Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide
Name: Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide
- Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide 200 mg
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Uses for Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide
Treatment of HIV Infection
Treatment of HIV-1 infection in antiretroviral-naive (have not previously received antiretroviral therapy) or antiretroviral-experienced (previously treated) adults and adolescents ≥12 years of age.1 2 3 4 5 200 201
Fixed combination of EVG/c/FTC/TAF 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/TAF is a recommended INSTI-based regimen, but use only in patients with baseline estimated Clcr ≥30 mL/minute.200
For initial treatment in HIV-infected children and adolescents, experts state that EVG/c/FTC/TAF is a preferred HIV INSTI-based regimen in adolescents ≥12 years of age weighing ≥35 kg, including adolescents in early puberty (sexual maturity rating [SMR] 1–3), but use only in patients with baseline estimated Clcr ≥30 mL/minute.201
For antiretroviral-experienced adults, manufacturer states EVG/c/FTC/TAF can be used to replace the current antiretroviral regimen in those with plasma HIV-1 RNA levels <50 copies/mL on a stable antiretroviral regimen for ≥6 months who have no history of treatment failure and are infected with HIV-1 with no known substitutions associated with resistance to the antiretroviral components of the fixed combination (i.e., elvitegravir, emtricitabine, tenofovir).1
Interactions for Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide
Elvitegravir: Substrate of CYP3A;1 24 25 weak inducer and weak inhibitor of CYP3A.24 25 Induces CYP2C9.1 Does not inhibit CYP1A, 2A6, 2C9, 2C19, 2D6, or 2E1.24 Inhibits organic anion transport polypeptides (OATP)1B1 and 1B3.1 24
Cobicistat: Substrate and inhibitor of CYP3A and 2D6.1 24 25 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 alafenamide: Weak inhibitor of CYP3A;1 25 does not induce or inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6.1 25 Substrate of P-gp, BCRP, and OATP1B1 and 1B3.1 25
The following interactions are based on studies using elvitegravir, elvitegravir administered with cobicistat (cobicistat-boosted elvitegravir), elvitegravir administered with low-dose ritonavir (ritonavir-boosted elvitegravir), cobicistat, or EVG/c/FTC/TAF or are predicted to occur.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, cobicistat, and/or tenofovir alafenamide;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 concentrations of such substrates.1
P-gp inhibitors: Potential increased tenofovir alafenamide concentrations.1 Cobicistat (a P-gp inhibitor) increases tenofovir alafenamide plasma concentrations when the drugs administered as EVG/c/FTC/TAF;1 further increases not expected if an additional P-gp inhibitor used with EVG/c/FTC/TAF.1
P-gp inducers: Decreased absorption and decreased plasma concentrations of tenofovir alafenamide expected.1
Drugs Affected by Breast Cancer Resistance Protein
BCRP substrates: Potential increased concentrations of such substrates.1
BCRP inhibitors: Potential increased tenofovir alafenamide concentrations.1 Cobicistat (a BCRP inhibitor) increases tenofovir alafenamide plasma concentrations when the drugs administered as EVG/c/FTC/TAF;1 further increases not expected if an additional BCRP inhibitor used with EVG/c/FTC/TAF.1
Drugs Affected by Organic Anion Transport Polypeptides
OATP1B1 or 1B3 substrates: Potential increased 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 aminoglycoside;1 may increase risk of adverse effects1 | |
| Antacids, aluminum- or magnesium-containing | Decreased elvitegravir concentrations and AUC when administered simultaneously1 | Give antacids at least 2 hours before or after EVG/c/FTC/TAF1 |
| Antiarrhythmic agents (e.g., amiodarone, disopyramide, flecainide, lidocaine [systemic], mexiletine, propafenone, quinidine) | Amiodarone, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine: Possible increased antiarrhythmic agent concentrations1 | Amiodarone, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine: Use concomitantly with caution;1 monitor antiarrhythmic agent concentrations if possible1 |
