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Elvitegravir

Class: HIV 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: C23H23ClFNO5
CAS Number: 697761-98-1
Brands: Vitekta

Introduction

Antiretroviral; HIV integrase strand transfer inhibitor (INSTI).1 200

Uses for Elvitegravir

Treatment of HIV Infection

Treatment of HIV-1 infection in antiretroviral-experienced (previously treated) adults.1

Single-entity elvitegravir used only in multiple-drug antiretroviral regimens that contain certain ritonavir-boosted HIV protease inhibitors (PIs) and another antiretroviral.1 Do not use in antiretroviral regimens that contain an HIV PI and cobicistat (cobicistat-boosted HIV PI).1

Used in conjunction with ritonavir-boosted atazanavir, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, fixed combination of lopinavir and ritonavir (lopinavir/ritonavir), or ritonavir-boosted tipranavir.1 Do not use in conjunction with other HIV PIs.1

Elvitegravir Dosage and Administration

Administration

Oral Administration

Administer orally once daily with food.1

Use only in multiple-drug antiretroviral regimens that contain certain ritonavir-boosted HIV PIs and another antiretroviral.1 (See Table 1 in Dosage and Administration.) Select specific multiple-drug regimen based on treatment history and, when available, resistance testing.1

Dosage

Adults

Treatment of HIV Infection
Oral

Previously treated adults: 85 or 150 mg once daily, depending on specific ritonavir-boosted HIV PI included in the multiple-drug regimen.1 (See Table 1.)

Multiple-drug regimen must also contain another antiretroviral.1

Table 1. Dosage Recommendations for Elvitegravir and Concomitant Ritonavir-boosted HIV PI.1

Elvitegravir Dosage

Dosage of Concomitant HIV PI

Dosage of Ritonavir

85 mg once daily

Atazanavir 300 mg once daily

100 mg once daily

85 mg once daily

Lopinavir 400 mg twice daily

100 mg twice daily

150 mg once daily

Darunavir 600 mg twice daily

100 mg twice daily

150 mg once daily

Fosamprenavir 700 mg twice daily

100 mg twice daily

150 mg once daily

Tipranavir 500 mg twice daily

200 mg twice daily

Special Populations

Hepatic Impairment

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

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

Renal Impairment

Dosage adjustments not needed.1

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 (See Geriatric Use under Cautions.)

Cautions for Elvitegravir

Contraindications

  • Manufacturer states none known.1

  • Must be used in conjunction with certain ritonavir-boosted HIV PIs and another antiretroviral;1 consider contraindications for each antiretroviral included in the multiple-drug regimen.1 (See Precautions Related to Multiple-drug Treatment Regimens under Cautions: Warnings/Precautions.)

Warnings/Precautions

Interactions

Concomitant use with certain drugs may result in decreased plasma concentrations of elvitegravir and may lead to loss of therapeutic effect and possible development of resistance.1 Concomitant use with certain other drugs may result in increased plasma concentrations of elvitegravir or the other drug resulting in clinically important adverse effects associated with elvitegravir or the other drug.1 (See Interactions.)

Consider potential drug interactions prior to and during therapy.1 Review drugs used concomitantly with elvitegravir;1 monitor patient for adverse reactions associated with these drugs.1

Precautions Related to Multiple-drug Treatment Regimens

Used only in multiple-drug regimens that contain certain ritonavir-boosted HIV PIs and another antiretroviral (see Uses).1 Consider cautions, precautions, and contraindications associated with each drug in the multiple-drug regimen.1 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.1

Do not use single-entity elvitegravir in conjunction with a cobicistat-boosted HIV PI;1 dosage recommendations for such regimens not established and suboptimal plasma concentrations of elvitegravir and/or the HIV PI may result and may lead to loss of therapeutic effect and development of resistance.1

Do not use single-entity elvitegravir in conjunction with any preparation containing elvitegravir, including fixed combination of emtricitabine, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF) (EVG/c/FTC/TDF)1 235 or fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (EVG/c/FTC/TAF).243

