Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Disoproxil Fumarate

[Section Outline]

Treatment of HIV Infection
Postexposure Prophylaxis following Nonoccupational Exposure to HIV
Postexposure Prophylaxis following Occupational Exposure to HIV

Treatment of HIV Infection

The fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF) (EVG/c/FTC/TDF) is used as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients 12 years of age and older weighing ≥35 kg who have no antiretroviral treatment history or to replace the current antiretroviral regimen in patients who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of EVG/c/FTC/TDF.1,2,3,4,5,20,21 The fixed-dose combination of EVG/c/FTC/TDF is among alternative regimens recommended in guidelines for treatment of HIV in adults and sexually mature adolescent patients, but is not recommended in pregnant patients.200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.200,201,202

Clinical Experience

Antiretroviral-naïve Adults

The comparative efficacy and safety of EVG/c/FTC/TDF and the fixed combination of efavirenz, emtricitabine, and tenofovir DF (EFV/FTC/TDF) were evaluated in a randomized, active-control, phase 3 study in antiretroviral-naïve HIV-infected adults (study 102).1,2,3 All patients had baseline HIV-1 RNA ≥5000 copies/mL, baseline creatinine clearance ≥70 mL/minute, and were randomized to receive EVG/c/FTC/TDF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir DF 300 mg) once daily with food or EFV/FTC/TDF (efavirenz 600 mg, emtricitabine 200 mg, tenofovir DF 300 mg) once daily in the fasting state.1,2 Among 700 patients enrolled in study 102, the mean age was 38 years, 89% were male, 63% were white, 28% were Black, 2% were Asian, 24% were Hispanic; mean baseline HIV-1 RNA was 4.8 log₁₀ copies/mL, and mean baseline CD4+ T-cell count was 386 cells/mm³.1 At 144 weeks, 80% of those receiving EVG/c/FTC/TDF had HIV-1 RNA <50 copies/mL compared with 75% of those receiving EFV/FTC/TDF.1,3 The mean increase in CD4+ T-cell count from baseline was 298 cells/mm³ in those receiving EVG/c/FTC/TDF compared with 272 cells/mm³ in those receiving EFV/FTC/TDF.1

In a similarly designed phase 3 study, the comparative efficacy and safety of EVG/c/FTC/TDF and a regimen of ritonavir-boosted atazanavir in conjunction with tenofovir DF and emtricitabine was evaluated in antiretroviral-naïve HIV-infected adults (study 103).1,4,5 All patients had baseline HIV-1 RNA ≥5000 copies/mL, baseline creatinine clearance ≥70 mL/minute, and were randomized to receive EVG/c/FTC/TDF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir DF 300 mg) once daily with food or atazanavir 300 mg and ritonavir 100 mg in conjunction with the fixed combination of emtricitabine 200 mg and tenofovir DF 300 mg (FTC/TDF) once daily with food.1,4 Among 708 patients enrolled in study 103, the mean age was 38 years, 90% were male, 74% were white, 17% were Black, 5% were Asian, 16% were Hispanic, mean baseline HIV-1 RNA was 4.8 log₁₀ copies/mL, and mean baseline CD4+ T-cell count was 370 cells/mm³.1 At 144 weeks, 78% of those receiving EVG/c/FTC/TDF had HIV-1 RNA <50 copies/mL compared with 75% of those receiving ritonavir-boosted atazanavir with FTC/TDF.1 The mean increase in CD4+ T-cell count from baseline was 261 cells/mm³ in those receiving EVG/c/FTC/TDF compared with 269 cells/mm³ in those receiving ritonavir-boosted atazanavir with FTC/TDF.1

Antiretroviral-experienced Adults

The comparative efficacy and safety of EVG/c/FTC/TDF and an HIV protease inhibitor (PI)-based regimen in antiretroviral-experienced, virologically suppressed (HIV-1 RNA <50 copies/mL) adults were evaluated in a randomized, open-label, phase 3b noninferiority study (study 115; STRATEGY-PI).1,20 Among 433 patients enrolled in study 115, the mean age was 41 years, 86% were male, 80% were white, 15% were Black, and mean baseline CD4+ T-cell count was 610 cells/mm³.1,20 At initial screening, all patients were receiving either their first or second antiretroviral regimen with no history of virologic failure, had no current evidence or history of resistance to the antiretroviral components of EVG/c/FTC/TDF, and had been receiving a ritonavir-boosted HIV PI (40% atazanavir, 40% darunavir, 17% lopinavir, 3% fosamprenavir, <1% saquinavir) in conjunction with the fixed combination of emtricitabine 200 mg and tenofovir DF 300 mg (FTC/TDF) for at least 6 months.1 Patients were randomized in a 2:1 ratio to either switch to EVG/c/FTC/TDF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir DF 300 mg) or continue receiving their baseline HIV PI-based antiretroviral regimen.1,20 At 48 weeks, 94% of those receiving EVG/c/FTC/TDF had plasma HIV-1 RNA levels <50 copies/mL compared with 87% of those receiving a ritonavir-boosted HIV PI with FTC/TDF.1,20

