of EVG/COBI/TDF/FTC.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, also reported in patients receiving tenofovir.1 221

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

Use of Fixed Combinations

EVG/COBI/TDF/FTC used as a complete regimen for treatment of HIV-1 infection; do not use in conjunction with other antiretrovirals.1 200 (See Specific Drugs under Interactions.)

Do not use EVG/COBI/TDF/FTC concomitantly with any preparation that contains any of its active components (elvitegravir, cobicistat, emtricitabine, tenofovir).1 In addition, do not use EVG/COBI/TDF/FTC concomitantly with any preparation containing lamivudine or adefovir dipivoxil.1

Consider cautions, precautions, and contraindications associated with each component of EVG/COBI/TDF/FTC.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

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

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 jiroveci [formerly P. carinii]); this may necessitate further evaluation and treatment.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution; 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

Lactation

Elvitegravir and cobicistat distributed into milk in rats; not known whether these drugs distributed into human milk.1 Tenofovir and emtricitabine components of EVG/COBI/TDF/FTC are 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/COBI/TDF/FTC not established in pediatric patients <18 years of age.1

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) does not have a clinically important effect on pharmacokinetics of elvitegravir, cobicistat, or tenofovir and is not expected to affect pharmacokinetics of emtricitabine.1

Data not available to date regarding pharmacokinetics or safety of EVG/COBI/TDF/FTC in patients with severe hepatic impairment (Child-Pugh Class C);1 not recommended in such patients.1

Renal Impairment

Do not initiate EVG/COBI/TDF/FTC 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.1

Interactions for Stribild

Elvitegravir is metabolized by CYP3A and induces CYP2C9.1 9 Elvitegravir does not induce CYP1A2 and does not inhibit CYP1A, 2A6, 2C9, 2C19, 2D6, or 2E1 in vitro.9

Cobicistat is metabolized by and is an inhibitor of CYP3A and 2D6.1 Cobicistat also is an inhibitor of p-glycoprotein transport, organic anion transport polypeptides (OATP) 1B1 and 1B3, and breast cancer resistance protein (BCRP).1

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/COBI/TDF/FTC 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

Potential pharmacokinetic interactions when EVG/COBI/TDF/FTC used concomitantly with drugs that are primarily metabolized by CYP3A or 2D6 (increased concentrations of the concomitant drug).1

Potential pharmacokinetic interactions when EVG/COBI/TDF/FTC used concomitantly with drugs that induce CYP3A (decreased concentrations of elvitegravir and/or cobicistat); possible decreased antiretroviral efficacy and development of resistance.1

Potential pharmacokinetic interactions when EVG/COBI/TDF/FTC used concomitantly with drugs that inhibit CYP3A (increased concentrations of cobicistat).1

Drugs Affected by P-glycoprotein Transport

Potential pharmacokinetic interactions when EVG/COBI/TDF/FTC used concomitantly with drugs that are substrates for P-glycoprotein transport (increased concentrations of the concomitant drug).1 200

Drugs Affected by Organic Anion Transport Polypeptides

Potential pharmacokinetic interactions when EVG/COBI/TDF/FTC used concomitantly with drugs that are substrates for OATP1B1 or 1B3 (increased concentrations of the concomitant drug).1

Drugs Transported by Breast Cancer Resistance Protein

Potential pharmacokinetic interaction when EVG/COBI/TDF/FTC used concomitantly with drugs that are substrates for BCRP transport (increased concentrations of the concomitant drug).1

Drugs Affecting Renal Function

Tenofovir and emtricitabine, components of EVG/COBI/TDF/FTC, are primarily excreted renally by a combination of glomerular filtration and active tubular secretion.1

Potential interactions when EVG/COBI/TDF/FTC used concomitantly with drugs that reduce renal function or compete for active tubular secretion (increased concentrations of tenofovir, emtricitabine, and/or concomitant drug).1

Specific Drugs

Drug

Interaction

Comments

Alfuzosin

Possible increased alfuzosin concentrations; may result in hypotension1

Concomitant use contraindicated1 200

Antacids, aluminum- or magnesium-containing

Decreased elvitegravir concentrations and AUC when administered simultaneously1 9

Give antacids and EVG/COBI/TDF/FTC at least 2 hours apart1 200

Antiarrhythmic agents (amiodarone, digoxin, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine)

Possible increased concentrations of the antiarrhythmic agent1

Use concomitantly with caution;1 200 monitor antiarrhythmic agent concentrations if possible1 200

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

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

Ethosuximide: Possible increased ethosuximide concentrations1

Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Consider alternative anticonvulsant1 200