Immune Reconstitution Syndrome

During initial antiretroviral 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

Experts state only limited data available to date regarding safety and pharmacokinetics of elvitegravir in pregnant women.202 Data insufficient to make elvitegravir dosage recommendations for pregnant women;202 not recommended for initial treatment in antiretroviral-naive pregnant women.202

Lactation

Distributed into milk in rats;1 not known whether 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 not established in pediatric patients <18 years of age.1

Limited data indicate elvitegravir exposures in HIV-infected adolescents 12 through 17 years of age are comparable to those reported in adults;1 data insufficient to establish safety and efficacy in this age group.1

Experts state pharmacokinetic and safety data insufficient to date regarding use in pediatric patients.201 Elvitegravir in conjunction with a ritonavir-boosted PI is not recommended for initial treatment in pediatric patients.201

Geriatric Use

Insufficient experience in adults ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1 Pharmacokinetics not fully evaluated in geriatric patients.1

Select dosage 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 effects on elvitegravir pharmacokinetics.1

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

Renal Impairment

Severe renal impairment (estimated Clcr <30 mL/minute): No clinically important effects on elvitegravir pharmacokinetics.1

Common Adverse Effects

Diarrhea.1

Interactions for Elvitegravir

Elvitegravir: Substrate for CYP3A;1 9 21 weak inducer and weak inhibitor of CYP3A.9 21 Induces CYP2C9.9 Does not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, or 2E1 in vitro.9 21

Single-entity elvitegravir is used in conjunction with certain ritonavir-boosted HIV PIs and another antiretroviral (see Uses).1 200 Consider potential drug interactions associated with each drug in the multiple-drug regimen.1

The following drug interactions are based on studies that used elvitegravir or elvitegravir administered with low-dose ritonavir (ritonavir-boosted elvitegravir) or are predicted to occur.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A inhibitors: Concomitant low-dose ritonavir (potent CYP3A4 inhibitor) increases elvitegravir plasma concentrations and AUC;1 9 21 used for therapeutic advantage.1 9 21 Concomitant use of another CYP3A inhibitor with elvitegravir and low-dose ritonavir not expected to result in any additional effects on elvitegravir exposures.21

CYP3A inducers: Possible pharmacokinetic interactions with elvitegravir used in conjunction with a ritonavir-boosted PI (decreased plasma concentrations of elvitegravir, ritonavir, and/or the HIV PI and possible decreased antiretroviral efficacy and development of resistance).1 21

Drugs Affecting Uridine Diphosphate-glucuronosyltransferases

UGT1A1 inhibitors: Possible increased elvitegravir concentrations.21

Specific Drugs

Drug

Interaction

Comments

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

Decreased elvitegravir concentrations and AUC when administered simultaneously1 200

Give antacids at least 2 hours before or 6 hours after elvitegravir1 200

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

Possible increased antiarrhythmic agent concentrations200

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

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

Dabigatran: Possible increased dabigatran concentrations200

Warfarin: Possible altered warfarin concentrations200

Apixaban, rivaroxaban, ticagrelor, vorapaxar: Concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI not recommended200

Dabigatran: Some experts state dosage adjustments not needed if used with elvitegravir in conjunction with a ritonavir-boosted HIV PI in patients with Clcr >50 mL/minute;200 do not use concomitantly in those with Clcr <50 mL/minute200

Warfarin: Monitor INR and adjust warfarin dosage accordingly200

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

Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Possible decreased elvitegravir concentrations1

Ethosuximide: Possible increased ethosuximide concentrations200

Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI not recommended;1 consider alternative anticonvulsant200

Ethosuximide: If used concomitantly with elvitegravir in conjunction with a ritonavir-boosted HIV PI, monitor clinically for ethosuximide-associated adverse effects200

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

Possible increased tricyclic antidepressant concentrations200

If tricyclic antidepressant initiated in patient receiving elvitegravir in conjunction with a ritonavir-boosted HIV PI, use lowest initial antidepressant dosage and carefully titrate dosage based on clinical response and/or antidepressant plasma concentrations200