| Anticonvulsants (carbamazepine, ethosuximide, oxcarbazepine, phenobarbital, phenytoin) | Carbamazepine, phenobarbital, phenytoin: Possible decreased elvitegravir, cobicistat, and tenofovir alafenamide concentrations with possible decreased antiretroviral efficacy and development of resistance1 Ethosuximide: Possible increased ethosuximide concentrations;1 possible decreased elvitegravir, cobicistat, and tenofovir alafenamide concentrations1 Oxcarbazepine: Possible decreased elvitegravir, cobicistat, and tenofovir alafenamide concentrations1 | Carbamazepine, phenobarbital, phenytoin: Concomitant use contraindicated1 Ethosuximide: Clinical monitoring recommended1 Oxcarbazepine: Consider alternative anticonvulsant1 |
| Antidepressants, tricyclics (amitriptyline, desipramine, imipramine, nortriptyline) | Possible increased tricyclic antidepressant concentrations and AUC1 Desipramine: Increased desipramine concentrations when used concomitantly with cobicistat1 | Carefully titrate tricyclic antidepressant dosage and monitor clinical response1 |
| Antifungals, azoles | Itraconazole: Possible increased itraconazole, elvitegravir, and cobicistat concentrations1 Ketoconazole: Increased ketoconazole, elvitegravir, and cobicistat concentrations1 Voriconazole: Possible increased voriconazole, elvitegravir, and cobicistat concentrations1 | Itraconazole: Do not exceed itraconazole dosage of 200 mg daily1 Ketoconazole: Do not exceed ketoconazole dosage of 200 mg daily1 Voriconazole: Avoid concomitant use unless benefits outweigh risks1 |
| Antimycobacterials (rifabutin, rifampin, rifapentine) | Rifabutin: Decreased elvitegravir concentrations and AUC and increased rifabutin metabolite concentrations and AUC when used with cobicistat-boosted elvitegravir;1 possible decreased tenofovir alafenamide concentrations;1 possible decreased antiretroviral efficacy and development of resistance1 Rifampin: Possible decreased elvitegravir, cobicistat, and tenofovir alafenamide concentrations with possible decreased antiretroviral efficacy and development of resistance1 Rifapentine: Possible decreased elvitegravir, cobicistat, and tenofovir alafenamide concentrations with possible decreased antiretroviral efficacy and development of resistance1 | Rifabutin: Concomitant use not recommended1 Rifampin: Concomitant use contraindicated1 Rifapentine: Concomitant use not recommended1 |
| Antipsychotics (e.g., perphenazine, pimozide, quetiapine, risperidone, thioridazine) | Perphenazine, risperidone, thioridazine: Possible increased antipsychotic concentrations1 Pimozide: Possible increased pimozide concentrations resulting in serious and/or life-threatening reactions (e.g., cardiac arrhythmias)1 Quetiapine: Increased quetiapine concentrations expected1 | Perphenazine, risperidone, thioridazine: Decreased antipsychotic dosage may be needed1 Pimozide: Concomitant use contraindicated1 Quetiapine: Consider alternative antiretroviral;1 if EVG/c/FTC/TAF necessary in patient receiving stable quetiapine dosage, reduce quetiapine dosage to one-sixth of original dosage and monitor for quetiapine-associated adverse effects1 |
| β-Adrenergic blocking agents (metoprolol, timolol) | Metoprolol, timolol: Possible increased β-blocking agent concentrations1 | Metoprolol, timolol: Monitor clinically;1 reduced β-blocker dosage may be needed1 |
| Benzodiazepines (e.g., clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, triazolam) | Diazepam: Possible increased diazepam concentrations1 Lorazepam: Clinically important effects on lorazepam concentrations not expected1 Midazolam or triazolam: Increased benzodiazepine concentrations;1 potential for serious and/or life-threatening adverse effects (e.g., prolonged or increased sedation or respiratory depression)1 Clorazepate, estazolam, flurazepam: Possible increased benzodiazepine concentrations1 | Diazepam: Use concomitantly only in monitored setting where respiratory depression and/or prolonged sedation can be managed1 Oral midazolam or triazolam: Concomitant use contraindicated1 Parenteral midazolam: Use concomitantly only in monitored setting where respiratory depression and/or prolonged sedation can be managed;1 consider reduced midazolam dosage, particularly if >1 dose will be used1 |