In a similarly designed study, the comparative efficacy and safety of EVG/c/FTC/TDF and an HIV nonnucleoside reverse transcriptase inhibitor-based (NNRTI-based) regimen in antiretroviral-experienced, virologically suppressed (HIV-1 RNA <50 copies/mL) adults were evaluated in a randomized, open-label, phase 3b noninferiority study (study 121; STRATEGY-NNRTI).1,21 Among 434 patients enrolled in study 121, the mean age was 41 years, 93% were male, 78% were white, 17% were Black, and mean baseline CD4+ T-cell count was 588 cells/mm³.1,21 At initial screening, all patients were receiving either their first or second antiretroviral regimen with no history of virologic failure, had no current evidence or history of resistance to the antiretroviral components of EVG/c/FTC/TDF, and had been receiving an HIV NNRTI in conjunction with the fixed combination of emtricitabine 200 mg and tenofovir DF 300 mg (FTC/TDF) for at least 6 months.1,21 Patients were randomized in a 2:1 ratio to either switch to EVG/c/FTC/TDF (elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir DF 300 mg) or continue receiving their baseline NNRTI-based antiretroviral regimen.1,21 Randomization was stratified by use of efavirenz in the NNRTI-based regimen (78% were receiving efavirenz [74% as EFV/FTC/TDF]);1,21 17% were receiving nevirapine, 4% were receiving rilpivirine (as emtricitabine/rilpivirine/tenofovir DF), and 1% were receiving etravirine.1 At 48 weeks, 93% of those receiving EVG/c/FTC/TDF had HIV-1 RNA <50 copies/mL compared with 88% of those receiving an HIV NNRTI with FTC/TDF.1

Pediatric Patients

The efficacy and safety of EVG/c/FTC/TDF in antiretroviral-naïve HIV-infected children 12 to <18 years of age weighing at least 35 kg were evaluated in an uncontrolled, open-label study (Study 112).1 The study included 50 patients (mean age 15 years, 70% male, 68% black, 28% Asian, mean baseline HIV-1 RNA level 4.6 log₁₀ copies/mL, mean baseline CD4+ T-cell count 399 cells/mm³, mean CD4+ percentage 20.9%) and all patients received EVG/c/FTC/TDF.1 At 48 weeks, 88% had HIV-1 RNA <50 copies/mL; the mean increase in CD4+ T-cell count from baseline was 229 cells/mm3.1

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy (ART) is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of ART are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 nucleoside reverse transcriptase inhibitors (NRTIs) administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), antiretroviral regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other antiinfective regimens.200

The fixed-dose combination of EVG/c/FTC/TDF is commonly used as a complete antiretroviral regimen.200 In the 2023 HHS adult and adolescent HIV treatment guideline, EVG/c/FTC/TDF is listed among initial regimens recommended in certain clinical situations.200

In the 2023 HHS pediatric HIV treatment guideline, HHS recommends limiting use of EVG/c/FTC/TDF to sexually mature adolescents (according to recommendations in the HHS adult and adolescent HIV treatment guideline) due to concerns related to decreased bone mineral density with tenofovir DF use in pre-pubertal patients.201

In the 2023 HHS perinatal HIV treatment guideline, EVG/c/FTC/TDF is not recommended as an initial regimen in pregnancy due to data suggesting insufficient levels of cobicistat and elvitegravir in the second and third trimesters and risk of viral breakthrough at delivery.202 In patients who become pregnant while virologically suppressed on EVG/c/FTC/TDF, HHS recommends continuing therapy with frequent viral load monitoring or considering switching therapy.202

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

EVG/c/FTC/TDF is used as a complete regimen for postexposure prophylaxis of HIV infection following nonoccupational exposure †(nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission.25,198 EVG/c/FTC/TDF is listed among alternative regimen options in guidelines for nPEP.198

Clinical Experience

The fixed-dose combination of EVG/c/FTC/TDF was evaluated as nPEP in adults presenting to an emergency department following suspected sexual exposure to HIV in the open-label, randomized STRIBPEP study.25 Patients were randomized 3:1 to EVG/c/FTC/TDF (n=119) or tenofovir DF plus emtricitabine and ritonavir-boosted lopinavir (TDF/FTC + LPV/RTV, n=38), both administered for 28 days.25 A higher proportion of patients in the TDF/FTC + LPV/RTV arm had not completed their assigned treatment at 28 days compared to those in the EVG/c/FTC/TDF arm (47% and 33%, respectively), and a substantially higher proportion in the TDF/FTC + LPV/RTV arm reported <94% adherence to the regimen (47% vs 9%, respectively).25 HIV infection was detected in 2 patients (1 in each arm) on the day 1 follow-up visit.25 HIV infection was detected in 1 patient assigned to EVG/c/FTC/TDF at day 90 follow-up; this patient reported multiple high-risk exposures prior to and after initiating study treatment.25

Clinical Perspective

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).198 The alternative nPEP regimen recommended in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada^®).198 EVG/c/FTc/TDF is one of several other alternative regimens recommended by CDC for nPEP.198

Consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals.198 However, initiation of nPEP should not be delayed while waiting for expert consultation.198

Postexposure Prophylaxis following Occupational Exposure to HIV

EVG/c/FTC/TDF is used as a complete regimen for postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.199

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®) for 28 days.199 These experts recommend several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs).199 The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir^®), or zidovudine and emtricitabine.199 EVG/c/FTC/TDF is also recommended as an alternative complete PEP regimen.199

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199

Dosage and Administration ⬆ ⬇

[Section Outline]