Ethosuximide: Monitor clinically for ethosuximide-associated adverse effects1 200

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

Possible increased concentrations and AUC of the tricyclic antidepressant1 200

Use lowest initial antidepressant dosage; carefully titrate dosage according to response1 200

Antifungal agents, azoles

Itraconazole: Possible increased concentrations of itraconazole, elvitegravir, and/or cobicistat1

Ketoconazole: Increased concentrations of ketoconazole, elvitegravir, and/or cobicistat1

Posaconazole: Possible increased concentrations of posaconazole, elvitegravir, and/or cobicistat200

Voriconazole: Possible increased concentrations of voriconazole, elvitegravir, and/or cobicistat1 200

Itraconazole: High itraconazole dosage (>200 mg daily) not recommended;1 consider monitoring itraconazole concentrations;200 use itraconazole dosage >200 mg daily only if itraconazole concentrations monitored200

Ketoconazole: High ketoconazole dosage (>200 mg daily) not recommended1

Posaconazole: Monitor posaconazole concentrations200

Voriconazole: Avoid concomitant use unless benefits outweigh risks;1 if used concomitantly, 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/or cobicistat concentrations with possible decreased antiretroviral efficacy and development of resistance1

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

Rifabutin: Concomitant use not recommended1 200

Rifampin: Concomitant use contraindicated1 200

Rifapentine: Concomitant use not recommended1 200

Antipsychotic agents (perphenazine, pimozide, risperidone, 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

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

PImozide: Concomitant use contraindicated1 200

Avanafil

No data to date200

Concomitant use not recommended200

β-Adrenergic blocking agents (metoprolol, timolol)

Metoprolol, timolol: Possible increased β-blocking agent concentrations1

Metoprolol, timolol: Monitor clinically;1 decreased β-blocking agent dosage may be necessary;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; 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 200

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 necessary;1 if initiated in patient receiving EVG/COBI/TDF/FTC, use low initial dosage200

Diazepam: Consider alternative benzodiazepine with less potential for interaction (e.g., lorazepam, oxazepam, temazepam)200

Boceprevir

No data to date200

Concomitant use not recommended200

Bosentan

Possible increased bosentan concentrations1

In patient already receiving EVG/COBI/TDF/FTC 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/COBI/TDF/FTC; after ≥10 days of EVG/COBI/TDF/FTC, resume bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability1 200

Buprenorphine

Increased buprenorphine and norbuprenorphine concentrations and AUCs200

Monitor clinically; dosage adjustments not necessary200

Bupropion

Possible increased bupropion concentrations1

Carefully titrate antidepressant dosage while monitoring response1

Buspirone

Possible increased buspirone concentrations1

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

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

Possible increased concentrations of the calcium-channel blocking agent1

Use concomitantly with caution; monitor for toxicity1 200

Cisapride

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

Concomitant use contraindicated1

Cobicistat

Increased elvitegravir concentrations and AUC;1 200 used to therapeutic advantage in fixed combination EVG/COBI/TDF/FTC;1 8 9 200 acts as a pharmacologic enhancer (cobicistat-boosted elvitegravir)1 8 9 200

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

No in vitro evidence of antagonistic antiretroviral effects with elvitegravir, tenofovir, or emtricitabine1

Component of fixed combination EVG/COBI/TDF/FTC1

Colchicine

Possible increased colchicine concentrations1

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

Colchicine for treatment of gout flares: In those receiving EVG/COBI/TDF/FTC, 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/COBI/TDF/FTC, 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/COBI/TDF/FTC, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)1 200

Corticosteroids (dexamethasone, fluticasone)

Fluticasone nasal spray/oral inhalation: Increased fluticasone concentrations; may result in decreased cortisol concentrations1

Systemic dexamethasone: Possible decreased elvitegravir and/or cobicistat concentrations with possible decreased antiretroviral efficacy and development of resistance1

Fluticasone nasal spray/oral inhalation: Consider alternative corticosteroid, particularly for long-term use1 200

Systemic dexamethasone: Use concomitantly with caution;200 monitor virologic response200

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 200

Estrogens/Progestins

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

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

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 (famotidine)

Famotidine: No clinically important effect on elvitegravir concentrations or AUC1

Dosage adjustment not needed if EVG/COBI/TDF/FTC used concomitantly with a histamine H2-receptor antagonist1 200

HIV entry and fusion inhibitors (enfuvirtide, maraviroc)

Maraviroc: Increased maraviroc concentrations and AUC10 200

Enfuvirtide, maraviroc: No in vitro evidence of antagonistic antiretroviral effects1