| Bosentan | Possible increased bosentan concentrations1 | In patient already receiving EVG/c/FTC/TAF for ≥10 days, initiate bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability1 In patient already receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating EVG/c/FTC/TAF;1 after ≥10 days of EVG/c/FTC/TAF, resume bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability1 |
| Buprenorphine/naloxone | Increased buprenorphine and norbuprenorphine concentrations and AUCs;1 decreased naloxone concentrations and AUC1 | Monitor closely for sedation and adverse cognitive effects;1 dosage adjustments not needed1 |
| Bupropion | Possible increased bupropion concentrations1 | Carefully titrate antidepressant dosage based on clinical response1 |
| Buspirone | Possible increased buspirone concentrations1 | Monitor clinically;1 reduced buspirone dosage may be needed1 |
| Calcium-channel blocking agents (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil) | Possible increased calcium-channel blocking agent concentrations1 | Use concomitantly with caution1 ; monitor clinically1 |
| 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 acts as a pharmacokinetic enhancer (cobicistat-boosted elvitegravir);1 used to therapeutic advantage in fixed-combination EVG/c/FTC/TAF1 Increased tenofovir alafenamide concentrations and AUC as the result of cobicistat inhibition of P-gp, BCRP, and OATP1B1 and 1B31 25 Does not antagonize antiretroviral effects of elvitegravir, tenofovir, or emtricitabine1 | Component of fixed-combination EVG/c/FTC/TAF1 |
| Colchicine | Increased colchicine concentrations expected1 | Patients with renal or hepatic impairment: Concomitant use not recommended1 Colchicine for treatment of gout flares: In those receiving EVG/c/FTC/TAF, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later1 Colchicine for prophylaxis of gout flares: In those receiving EVG/c/FTC/TAF, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 mg once daily1 Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving EVG/c/FTC/TAF, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)1 |
| Corticosteroids (dexamethasone, fluticasone) | Dexamethasone (systemic): Possible decreased elvitegravir and cobicistat concentrations1 Fluticasone (orally inhaled, intranasal): Possible increased fluticasone concentrations1 | Dexamethasone (systemic): Consider alternative corticosteroid1 Fluticasone (orally inhaled, intranasal): Consider alternative corticosteroid, particularly for long-term use1 |
| Digoxin | Increased digoxin concentrations1 | Use concomitantly with caution; monitor digoxin concentrations1 |
| 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 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., transdermal systems, 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 Other hormonal contraceptives (e.g., transdermal systems, vaginal ring, injections): Consider alternative nonhormonal methods of contraception1 |
| 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/TAF not expected1 | |
| HIV integrase inhibitors (INSTIs) | Elvitegravir: Component of fixed-combination EVG/c/FTC/TAF; do not use concomitantly1 | |
| HIV nucleoside and nucleotide reverse transcriptase inhibitor antiretrovirals (NRTIs) | Emtricitabine, tenofovir alafenamide: Components of EVG/c/FTC/TAF;1 do not use any preparation containing emtricitabine or tenofovir alafenamide concomitantly with EVG/c/FTC/TAF1 Tenofovir DF: Do not use any preparation containing tenofovir DF concomitantly with EVG/c/FTC/TAF1 Other NRTIs (including lamivudine): Do not use concomitantly with EVG/c/FTC/TAF1 | |
| HIV protease inhibitors (PIs) (ritonavir) | Ritonavir: Do not use ritonavir or any ritonavir-containing preparation concomitantly with EVG/c/FTC/TAF1 | |