General
Administration
Dosage
Special Populations

General

Pretreatment Screening

Patients should be tested for hepatitis B virus (HBV) infection prior to initiation of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF) (EVG/c/FTC/TDF).1
Serum creatinine, estimated creatinine clearance, urine glucose, and urine protein should be determined prior to initiation of EVG/c/FTC/TDF.1
In patients with chronic kidney disease (CKD), serum phosphorus should be determined prior to initiation of EVG/c/FTC/TDF.1

Patient Monitoring

Routinely monitor serum creatinine, estimated creatinine clearance, urine glucose, and urine protein during treatment in all patients.1
Routinely monitor serum phosphorus during treatment in patients with CKD.1

Administration

The fixed combination of EVG/c/FTC/TDF is administered orally once daily with food.1

Store below 30°C in the original container and keep container tightly closed.1

Dosage

Each fixed-combination tablet of EVG/c/FTC/TDF contains elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir DF 300 mg.1

Adult Dosage

Treatment of HIV Infection

For the treatment of HIV-1 infection in antiretroviral-naïve or -experienced adults, the usual dosage of EVG/c/FTC/TDF is 1 tablet (150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir DF) once daily.1

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

For postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) when the exposure represents a substantial risk for HIV transmission, the recommended dosage of EVG/c/FTC/TDF is 1 tablet (150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir DF) once daily.198

Initiate nPEP as soon as possible (within 72 hours) following nonoccupational exposure associated with a substantial risk for HIV transmission and continue for 28 days.198 If the exposed individual seeks care more than 72 hours after the exposure, nPEP is not recommended.198

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel or other individuals, the recommended dosage of EVG/c/FTC/TDF is 1 tablet (150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir DF) once daily.199

PEP should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.199

Pediatric Dosage

Treatment of HIV Infection

For the treatment of HIV-1 infection in antiretroviral-naïve or -experienced adolescents 12 years of age or older weighing at least 35 kg, the usual dosage of EVG/c/FTC/TDF is 1 tablet (150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir DF) once daily.1

Special Populations

Hepatic Impairment

Dosage adjustments are not necessary if EVG/c/FTC/TDF is used in adults with mild or moderate hepatic impairment (Child-Pugh class A or B).1

EVG/c/FTC/TDF should not be used in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

EVG/c/FTC/TDF should not be initiated in adults with estimated creatinine clearance <70 mL/minute.1

If estimated creatinine clearance decreases to <50 mL/minute, or if clinically significant renal dysfunction or evidence of Fanconi syndrome develop during EVG/c/FTC/TDF treatment, the drug should be discontinued.1

Data are insufficient to make dosage recommendations for pediatric patients with renal impairment.1

Geriatric Use

No dosage adjustments are necessary in geriatric patients; however, EVG/c/FTC/TDF should be used with caution.1

Cautions ⬆ ⬇

[Section Outline]

Contraindications
Warnings/Precautions
Common Adverse Effects

Contraindications

Concomitant use of the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF) (EVG/c/FTC/TDF) with drugs highly dependent on cytochrome P-450 isoenzyme 3A (CYP3A) for metabolism and for which elevated plasma concentrations are associated with serious and/or life-threatening events (e.g., alfuzosin, cisapride, ergot alkaloids, lovastatin, lurasidone, oral midazolam, pimozide, sildenafil used for treatment of pulmonary arterial hypertension [PAH], simvastatin, triazolam) is contraindicated.1
Concomitant use of EVG/c/FTC/TDF with drugs that are potent inducers of CYP3A and which may decrease elvitegravir and/or cobicistat concentrations resulting in possible decreased antiretroviral efficacy and development of resistance (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]) is contraindicated.1

Warnings/Precautions

Warnings

Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV and HBV

The prescribing information of EVG/c/FTC/TDF includes a boxed warning regarding the risk of severe acute exacerbations of HBV in patients coinfected with HIV-1 and HBV who have discontinued emtricitabine or tenofovir DF, two of the components of EVG/c/FTC/TDF.1 In some patients, post-treatment exacerbations of HBV have been associated with hepatic decompensation and hepatic failure.1 HIV-infected patients should be tested for HBV before antiretroviral therapy is initiated.1 EVG/c/FTC/TDF is not indicated for treatment of chronic HBV infection, and safety and efficacy of EVG/c/FTC/TDF have not been established in HIV-infected patients coinfected with HIV-1.1 Hepatic function should be closely monitored with clinical and laboratory follow-up for at least several months after EVG/c/FTC/TDF is discontinued in patients coinfected with HIV and HBV.1 If appropriate, initiation of HBV treatment may be warranted.1

Other Warnings/Precautions

Renal Toxicity

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), have been reported in patients receiving tenofovir DF (a component of EVG/c/FTC/TDF).1

In clinical trials, 1.9% of patients receiving EVG/c/FTC/TDF and up to 2.3% of patients receiving an active comparator discontinued treatment by 144 weeks because of adverse renal effects.1 Laboratory findings consistent with proximal renal tubular dysfunction resulting in discontinuance of the drugs occurred in 4 (0.6%) patients receiving EVG/c/FTC/TDF during the first 48 weeks of treatment;1 estimated creatinine clearances <70 mL/minute were reported at baseline in 2 of the 4 patients receiving EVG/c/FTC/TDF.1 Laboratory findings improved after EVG/c/FTC/TDF was discontinued, but did not completely resolve in all patients; no patient required renal replacement therapy.1

Cobicistat (a component of EVG/c/FTC/TDF) may cause a modest increase in serum creatinine and modest decrease in estimated creatinine clearance due to inhibition of tubular secretion of creatinine; there is a corresponding decrease in serum creatinine-based estimated glomerular filtration rate (eGFR), but renal glomerular function is not affected.1 Elevated serum creatinine concentrations generally were reversible when the drug was discontinued.1