Antifungal agents, azoles

Itraconazole, posaconazole: Possible increased elvitegravir concentrations200

Ketoconazole: Increased ketoconazole and elvitegravir concentrations1

Voriconazole: Possible altered voriconazole and elvitegravir concentrations200

Ketoconazole: If used with elvitegravir in conjunction with a ritonavir-boosted HIV PI, do not exceed ketoconazole dosage of 200 mg daily;1 elvitegravir dosage adjustment not needed1

Antimycobacterials (rifabutin, rifampin, rifapentine)

Rifabutin: Decreased elvitegravir concentrations and increased rifabutin metabolite concentrations and AUC1

Rifampin, rifapentine: Possible decreased elvitegravir concentrations with possible decreased antiretroviral efficacy and development of resistance1 200

Rifabutin: If used with elvitegravir in conjunction with a ritonavir-boosted HIV PI, reduce usual rifabutin dosage of 300 mg daily by at least 75% (e.g., rifabutin 150 mg every other day or 3 times weekly) and increase monitoring for rifabutin-associated adverse effects;1 elvitegravir dosage adjustment not needed1

Rifampin, rifapentine: Concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI not recommended1 200

Antipsychotic agents (quetiapine)

Quetiapine: Increased quetiapine concentrations expected200

Avanafil

Data not available200

Concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI not recommended200

β-Adrenergic blocking agents (metoprolol, timolol)

Metoprolol, timolol: Possible increased β-adrenergic blocking agent concentrations200

Metoprolol, timolol: Reduced β-adrenergic blocking agent dosage may be needed;200 adjust dosage based on clinical response;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 expected200

Clonazepam, clorazepate, diazepam, estazolam, flurazepam: Possible increased benzodiazepine concentrations200

Oral midazolam or triazolam: Concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI not recommended200

Parenteral midazolam: Use only in monitored setting where respiratory depression and/or prolonged sedation can be managed;200 consider reduced midazolam dosage, particularly if >1 dose will be used200

Clonazepam, clorazepate, diazepam, estazolam, flurazepam: Reduced benzodiazepine dosage may be needed;200 if initiated in patient receiving elvitegravir in conjunction with a ritonavir-boosted HIV PI, use low initial benzodiazepine dosage200

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

Bosentan

Possible increased bosentan concentrations1

In patient already receiving elvitegravir in conjunction with a ritonavir-boosted HIV PI 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 elvitegravir in conjunction with a ritonavir-boosted HIV PI;1 after ≥10 days of the antiretroviral regimen, 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 decreased bupropion concentrations200

Carefully titrate antidepressant dosage based on antidepressant response200

Buspirone

Possible increased buspirone concentrations200

Reduced buspirone dosage may be needed;200 if initiated in patient receiving elvitegravir in conjunction with a ritonavir-boosted HIV PI, use low initial dosage200

Calcium-channel blocking agents

Possible increased calcium-channel blocking agent concentrations200

Use concomitantly with caution;200 titrate dosage of calcium-channel blocking agent and monitor for efficacy and adverse effects200

Calcium supplements

Possible decreased elvitegravir concentrations200

Administer elvitegravir at least 2 hours before or 6 hours after oral calcium supplements;200 monitor for antiretroviral efficacy200

Cobicistat

Data not available1 200

Do not use concomitantly with single-entity elvitegravir or with elvitegravir in conjunction with a ritonavir-boosted HIV PI1 200

Colchicine

Possible increased colchicine concentrations200

Patients with renal or hepatic impairment: Concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI not recommended200

Colchicine for treatment of gout flares: In those receiving elvitegravir in conjunction with a ritonavir-boosted HIV PI, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later200

Colchicine for prophylaxis of gout flares: In those receiving elvitegravir in conjunction with a ritonavir-boosted HIV PI, reduce 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 daily200

Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving elvitegravir in conjunction with a ritonavir-boosted HIV PI, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)200