| HMG-CoA reductase inhibitors (statins) | Atorvastatin: Possible increased atorvastatin concentrations1 Lovastatin, simvastatin: Possible increased statin concentrations may lead to serious adverse effects, including myopathy and rhabdomyolysis1 Rosuvastatin: Increased rosuvastatin concentrations and AUC;1 no clinically important effect on elvitegravir pharmacokinetics1 | Atorvastatin: Initiate using lowest atorvastatin dosage and titrate carefully; monitor for atorvastatin-associated adverse effects1 Lovastatin, simvastatin: Concomitant use contraindicated1 |
| Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus) | Cyclosporine: Possible increased cyclosporine, elvitegravir, and cobicistat concentrations1 Sirolimus, tacrolimus: Possible increased immunosuppressive agent concentrations1 | Cyclosporine: Monitor cyclosporine concentrations;1 monitor for EVG/c/FTC/TAF-associated adverse effects1 Sirolimus, tacrolimus: Monitor immunosuppressive agent concentrations1 |
| Ledipasvir | Fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir): Increased ledipasvir and sofosbuvir concentrations and AUCs and increased elvitegravir concentrations when used concomitantly with cobicistat-boosted elvitegravir1 | Ledipasvir/sofosbuvir: Clinically important pharmacokinetic interactions with EVG/c/FTC/TAF not expected1 |
| Macrolides (clarithromycin) | Clarithromycin: Possible increased macrolide 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/minute1 |
| Methadone | Clinically important pharmacokinetic interactions not expected1 | |
| NSAIAs | High-dose or multiple NSAIAs: Competition for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the concomitant NSAIA;1 may increase risk of adverse effects1 | Avoid EVG/c/FTC/TAF in patients who are receiving or have recently received a nephrotoxic drug (e.g., high-dose or multiple NSAIAs)1 |
| 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;1 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/TAF1 |
| 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/TAF not expected1 | |
| Salmeterol | Possible increased salmeterol concentrations;1 may increase risk of QT prolongation, palpitations, or sinus tachycardia1 | Concomitant use with EVG/c/FTC/TAF not recommended1 |
| Selective serotonin-reuptake inhibitors (SSRIs) | SSRIs: Possible increased SSRI concentrations1 Sertraline: Clinically important interactions not expected1 | SSRIs: Carefully titrate SSRI dosage and monitor antidepressant response1 |
| 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/TAF contraindicated1 Sildenafil for treatment of erectile dysfunction: Do not exceed sildenafil dosage of 25 mg once every 48 hours;1 closely monitor for sildenafil-related adverse effects1 |
| Sofosbuvir | Clinically important pharmacokinetic interactions not expected1 | |
| St. John’s wort (Hypericum perforatum) | Possible decreased elvitegravir, cobicistat, and tenofovir alafenamide concentrations with possible decreased antiretroviral efficacy and development of resistance1 | Concomitant use contraindicated1 |
| 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/TAF for ≥1 week: Use initial tadalafil dosage of 20 mg once daily;1 if tolerated, increase dosage to 40 mg once daily1 EVG/c/FTC/TAF in patients receiving tadalafil for PAH: Discontinue tadalafil for at least 24 hours prior to initiating EVG/c/FTC/TAF;1 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 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 effects1 |
| Trazodone | Possible increased trazodone concentrations1 | Carefully titrate trazodone dosage and monitor antidepressant response1 |
| 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;1 closely monitor for vardenafil-related adverse effects1 |
| Warfarin | Effect on warfarin pharmacokinetics not known1 | Monitor INR1 |
| Zolpidem | Possible increased zolpidem concentrations1 | Monitor clinically;1 reduced zolpidem dosage may be needed1 |
Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Pharmacokinetics
Absorption
Bioavailability
Following an oral dose of EVG/c/FTC/TAF with food, peak plasma concentrations of elvitegravir and cobicistat occur at 4 and 3 hours, respectively, and peak plasma concentrations of emtricitabine and tenofovir occur at 3 and 1 hours, respectively.1
Cobicistat component of EVG/c/FTC/TAF increases plasma concentrations of elvitegravir and tenofovir alafenamide.1 25 (See Specific Drugs under Interactions.)