Serum creatinine, estimated creatinine clearance, urine glucose, and urine protein should be determined prior to initiation of EVG/c/FTC/TDF and routinely monitored during treatment in all patients.1 Assess serum phosphorus in patients with CKD.1 Discontinue EVG/c/FTC/TDF if clinically significant renal dysfunction develops or there is evidence of Fanconi syndrome.1

EVG/c/FTC/TDF should not be initiated in patients with estimated creatinine clearances <70 mL/minute, and the drug should be discontinued if estimated creatinine clearance decreases to <50 mL/minute during treatment.1

Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline while receiving EVG/c/FTC/TDF should be closely monitored for renal toxicity.1

Because persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy, renal function should be promptly evaluated in patients at risk for renal dysfunction who present with such symptoms.1

EVG/c/FTC/TDF should be avoided in patients who are receiving or have recently received a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory agents [NSAIAs]).1 Acute renal failure has been reported after initiation of high-dose or multiple NSAIA therapy in HIV-infected patients at risk for renal dysfunction who appeared stable while receiving tenofovir DF.1 Hospitalization and renal replacement therapy were required in some patients.1 Alternatives to NSAIAs should be considered if such therapy is needed in patients at risks for renal dysfunction.1

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving HIV nucleoside reverse transcriptase inhibitors (NRTIs), including emtricitabine and tenofovir DF, in conjunction with other antiretroviral agents.1

EVG/c/FTC/TDF treatment should be interrupted in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (signs of hepatotoxicity may include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).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 levels and 1,25 vitamin D levels have been reported during clinical trials of tenofovir DF (a component of EVG/c/FTC/TDF).1 The effects of tenofovir-associated changes in BMD on long-term bone health and future fracture risk are unknown.1

Osteomalacia associated with proximal renal tubulopathy, which manifested as bone pain or pain in extremities and may contribute to fractures, has been reported in patients receiving tenofovir DF.1 Arthralgias and muscle pain or weakness also have been reported in patients with proximal renal tubulopathy.1 Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk for renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving preparations containing tenofovir DF.1

In a clinical study evaluating safety and efficacy of EVG/c/FTC/TDF (study 103), the mean percentage decrease in BMD from baseline to week 144 in patients receiving EVG/c/FTC/TDF was similar to that in patients receiving a regimen of ritonavir-boosted atazanavir and the fixed combination of emtricitabine and tenofovir DF (FTC/TDF).1 The mean change from baseline in BMD at the lumbar spine or hip was -1.4 or -2.8%, respectively, in those receiving EVG/c/FTC/TDF and -3.7 or -3.8%, respectively, in those receiving ritonavir-boosted atazanavir with FTC/TDF.1 Data from clinical studies 102 and 103 indicate that 3.9% of those receiving EVG/c/FTC/TDF experienced bone fractures compared with 2.3% of those receiving a fixed combination containing efavirenz, emtricitabine, tenofovir DF (EFV/FTC/TDF) and 5.4% of those receiving ritonavir-boosted atazanavir and FTC/TDF.1 In clinical studies evaluating tenofovir DF in pediatric and adolescent patients, bone effects were similar to those reported in adults.1

BMD monitoring should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.1 Although the effect of calcium and vitamin D supplementation was not studied, such supplementation may be beneficial for all patients.1 If bone abnormalities are suspected, appropriate consultation should be obtained.1

Interactions

Concomitant use of EVG/c/FTC/TDF with certain drugs may result in clinically important interactions, including some that may decrease plasma concentrations of the antiretroviral agents leading to loss of therapeutic effect and possible development of resistance and some that may increase plasma concentrations of the antiretroviral agents and/or concomitant drugs leading to clinically important adverse reactions, including potentially severe, life-threatening, or fatal events.1 Loss of therapeutic effect of concomitant drugs that utilize CYP3A to form active metabolites may also occur.1,1

The potential for drug interactions should be considered prior to and during EVG/c/FTC/TDF therapy.1 Drugs used concomitantly should be reviewed during EVG/c/FTC/TDF therapy and the patient should be monitored for adverse reactions associated with the concomitant drugs.1

Use of Fixed Combinations

The usual cautions, precautions, contraindications, and interactions associated with each component of EVG/c/FTC/TDF should be considered.1 Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug in the fixed combination.1 For cautionary information related to emtricitabine or tenofovir disoproxil fumarate, see Cautions in Emtricitabine 8:18.08.20 and in Tenofovir Disoproxil Fumarate 8:18.08.20.