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

Fluticasone (orally inhaled, intranasal): Increased fluticasone concentrations;200 may result in adrenal insufficiency, including Cushing's syndrome200

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 concentrations1

Fluticasone (orally inhaled, intranasal): Consider alternative corticosteroid (e.g., beclomethasone), particularly for long-term use200

Methylprednisolone, prednisolone, triamcinolone (intra-articular, epidural, intraorbital, other local injections): Do not use concomitantly with elvitegravir in conjunction with a ritonavir-boosted HIV PI200

Dexamethasone (systemic):Consider alternative corticosteroid1

Dasabuvir

Fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) copackaged with dasabuvir: Data not available regarding concomitant use with elvitegravir200

Ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir: Concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI not recommended200

Digoxin

Possible increased digoxin concentrations200

Estrogens/progestins

Oral contraceptives containing ethinyl estradiol and norgestimate: Decreased ethinyl estradiol concentrations and AUC and increased norgestimate concentrations and AUC;1 no effect on elvitegravir concentrations1

Oral contraceptives containing ethinyl estradiol and norgestimate: Consider alternative nonhormonal methods of contraception in patients receiving elvitegravir in conjunction with a ritonavir-boosted HIV PI1

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

Clinically important interactions not expected1 200

Elvitegravir dosage adjustment not needed200

HIV entry and fusion inhibitors (enfuvirtide, maraviroc)

Maraviroc: Increased maraviroc concentrations and AUC;10 224 no effect on elvitegravir pharmacokinetics1 10 224

Enfuvirtide, maraviroc: No in vitro evidence of antagonistic antiretroviral effects with elvitegravir1

Maraviroc: If used concomitantly with elvitegravir in conjunction with a ritonavir-boosted HIV PI, recommended maraviroc dosage is 150 mg twice daily224

HIV integrase inhibitors (INSTIs)

Raltegravir: No in vitro evidence of antagonistic antiretroviral effects with elvitegravir1

HIV nonnucleoside reverse transcriptase inhibitor antiretrovirals (NNRTIs)

Efavirenz, nevirapine: Possible decreased elvitegravir concentrations200

Etravirine: No clinically important interactions1 6 200

Rilpivirine: Increased rilpivirine concentrations expected200

Efavirenz, etravirine, nevirapine: No in vitro evidence of antagonistic antiretroviral effects with elvitegravir1

Efavirenz, nevirapine: Concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI not recommended200

HIV nucleoside and nucleotide reverse transcriptase inhibitor antiretrovirals (NRTIs)

Abacavir, didanosine, stavudine, tenofovir DF: No clinically important drug interactions1

Abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine: No in vitro evidence of antagonistic antiretroviral effects with elvitegravir1

Didanosine: If used concomitantly with elvitegravir in conjunction with a ritonavir-boosted HIV PI, give didanosine (without food) at least 1 hour before or 2 hours after elvitegravir (with food)1

HIV protease inhibitors (PIs)

Atazanavir (with low-dose ritonavir), fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): Increased elvitegravir concentrations, but no effect on concentrations of the HIV PI1 21 200

Darunavir (with low-dose ritonavir), fosamprenavir (with low-dose ritonavir), tipranavir (with low-dose ritonavir): No clinically important effects on pharmacokinetics of elvitegravir or the HIV PI1 21 200

Ritonavir (low dose): Increased elvitegravir concentrations and AUC1 9 21 200

Saquinavir: Data not available200

Amprenavir (active metabolite of fosamprenavir), atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir: No in vitro evidence of antagonistic antiretroviral effects with elvitegravir1

Atazanavir: Use elvitegravir dosage of 85 mg once daily in conjunction with atazanavir 300 mg once daily and ritonavir 100 mg once daily;1 concomitant use with cobicistat-boosted atazanavir not recommended1 200

Darunavir: Use elvitegravir dosage of 150 mg once daily in conjunction with darunavir 600 mg twice daily and ritonavir 100 mg twice daily;1 concomitant use with cobicistat-boosteddarunavir not recommended1 200