Enfuvirtide, maraviroc: Do not use concomitantly with EVG/COBI/TDF/FTC1 200

HIV integrase inhibitors (raltegravir)

Raltegravir: No in vitro evidence of antagonistic antiretroviral effects1

Raltegravir: Do not use concomitantly with EVG/COBI/TDF/FTC1 200

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

Possible altered/suboptimal concentrations of elvitegravir, cobicistat, and/or the HIV protease inhibitor1

Atazanavir, darunavir, amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir: No in vitro evidence of antagonistic antiretroviral effects1

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

HIV protease inhibitors: Do not use concomitantly with EVG/COBI/TDF/FTC1 200

Ritonavir: Do not use ritonavir or any ritonavir-containing preparation concomitantly with EVG/COBI/TDF/FTC1

HMG-CoA reductase inhibitors (statins)

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

Rosuvastatin: Increased rosuvastatin concentrations and AUC;1 not considered clinically important1

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

Lovastatin: Concomitant use contraindicated1 200

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

Simvastatin: Concomitant use contraindicated1 200

Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)

Cyclosporine, sirolimus, tacrolimus: Potential for increased immunosuppressive agent concentrations1

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

Some experts recommend initial adjustment of immunosuppressive agent dosage;200 consultation with specialist may be necessary200

Macrolides (clarithromycin, telithromycin)

Clarithromycin: Possible increased clarithromycin and/or cobicistat concentrations1

Telithromycin: Possible increased telithromycin and/or cobicistat concentrations1

Clarithromycin: In patients with renal impairment, reduce clarithromycin dosage by 50% if Clcr 50–60 mL/minute;1 200 do not use EVG/COBI/TDF/FTC if Clcr <50 mL/minute1 200

Methadone

No clinically important pharmacokinetic interaction200

Dosage adjustments not necessary200

Nonnucleoside reverse transcriptase inhibitor antiretrovirals (NNRTIs)

Possible altered/suboptimal elvitegravir, cobicistat, and/or NNRTI concentrations1

Efavirenz, etravirine, nevirapine: No in vitro evidence of antagonistic antiretroviral effects1

NRTIs: Do not use concomitantly with EVG/COBI/TDF/FTC 1 200

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 tenofovir, emtricitabine, and/or the concomitant antiviral1

Entecavir, famciclovir: Clinically important interaction not expected1

Ribavirin: Clinically important interaction not expected1

Adefovir: Do not use concomitantly with EVG/COBI/TDF/FTC1 200

Nucleoside and nucleotide reverse transcriptase inhibitor antiretrovirals (NRTIs)

Abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine: No in vitro evidence of antagonistic antiretroviral effects1

Emtricitabine and tenofovir: Components of EVG/COBI/TDF/FTC; do not use any preparation containing emtricitabine or tenofovir concomitantly with EVG/COBI/TDF/FTC1 200

Other NRTIs (including lamivudine): Do not use concomitantly with EVG/COBI/TDF/FTC1 200

Proton-pump inhibitors (omeprazole)

Omeprazole: No clinically important effect on elvitegravir concentrations or AUC1

Dosage adjustments not necessary if EVG/COBI/TDF/FTC used concomitantly with a proton-pump inhibitor1 200

Salmeterol

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

Concomitant use not recommended1 200

Selective serotonin-reuptake inhibitors (SSRIs)

Possible increased SSRI concentrations1

Use lowest initial SSRI dosage; carefully titrate dosage according to response1 200

Sildenafil

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

Sildenafil (Revatio) for treatment of PAH: Concomitant use with EVG/COBI/TDF/FTC contraindicated;1 safe and effective dosage for concomitant use not established1

Sildenafil for treatment of erectile dysfunction: Initiate using sildenafil dosage of 25 mg once every 48 hours;1 200 closely monitor for sildenafil-related adverse effects1 200

St. John’s wort (Hypericum perforatum)

Possible decreased elvitegravir and/or cobicistat concentrations; possible decreased antiretroviral efficacy and development of resistance1

Concomitant use contraindicated1 200

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/COBI/TDF/FTC for ≥1 week: Use initial tadalafil dosage of 20 mg once daily; if tolerated, increase dosage to 40 mg once daily1 200

EVG/COBI/TDF/FTC in patients receiving tadalafil for PAH: Discontinue tadalafil for at least 24 hours prior to initiating EVG/COBI/TDF/FTC; 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; closely monitor for tadalafil-related adverse effects;1 some experts recommend initiating tadalafil at a dose of 5 mg200

Telaprevir

No data to date200

Concomitant use not recommended200

Trazodone

Possible increased trazodone concentrations1

Use lowest initial trazodone dosage; carefully titrate dosage according to 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