EVG/c/FTC/TDF is used alone as a complete regimen for the treatment of HIV-1 infection and should not be used in conjunction with other antiretroviral agents.1

EVG/c/FTC/TDF should not be used concomitantly with any preparation that contains any of its components (elvitegravir, cobicistat, emtricitabine, tenofovir DF).1 In addition, EVG/c/FTC/TDF should not be used concomitantly with any preparation containing lamivudine, adefovir dipivoxil, or ritonavir.1

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients receiving multiple-drug antiretroviral therapy, including EVG/c/FTC/TDF.1 During the initial phase of treatment, HIV-infected patients whose immune systems respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium , M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]); such response may necessitate further evaluation and treatment.1

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

Specific Populations

Pregnancy

Use of EVG/c/FTC/TDF is not recommended during pregnancy, and should not be initiated during pregnancy due to substantially lower elvitegravir and cobicistat exposures in the second and third trimesters.1 An alternative regimen is recommended for individuals who become pregnant during treatment with EVG/c/FTC/TDF.1

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to EVG/c/FTC/TDF during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting [Web].1

The overall risk of birth defects with EVG/c/FTC/TDF use in pregnancy was not markedly different compared to the background rate for major birth defects of 2.7% in the United States reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).1 Limitations of using an external comparator (the MACDP) includes differences in populations and methodology, and confounding due to the underlying disease.1 The rate of miscarriage is not reported in the APR.1

Lactation

Elvitegravir and cobicistat are distributed into milk in rats; it is not known whether these drugs are distributed into human milk.1 The emtricitabine and tenofovir components of EVG/c/FTC/TDF are distributed into human milk.1

It is not known whether EVG/c/FTC/TDF affects human milk production or affects the breast-fed infant.1

Because of the risk of adverse effects in the infant and the risk of HIV transmission, HIV-infected women should not breast-feed infants.1

Pediatric Use

Safety and efficacy of EVG/c/FTC/TDF have not been established in pediatric patients younger than 12 years of age or in those weighing less than 35 kg.1

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

Bone effects reported when tenofovir DF is used in pediatric and adolescent patients are similar to those reported in adults.1 In clinical studies, total body BMD gain in tenofovir DF-treated pediatric patients was less than that reported in control groups; skeletal growth appeared to be unaffected.1 Effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.1

Following oral administration of EVG/c/FTC/TDF, elvitegravir and tenofovir exposures in children and adolescents 12 to less than 18 years of age were 30 and 37% higher, respectively, than those reported in adults; this difference is not considered clinically important based on exposure-response relationships.1 Cobicistat and emtricitabine exposures in children and adolescents 12 to less than 18 years of age were similar to those reported in adults.1

Geriatric Use

Experience in adults 65 years of age and older is insufficient to determine whether they respond differently than younger adults.1

EVG/c/FTC/TDF should be used with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1

Hepatic Impairment

Moderate hepatic impairment (Child-Pugh class B) does not have a clinically important effect on the pharmacokinetics of elvitegravir, cobicistat, or tenofovir DF and is not expected to affect the pharmacokinetics of emtricitabine.1

EVG/c/FTC/TDF is not recommended in patients with severe hepatic impairment (Child-Pugh class C).1 Data are not available to date regarding the pharmacokinetics or safety of EVG/c/FTC/TDF in such patients.1

Renal Impairment

Serum creatinine, estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be determined prior to initiating EVG/c/FTC/TDF and routinely monitored during treatment in all patients.1

EVG/c/FTC/TDF should not be initiated in adults with estimated creatinine clearances <70 mL/minute.1 If estimated creatinine clearance decreases to <50 mL/minute, clinically significant decreases in renal function, or evidence of Fanconi syndrome develop during EVG/c/FTC/TDF treatment, the fixed-combination drug should be discontinued.1

Data are insufficient to make dosage recommendations for pediatric patients with renal impairment.1

Common Adverse Effects

The most common (incidence ≥10%) adverse effects in patients receiving EVG/c/FTC/TDF are nausea and diarrhea.1

Drug Interactions ⬆ ⬇

[Section Outline]

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Drugs Affected by P-glycoprotein Transport
Drugs Affected by Breast Cancer Resistance Protein
Drugs Affected by Organic Anion Transport Polypeptides
Drugs Affecting Renal Function
Alfuzosin
Anticoagulants
Anticonvulsants
Antifungal Agents
Antimycobacterial Agents
Antiplatelet Agents
Antipsychotic Agents
Antiretroviral Agents
Beta-Adrenergic Blocking Agents
Benzodiazepines
Bosentan
Bupropion
Buspirone
Calcium-channel Blocking Agents
Calcium, Iron, Multivitamins, and Other Preparations Containing Polyvalent Cations
Cardiac Drugs
Cisapride
Cobicistat
Colchicine
Corticosteroids
Ergot Alkaloids
Estrogens and Progestins
GI Drugs
HCV Antivirals
HMG-CoA Reductase Inhibitors
Immunosuppressive Agents
Lomitapide
Macrolides
Nucleoside and Nucleotide Antivirals
Opiates Agonists, Opiate Partial Agonists, and Opiate Antagonists
Phosphodiesterase Type 5 Inhibitors
Salmeterol
Selective Serotonin-reuptake Inhibitors
Trazodone
Tricyclic Antidepressants
Zolpidem
Dietary and Herbal Supplements

The following drug interactions are based on studies that used elvitegravir, elvitegravir administered with cobicistat ( cobicistat-boosted elvitegravir), elvitegravir administered with low-dose ritonavir ( ritonavir-boosted elvitegravir), cobicistat alone, or the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF) (EVG/c/FTC/TDF) or are predicted to occur.1

Potential drug interactions associated with each drug in the fixed combination should be considered.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Elvitegravir is a substrate of cytochrome P-450 (CYP) 3A and a weak inducer and weak inhibitor of CYP3A; elvitegravir is an inducer of CYP2C9.1 The drug does not inhibit CYP1A, 2A6, 2C9, 2C19, 2D6, or 2E1 in vitro.1

Cobicistat is a substrate of CYP3A and, to a minor extent, CYP2D6; cobicistat also is an inhibitor of CYP3A and 2D6.1