Food
Relative to fasting, administration of EVG/c/FTC/TAF with high-fat meal (approximately 800 kcal, 50% fat) increases mean systemic exposures of elvitegravir by 87%;1 changes in mean systemic exposures of cobicistat, emtricitabine, and tenofovir alafenamide not clinically important.1
Distribution
Extent
Elvitegravir, cobicistat, tenofovir: Distributed into milk in rats;1 not known whether distributed into human milk.1
Emtricitabine: Distributed into human milk.1
Plasma Protein Binding
Elvitegravir: Approximately 99%.1
Cobicistat: Approximately 98%.1
Emtricitabine: <4%.1
Tenofovir alafenamide: Approximately 80%.1
Elimination
Metabolism
Elvitegravir: Metabolized principally by CYP3A;1 also undergoes glucuronidation via UGT1A1/3.1 Cobicistat, a CYP3A inhibitor, is included in fixed-combination EVG/c/FTC/TAF to inhibit metabolism of and increase plasma concentrations of elvitegravir.1
Cobicistat: Metabolized principally by CYP3A and, to a lesser extent, by CYP2D6.1
Emtricitabine: Converted intracellularly to active 5′-triphosphate metabolite;1 9 not substantially metabolized further.1
Tenofovir alafenamide: Prodrug of tenofovir;1 hydrolyzed intracellularly by cathepsin A to form tenofovir and subsequently metabolized to active metabolite (tenofovir diphosphate).1 9 In vitro, also converted to tenofovir by carboxylesterase 1 in hepatocytes.1 6
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 (approximately 30% of a dose over 3 hours);1 not known whether removed by peritoneal dialysis.1
Tenofovir alafenamide: 31.7% in feces, <1% in urine.1 Removed by hemodialysis.1
Half-life
Elvitegravir: 12.9 hours.1
Cobicistat: 3.5 hours.1
Emtricitabine: 10 hours.1
Tenofovir alafenamide: 0.51 hours;1 active metabolite (tenofovir diphosphate) half-life within peripheral blood mononuclear cells is 150–180 hours.1 7
Special Populations
Mild hepatic impairment (Child-Pugh class A): No clinically important effects on pharmacokinetics of tenofovir alafenamide.1
Moderate hepatic impairment (Child-Pugh class B): No clinically important effects on pharmacokinetics of elvitegravir, cobicistat, or tenofovir alafenamide.1 Pharmacokinetics of emtricitabine unlikely to be affected.1
Severe hepatic impairment (Child-Pugh class C): Pharmacokinetics of EVG/c/FTC/TAF not studied.1
Stability
Storage
Oral
Tablets<30°C.1
Store in original container; keep tightly closed.1
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.
| Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
| Oral | Tablets, film-coated | Elvitegravir 150 mg, Cobicistat 150 mg, Emtricitabine 200 mg, and Tenofovir Alafenamide Fumarate 10 mg (of tenofovir alafenamide) | Genvoya | Gilead |
Uses For elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide
Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide combination is used to treat human immunodeficiency virus (HIV) infection. HIV is the virus that causes acquired immune deficiency syndrome (AIDS). elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is usually given to patients who have yet not received any medicine for HIV infection.
Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide combination will not cure or prevent HIV infection or AIDS. It helps keep HIV from reproducing and appears to slow down the destruction of the immune system. This may help delay problems that are usually related to AIDS or HIV disease from occurring. elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide will not keep you from spreading HIV to other people. People who receive elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide may continue to have other problems usually related to AIDS or HIV disease.
elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is available only with your doctor's prescription.
What are some things I need to know or do while I take Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide?
- Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
- This medicine interacts with many other drugs. The chance of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide's side effects may be raised or how well this medicine works may be lowered. The chance of the other drugs' side effects may also be raised. This may include very bad, life-threatening, or deadly side effects. Check with your doctor and pharmacist to make sure that it is safe for you to take elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide with all of your other drugs (prescription or OTC, natural products, vitamins).
- Have blood work checked as you have been told by the doctor. Talk with the doctor.
- Have your urine checked as you have been told by your doctor.
- This medicine is not a cure for HIV. Stay under the care of your doctor.
- This medicine does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
- This medicine may rarely cause swollen liver and an acid health problem in the blood. This may be deadly in some cases. The chance may be higher in women, in overweight people, and in people who have taken drugs like this one for a long time. Talk with your doctor.
- Birth control pills and other hormone-based birth control may not work as well to prevent pregnancy. Use some other kind of birth control also like a condom when taking this medicine.
- Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide while you are pregnant.