Fosamprenavir: Use elvitegravir dosage of 150 mg once daily in conjunction with fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily1

Lopinavir/ritonavir: Use elvitegravir dosage of 85 mg once daily in conjunction with 400 mg of lopinavir and 100 mg of ritonavir once daily1

Saquinavir: Dosage recommendations not available200

Tipranavir: Use elvitegravir dosage of 150 mg once daily in conjunction with tipranavir 500 mg twice daily and ritonavir 200 mg twice daily.1

HMG-CoA reductase inhibitors (statins)

Atorvastatin, pravastatin, rosuvastatin: Increased statin concentrations not expected1 200

Lovastatin, simvastatin: Substantially increased statin concentrations expected200

Lovastatin, simvastatin: Experts state concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI is contraindicated200

Immunosuppressive agents (cyclosporine, everolimus, sirolimus, tacrolimus)

Cyclosporine, everolimus, sirolimus, tacrolimus: Possible increased immunosuppressive agent concentrations200

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 elvitegravir 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 elvitegravir 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): Clinically important effect on elvitegravir concentrations not expected200

Methadone

Possible decreased methadone concentrations1 200

Increased methadone dosage may be needed1

Multivitamins

Possible decreased elvitegravir concentrations200

Administer elvitegravir at least 2 hours before or 6 hours after multivitamins;200 monitor for antiretroviral efficacy200

Ombitasvir

Ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir: Data not available regarding concomitant use with elvitegravir200

Ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir: Concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI not recommended200

Paritaprevir

Ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir: Data not available regarding concomitant use with elvitegravir200

Ombitasvir/paritaprevir/ritonavir copackaged with dasabuvir: Concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI not recommended200

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

Clinically important interactions not expected1 200

Elvitegravir dosage adjustments not needed200

Salmeterol

Possible increased salmeterol concentrations;200 may increase risk of salmeterol-associated adverse cardiac effects200

Concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI not recommended200

Selective serotonin-reuptake inhibitors (SSRIs)

Citalopram, escitalopram, fluoxetine, paroxetine, sertraline: Possible increased or decreased SSRI concentrations200

Fluvoxamine: Possible increased or decreased elvitegravir concentrations200

Citalopram, escitalopram, fluoxetine, paroxetine, sertraline: Titrate SSRI dosage based on clinical response200

Fluvoxamine: Some experts state consider an alterative to fluvoxamine or an alternative to elvitegravir in conjunction with a ritonavir-boosted HIV PI200

Sildenafil

Sildenafil for treatment of PAH: Experts state concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI contraindicated200

Sildenafil for treatment of erectile dysfunction: Experts state initiate sildenafil using dosage of 25 mg once every 48 hours;200 closely monitor for sildenafil-related adverse effects200

Simeprevir

Concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI not recommended200

Sofosbuvir

Clinically important pharmacokinetic interactions not expected200

Dosage adjustments not needed200

St. John’s wort (Hypericum perforatum)

Possible decreased elvitegravir concentrations1

Concomitant use with elvitegravir in conjunction with a ritonavir-boosted HIV PI not recommended1

Suvorexant

Increased suvorexant concentrations expected200

Concomitant use of suvorexant and elvitegravir in conjunction with a ritonavir-boosted HIV PI not recommended200

Tadalafil

Tadalafil for treatment of erectile dysfunction in patient receiving elvitegravir in conjunction with a ritonavir-boosted HIV PI: Experts state initiate tadalafil using a 5-mg dose and do not exceed tadalafil dosage of 10 mg once every 72 hours;200 closely monitor for tadalafil-related adverse effects200

Trazodone

Possible increased trazodone concentrations200

If trazodone initiated in patient receiving elvitegravir in conjunction with ritonavir-boosted HIV PI, use lowest initial trazodone dosage and carefully titrate dosage of the antidepressant200

Vardenafil

Vardenafil for treatment of erectile dysfunction in patient receiving elvitegravir in conjunction with a ritonavir-boosted HIV PI: Experts state initiate vardenafil using dosage of 2.5 mg once every 72 hours;200 closely monitor for vardenafil-related adverse effects200