Emtricitabine is not a substrate of CYP enzymes and does not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 3A4.1

Tenofovir DF and tenofovir are not substrates of CYP enzymes; tenofovir does not inhibit CYP3A4, 2D6, 2C9, or 2E1, but may have a slight inhibitory effect on CYP1A.1

Potential pharmacokinetic interactions if EVG/c/FTC/TDF is used concomitantly with drugs that are principally metabolized by CYP3A or 2D6 (increased plasma concentrations of the concomitant drug).1 Concomitant use of EVG/c/FTC/TDF with some drugs that are CYP3A substrates and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated.1

Potential pharmacokinetic interactions if EVG/c/FTC/TDF is used concomitantly with drugs that induce CYP3A (decreased plasma concentrations of elvitegravir and cobicistat and possible decreased antiretroviral efficacy and development of resistance).1 Concomitant use of EVG/c/FTC/TDF with some drugs that are potent inducers of CYP3A is contraindicated.1

Potential pharmacokinetic interactions if EVG/c/FTC/TDF is used concomitantly with drugs that inhibit CYP3A (increased plasma concentrations of cobicistat).1

Drugs Affected by P-glycoprotein Transport

Cobicistat is an inhibitor of P-glycoprotein (P-gp) transport.1

Potential pharmacokinetic interactions if EVG/c/FTC/TDF is used concomitantly with drugs that are P-gp substrates (increased plasma concentrations of the concomitant drug).1

Drugs Affected by Breast Cancer Resistance Protein

Cobicistat is an inhibitor of breast cancer resistance protein (BCRP).1

Potential pharmacokinetic interactions if EVG/c/FTC/TDF is used concomitantly with drugs that are substrates for BCRP (increased plasma concentrations of the concomitant drug).1

Drugs Affected by Organic Anion Transport Polypeptides

Elvitegravir and cobicistat are inhibitors of organic anion transport polypeptides (OATP) 1B1 and 1B3.1

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

Drugs Affecting Renal Function

The emtricitabine and tenofovir components of EVG/c/FTC/TDF are principally excreted by the kidneys by a combination of glomerular filtration and active tubular secretion.1

Potential pharmacokinetic interactions if EVG/c/FTC/TDF is used concomitantly with drugs that reduce renal function or compete for active tubular secretion (e.g., acyclovir, aminoglycosides [gentamicin], cidofovir, ganciclovir, valacyclovir, valganciclovir, high-dose or multiple nonsteroidal anti-inflammatory agents [NSAIAs]); may result in increased concentrations of emtricitabine, tenofovir, and/or the concomitant drug and may increase the risk of adverse effects.1

Alfuzosin

Potential pharmacokinetic interaction with alfuzosin (increased plasma concentrations of alfuzosin) may result in hypotension.1

Concomitant use of alfuzosin and EVG/c/FTC/TDF is contraindicated.1

Anticoagulants

Apixaban, Dabigatran, Edoxaban, Rivaroxaban

Due to an increased risk of bleeding, dosing recommendations for the concomitant use of apixaban with EVG/c/FTC/TDF depend on the dosage of apixaban.1 Refer to apixaban prescribing information for dosing instructions on the concomitant use of apixaban with strong CYP3A and P-gp inhibitors.1

Due to an increased risk of bleeding, dosing recommendations for the concomitant use of dabigatran and edoxaban with a P-gp inhibitor such as EVG/c/FTC/TDF are dependent upon underlying renal function and the indication for anticoagulant use.1 Refer to the prescribing information for the direct oral anticoagulant (DOAC) in use for dosage recommendations with a concomitant P-gp inhibitor.1

Concomitant use of rivaroxaban with EVG/c/FTC/TDF is not recommended due to an increased risk of bleeding.1

Warfarin

The effect of concomitant use of warfarin and EVG/c/FTC/TDF on the pharmacokinetics of warfarin is unknown.1

If warfarin is used concomitantly with EVG/c/FTC/TDF, monitor the international normalized ratio (INR).1

Anticonvulsants

Carbamazepine, Phenobarbital, Phenytoin

Concomitant use of carbamazepine and cobicistat-boosted elvitegravir results in decreased elvitegravir plasma concentrations and area under the plasma concentration-time curve (AUC) and may lead to loss of antiretroviral efficacy and development of resistance; increased carbamazepine plasma concentrations and AUC also occur.1 Potential pharmacokinetic interactions if phenobarbital or phenytoin is used concomitantly with EVG/c/FTC/TDF (decreased elvitegravir and cobicistat plasma concentrations with possible decreased antiretroviral efficacy and development of resistance).1

Concomitant use of EVG/c/FTC/TDF and carbamazepine, phenobarbital, or phenytoin is contraindicated.1

Ethosuximide

Potential pharmacokinetic interaction if ethosuximide is used concomitantly with EVG/c/FTC/TDF (increased ethosuximide plasma concentrations).1

If ethosuximide and EVG/c/FTC/TDF are used concomitantly, the patient should be monitored clinically for ethosuximide-related adverse effects.1

Oxcarbazepine

Potential pharmacokinetic interaction if oxcarbazepine is used concomitantly with EVG/c/FTC/TDF (decreased elvitegravir and cobicistat plasma concentrations).1 An alternative anticonvulsant should be considered.1

Antifungal Agents

Itraconazole

Potential pharmacokinetic interactions with itraconazole (increased itraconazole plasma concentrations expected, increased elvitegravir and cobicistat plasma concentrations possible).1