Pharmacology
Integrase strand transfer inhibitor, CYP3A enzyme inhibitor plus nucleoside and nucleotide reverse transcriptase inhibitor combination; the viral cDNA strand produced by reverse transcriptase is processed and inserted into the human genome by the enzyme HIV-1 integrase. Elvitegravir inhibits the catalytic activity of integrase, thus preventing integration of the proviral gene into human DNA. Cobicistat inhibits enzymes of the CYP3A subfamily and enhances systemic exposure to elvitegravir. Emtricitabine is a cytosine analogue and tenofovir alafenamide is converted to tenofovir in vivo; tenofovir is an analog of adenosine 5'-monophosphate. Emtricitabine and tenofovir interfere with HIV viral RNA dependent DNA polymerase activities resulting in inhibition of viral replication.
Absorption
AUC of elvitegravir increases with food; emtricitabine, tenofovir alafenamide and cobicistat not affected
Metabolism
Elvitegravir: By CYP3A enzymes and also hepatic glucuronidation mediated by UGT1A1/3
Cobicistat: By CYP3A enzymes and to a minor extent CYP2D6
Emtricitabine: Not significantly metabolized
Tenofovir alafenamide: Primarily intracellular metabolism; minimal extent by CYP3A
Excretion
Elvitegravir: Feces (94.8%), urine (6.7%); Cobicistat: Feces (86.2%), urine (8.2%); Emtricitabine: Feces (13.7%), urine (70%); Tenofovir: Feces (31.7%), urine (<1%)
Time to Peak
Elvitegravir: 4 hours; Cobicistat: 3 hours; Emtricitabine: 3 hours; Tenofovir alafenamide: 1 hour
Half-Life Elimination
Elvitegravir: 12.9 hours; Cobicistat: 3.5 hours; Emtricitabine: 10 hours; Tenofovir alafenamide: 0.51 hours
Protein Binding
Elvitegravir: ~99%; Cobicistat: ~98%; Emtricitabine: <4%; Tenofovir alafenamide: ~80%
Adverse Reactions
Includes data from both treatment-naive and treatment-experienced patients. Also see individual agents.
1% to 10%:
Central nervous system: Headache (6%), fatigue (5%)
Endocrine & metabolic: Increased LDL cholesterol, increased serum cholesterol
Gastrointestinal: Nausea (10%), diarrhea (7%)
Neuromuscular & skeletal: Decreased bone mineral density (≥5% decrease at lumbar spine: 12%; ≥7% decrease at femoral neck: 11%)
Frequency not defined:
Endocrine & metabolic: Increased HDL cholesterol, increased serum triglycerides
Hepatic: Exacerbation of hepatitis B
Renal: Increased serum creatinine (mean increase 0.1 mg/dL)
Warnings/Precautions
Concerns related to adverse effects:
• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves' disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.
• Lactic acidosis/severe hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported with use of nucleoside analogs, alone or in combination with other antiretrovirals. Suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (marked transaminase elevation may/may not accompany hepatomegaly and steatosis).
• Renal toxicity: Renal toxicity (acute renal failure and/or Fanconi syndrome) has been reported with the use of tenofovir prodrugs; patients with impaired renal function and those with concurrent or recent nephrotoxic therapy (including NSAID use) are at an increased risk. In all patients, assess serum creatinine, serum phosphorous, estimated creatinine clearance, urine glucose, and urine protein prior to treatment initiation and during therapy. Discontinue use in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Cobicistat component inhibits tubular creatinine secretion without affecting glomerular filtration; may cause elevations in serum creatinine early in therapy (typically within two weeks of initiation) and is reversible upon discontinuation. Closely monitor patients with a confirmed >0.4 mg/dL increase of serum creatinine from baseline for renal safety.
Disease-related concerns:
• Chronic hepatitis B: [US Boxed Warning]: Safety and efficacy in patients coinfected with HIV-1 and HBV have not been established; acute, severe exacerbations of hepatitis B have been reported in these patients following discontinuation of emtricitabine and/or tenofovir disoproxil fumarate. Not indicated for treatment of chronic HBV infection. Closely monitor hepatic function with clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue this therapy. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced hepatic disease or cirrhosis, because posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. All patients with HIV should be tested for HBV prior to initiation of treatment.
• Hepatic impairment: Use is not recommended in severe hepatic impairment (Child-Pugh class C); has not been studied.
• Renal impairment: Use is not recommended in patients with CrCl <30 mL/minute.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.