Warfarin

Possible altered warfarin concentrations1

Monitor INR and adjust warfarin dosage accordingly1 200

Zolpidem

Possible increased zolpidem concentrations1

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

Stribild Pharmacokinetics

Absorption

Bioavailability

Elvitegravir and cobicistat administered as fixed combination containing elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/COBI/TDF/FTC).1 Cobicistat component increases plasma concentrations of elvitegravir,1 8 200 but does not have clinically important effect on pharmacokinetics of emtricitabine or tenofovir disoproxil fumarate.8

Following an oral dose of EVG/COBI/TDF/FTC 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

Food

Relative to fasting, administration of EVG/COBI/TDF/FTC with a light or high-fat meal increases mean systemic exposure of elvitegravir by 34 and 87%, respectively.1 9

Tenofovir exposure also increased about 24% when EVG/COBI/TDF/FTC administered with food;1 mean systemic exposures of cobicistat and emtricitabine not affected by administration with food.1

Distribution

Extent

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

Plasma Protein Binding

Elvitegravir: 98-99%,1 preferentially to albumin over α1-acid glycoprotein.9 Blood-to-plasma ratio is 0.73.1

Cobicistat: 97-98%.1 Blood-to-plasma ratio is 0.5.1

Elimination

Metabolism

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

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

Elimination Route

Elvitegravir: 94.8% in feces, 6.7% in urine.1

Cobicistat: 86.2% in feces, 8.2% in urine.1

Half-life

Elvitegravir: Approximately 12.9 hours when administered as EVG/COBI/TDF/FTC.1

Cobicistat: Approximately 3.5 hours when administered as EVG/COBI/TDF/FTC.1

Special Populations

Mild to moderate hepatic impairment: No clinically important effect on pharmacokinetics of elvitegravir or cobicistat.1

Severe hepatic impairment: Pharmacokinetics not studied.1

Severe renal impairment: No clinically important effect on pharmacokinetics of elvitegravir or cobicistat.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Store in original container; keep tightly closed.1

Actions

  • Elvitegravir and cobicistat only available as fixed-combination antiretroviral containing elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/COBI/TDF/FTC).1

  • Elvitegravir is an HIV integrase strand transfer inhibitor antiretroviral.1 9 12 200 It inhibits activity of HIV-1 integrase, an enzyme that integrates HIV DNA into the host cell genome.1 9 12 Elvitegravir also has some activity against HIV type 2 (HIV-2),1 but is inactive against HBV or HCV.1

  • Cobicistat is a potent inhibitor of CYP3A and is included in EVG/COBI/TDF/FTC as a pharmacologic 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 Cobicistat has no antiretroviral or antiviral activity and is not active against HIV-1, HBV, or HCV.1 Cobicistat does not antagonize the antiretroviral activity of elvitegravir, emtricitabine, or tenofovir.1

  • EVG/COBI/TDF/FTC also contains emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF).1 200 Both drugs are NRTI antiretrovirals.200 218 221 Cobicistat does not have a clinically important effect on the pharmacokinetics of emtricitabine or tenofovir.8

  • HIV-1 resistant to elvitegravir have been produced in vitro and have emerged during EVG/COBI/TDF/FTC 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/COBI/TDF/FTC and were considered to be virologic treatment failures.1 17

  • Cross-resistance between elvitegravir and other HIV integrase inhibitors (e.g., raltegravir) has been reported.1 11 12 13 16 18

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 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 disoproxil fumarate (EVG/COBI/TDF/FTC) is a complete regimen for the treatment of HIV-1 infection and should not be used in conjunction with other antiretroviral agents.1

  • Importance of taking EVG/COBI/TDF/FTC 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 (components of EVG/COBI/TDF/FTC).1 Importance of contacting clinician if symptoms suggestive of lactic acidosis or hepatotoxicity (e.g., nausea, vomiting, unusual/unexpected stomach discomfort, weakness) occur.1

  • Advise patients that renal impairment, including cases of acute renal failure or Fanconi syndrome, has occurred.1 Importance of not using concomitantly with or shortly after nephrotoxic agents.1

  • Advise patients that decreased bone mineral density (BMD) has occurred.1

  • Redistribution/accumulation of body fat may occur with antiretroviral therapy, with as yet unknown long-term health effects.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.

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, 2004-2014, Selected Revisions October 22, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Gilead Sciences. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2012 Aug.

2. Sax PE, DeJesus E, Mills A et al. EVG/COBI/TDF/FTC, 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]

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 (February 12, 2013). 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 (July 31, 2012). 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; 2012 Nov.

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