If itraconazole and EVG/c/FTC/TDF are used concomitantly, itraconazole dosage should not exceed 200 mg daily.1

Ketoconazole

Pharmacokinetic interactions with ketoconazole (increased plasma concentrations of ketoconazole, elvitegravir, and cobicistat).1

If ketoconazole and EVG/c/FTC/TDF are used concomitantly, ketoconazole dosage should not exceed 200 mg daily.1

Voriconazole

Potential pharmacokinetic interactions with voriconazole (increased voriconazole plasma concentrations expected, increased elvitegravir and cobicistat plasma concentrations possible).1

Voriconazole and EVG/c/FTC/TDF should not be used concomitantly unless potential benefits outweigh risks.1

Antimycobacterial Agents

Rifabutin

Pharmacokinetic interactions when cobicistat-boosted elvitegravir (elvitegravir 150 mg and cobicistat 150 mg once daily) was used concomitantly with rifabutin 150 mg once every other day (decreased elvitegravir plasma concentrations and AUC, increased 25- O -desacetyl-rifabutin concentrations and AUC relative to those achieved with rifabutin 300 mg once daily without concomitant cobicistat-boosted elvitegravir); possible decreased antiretroviral efficacy and development of resistance.1

Concomitant use of rifabutin and EVG/c/FTC/TDF is not recommended.1

Rifampin

Potential pharmacokinetic interactions with rifampin (decreased elvitegravir and cobicistat plasma concentrations); possible decreased antiretroviral efficacy and development of resistance.1

Concomitant use of rifampin and EVG/c/FTC/TDF is contraindicated.1

Rifapentine

Potential pharmacokinetic interactions with rifapentine (decreased elvitegravir and cobicistat plasma concentrations); possible decreased antiretroviral efficacy and development of resistance.1

Concomitant use of rifapentine and EVG/c/FTC/TDF is not recommended.1

Antiplatelet Agents

Clopidogrel, Prasugrel, Ticagrelor

Pharmacokinetic interactions are expected if clopidogrel or ticagrelor is used concomitantly with EVG/c/FTC/TDF (decreased clopidogrel concentrations; increased ticagrelor concentrations).1

Concomitant use of EVG/c/FTC/TDF and clopidogrel or ticagrelor is not recommended.1

Clinically relevant interactions are not expected with the active metabolite of prasugrel and EVG/c/FTC/TDF.1

Antipsychotic Agents

Lurasidone

Concomitant use of lurasidone and EVG/c/FTC/TDF may result in serious and/or life-threatening adverse effects.1

Concomitant use of lurasidone and EVG/c/FTC/TDF is contraindicated.1

Perphenazine, Risperidone, Thioridazine

Potential pharmacokinetic interactions with antipsychotics, including perphenazine, risperidone, and thioridazine (increased antipsychotic plasma concentrations).1

If EVG/c/FTC/TDF is used concomitantly with perphenazine, risperidone, or thioridazine, decreased dosage of the antipsychotic may be necessary.1

Pimozide

Potential pharmacokinetic interaction with pimozide (increased pimozide plasma concentrations); potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias).1

Concomitant use of pimozide and EVG/c/FTC/TDF is contraindicated.1

Quetiapine

Pharmacokinetic interaction with quetiapine expected (increased quetiapine plasma concentrations).1

Alternative antiretroviral therapy should be considered.1 If EVG/c/FTC/TDF is necessary in a patient receiving a stable dosage of quetiapine, the quetiapine dosage should be reduced to one-sixth of the original dosage.1 Refer to the prescribing information for quetiapine for recommendations on monitoring for adverse events.1 Patients receiving quetiapine and EVG/c/FTC/TDF concomitantly should be closely monitored for quetiapine efficacy and adverse effects.1

Antiretroviral Agents

EVG/c/FTC/TDF should not be used in conjunction with any other antiretroviral agents.1

HIV Integrase Inhibitors (INSTIs)

Raltegravir

Raltegravir and EVG/c/FTC/TDF should not be used concomitantly.1

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

EVG/c/FTC/TDF contains emtricitabine and tenofovir DF and should not be used concomitantly with any preparation containing these or any other NRTIs.1

HIV Protease Inhibitors (PIs)

EVG/c/FTC/TDF should not be used concomitantly with HIV PIs.1

Ritonavir

EVG/c/FTC/TDF and ritonavir (or preparations containing ritonavir) should not be used concomitantly.1

Beta-Adrenergic Blocking Agents

Potential pharmacokinetic interactions with β-adrenergic blocking agents, including metoprolol and timolol (increased β-adrenergic blocking agent plasma concentrations).1

If EVG/c/FTC/TDF is used concomitantly with a β-adrenergic blocking agent, patients should be monitored clinically and decreased dosage of the β-adrenergic blocking agent may be necessary.1

Benzodiazepines

Midazolam or Triazolam

Pharmacokinetic interaction with midazolam or triazolam (increased benzodiazepine plasma concentrations); potential for serious and/or life-threatening adverse effects (e.g., prolonged or increased sedation or respiratory depression).1

Concomitant use of oral midazolam or triazolam with EVG/c/FTC/TDF is contraindicated.1

Concomitant use of parenteral midazolam and EVG/c/FTC/TDF should be undertaken in a monitored setting where respiratory depression and/or prolonged sedation can be managed.1 In addition, use of a reduced midazolam dosage should be considered, especially if more than a single dose of the drug will be administered.1