Zolpidem

Possible increased zolpidem concentrations200

Reduced zolpidem dosage may be needed;200 if initiated in patient receiving elvitegravir in conjunction with a ritonavir-boosted HIV PI, use low initial zolpidem dosage200

Elvitegravir Pharmacokinetics

Absorption

Bioavailability

Following an oral dose of elvitegravir (with low-dose ritonavir) given with food, peak plasma concentrations of elvitegravir attained approximately 4 hours after the dose.1 21

Elvitegravir plasma exposures increase in a less than dose proportional manner, likely due to solubility-limited absorption.1 21

Distribution

Extent

Elvitegravir is distributed into milk in rats;1 not known whether distributed into human milk.1

Plasma Protein Binding

98–99%.1

Elimination

Metabolism

Metabolized principally by CYP3A to produce inactive M1 metabolite (GS-9202);1 9 21 also undergoes glucuronidation via UGT1A1/3 to produce inactive M4 metabolite (GS-9200).1 9 21

Elimination Route

Approximately 95% of an oral dose eliminated in feces;1 21 approximately 7% eliminated in urine as metabolites.1 21

Half-life

8.7 hours when administered with low-dose ritonavir.1

Special Populations

Moderate hepatic impairment (Child-Pugh class B): No clinically important effects on elvitegravir pharmacokinetics.1

Severe hepatic impairment (Child-Pugh class C): Pharmacokinetics not studied.1

Severe renal impairment: No clinically important effects on elvitegravir pharmacokinetics.1

Adolescents 12 through 17 years of age: Pharmacokinetics similar to that reported in adults.1

Pediatric patients <12 years of age: Pharmacokinetics not established.1

Geriatric adults ≥65 years of age: Pharmacokinetics not fully established.1

Stability

Storage

Oral

Tablets

Room temperature at <30°C.1

Store and dispense in original container.1

Actions and Spectrum

  • Elvitegravir is an HIV integrase strand transfer inhibitor (INSTI) 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

  • Single-entity elvitegravir must be used in multiple-drug regimens that contain certain ritonavir-boosted HIV PIs and another antiretroviral (see Uses).1 Low-dose ritonavir is a pharmacologic enhancer and is used to decrease elvitegravir metabolism and increase plasma concentrations of the drug.1 9 21 200

  • HIV-1 resistant to elvitegravir have been produced in vitro and have emerged during elvitegravir therapy.1 12 13 17 18 Certain primary integrase substitutions (i.e., T66A/I, E92G/Q, S147G, Q148R) have been associated with reduced susceptibility to elvitegravir.1 During treatment with a regimen that included elvitegravir, development of T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H substitutions in the HIV-1 integrase protein was associated with elvitegravir resistance.1 In addition, E92A, F121C/Y, P145S, Q146I/L/R, and N155S substitutions have been reported occasionally and were shown to confer reduced susceptibility to elvitegravir.1

  • Cross-resistance between elvitegravir and other HIV INSTIs (e.g., dolutegravir raltegravir) reported.1 11 12 13 16 18 19 20

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;1 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

  • Importance of taking elvitegravir once daily with food.1

  • Importance of using single-entity elvitegravir in a multiple-drug regimen that includes certain ritonavir-boosted HIV PIs and another antiretroviral.1

  • Advise patients that signs and symptoms of inflammation from previous infections may occur soon after initiation of antiretroviral therapy in some individuals with 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

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

85 mg

Vitekta

Gilead

150 mg

Vitekta

Gilead

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Gilead Sciences Inc. Vitekta (elvitegravir) tablets prescribing information. Foster City, CA; 2015 Jul.

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]

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]

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. 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]

20. 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]

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

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.

224. ViiV Healthcare. Selzentry (maraviroc) tablets prescribing information. Research Triangle Park, NC; 2015 Apr.

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

243. Gilead Sciences. Genvoya (elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) tablets prescribing information. Foster City, CA; 2016 Mar.

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