Other Benzodiazepines

Potential pharmacokinetic interactions with clorazepate, diazepam, estazolam, or flurazepam (increased benzodiazepine plasma concentrations).1

If clorazepate, diazepam, estazolam, or flurazepam is used concomitantly with EVG/c/FTC/TDF, patients should be monitored clinically.1

Bosentan

Potential pharmacokinetic interaction with bosentan (increased bosentan plasma concentrations).1

In patients who have already been receiving EVG/c/FTC/TDF for at least 10 days, bosentan should be initiated using a dosage of 62.5 mg once daily or every other day based on individual tolerability.1

In patients who have already been receiving bosentan, bosentan should be discontinued for at least 36 hours prior to initiating EVG/c/FTC/TDF; after at least 10 days of EVG/c/FTC/TDF therapy, bosentan can be resumed using a dosage of 62.5 mg once daily or every other day based on individual tolerability.1

Bupropion

Potential pharmacokinetic interaction with bupropion (increased or decreased bupropion plasma concentrations).1

If bupropion is used concomitantly with EVG/c/FTC/TDF, dosage of the antidepressant should be titrated carefully based on clinical response.1

Buspirone

Potential pharmacokinetic interaction with buspirone (increased buspirone plasma concentrations).1

If buspirone is used concomitantly with EVG/c/FTC/TDF, patients should be monitored clinically; reduced buspirone dosage may be necessary.1

Calcium-channel Blocking Agents

Potential pharmacokinetic interactions with calcium-channel blocking agents, including amlodipine, diltiazem, felodipine, nicardipine, nifedipine, and verapamil (increased plasma concentrations of the calcium-channel blocking agent).1

The patient should be monitored for efficacy and adverse effects if calcium-channel blocking agents and EVG/c/FTC/TDF are used concomitantly.1

Calcium, Iron, Multivitamins, and Other Preparations Containing Polyvalent Cations

Oral calcium supplements, oral iron preparations, other oral supplements containing calcium, iron, aluminum, magnesium, or zinc (e.g., multivitamins), cation-containing antacids or laxatives, buffered medications, or other preparations containing polyvalent cations may decrease plasma concentrations of elvitegravir when used concomitantly.1

EVG/c/FTC/TDF should be administered at least 2 hours before or at least 2 hours after medications, antacids, and oral supplements containing calcium, iron, aluminum, magnesium, or zinc.1

Cardiac Drugs

Antiarrhythmic Agents

Potential pharmacokinetic interactions if EVG/c/FTC/TDF is used with amiodarone, digoxin, disopyramide, dronedarone, flecainide, lidocaine (systemic), mexiletine, propafenone, or quinidine (increased plasma concentrations of the antiarrhythmic agent or cardiac glycoside).1 Concomitant use of digoxin (single 0.5-mg dose) and cobicistat (single 150-mg dose) has resulted in increased plasma concentrations of digoxin.1

Plasma concentrations of the antiarrhythmic agents or cardiac glycoside should be monitored, if possible.1

Cisapride

Potential pharmacokinetic interaction with cisapride (increased cisapride plasma concentrations); potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias).1

Concomitant use of cisapride and EVG/c/FTC/TDF is contraindicated.1

Cobicistat

Pharmacokinetic interaction with elvitegravir (increased plasma concentrations and AUC of elvitegravir); occurs because cobicistat inhibits CYP3A.1 Cobicistat acts as a pharmacokinetic enhancer when used concomitantly with elvitegravir ( cobicistat-boosted elvitegravir) and this effect is used to therapeutic advantage in the EVG/c/FTC/TDF fixed combination.1

Cobicistat does not antagonize the antiretroviral effects of elvitegravir, emtricitabine, or tenofovir.1

Colchicine

Potential pharmacokinetic interaction (increased colchicine plasma concentrations expected).1

Colchicine and EVG/c/FTC/TDF should not be used concomitantly in patients with renal or hepatic impairment.1

When colchicine is used for treatment of gout flares in patients receiving EVG/c/FTC/TDF, an initial colchicine dose of 0.6 mg should be given followed by 0.3 mg 1 hour later; the colchicine course should be repeated no earlier than 3 days later.1

When colchicine is used for prophylaxis of gout flares in patients receiving EVG/c/FTC/TDF, colchicine dosage should be reduced to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decreased to 0.3 mg once every other day in those originally receiving 0.6 mg once daily.1

When colchicine is used for treatment of familial Mediterranean fever (FMF) in patients receiving EVG/c/FTC/TDF, a maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily) should be used.1

Corticosteroids

Corticosteroids Affected by Potent CYP3A Inhibition

Concomitant use of EVG/c/FTC/TDF and corticosteroids via all routes of administration whose exposures are substantially affected by potent CYP3A inhibitors (e.g., betamethasone, budesonide, ciclesonide, fluticasone, methylprednisolone, mometasone, triamcinolone) may increase plasma concentrations of the corticosteroid, which may result in adrenal insufficiency or Cushing's syndrome.1 Alternative corticosteroids (e.g., beclomethasone, prednisone, prednisolone) less affected by CYP3A inhibition relative to other corticosteroids should be considered in patients receiving EVG/c/FTC/TDF, particularly if long-term corticosteroid therapy is required.1

Dexamethasone

Concomitant use of systemic dexamethasone may decrease elvitegravir and cobicistat plasma concentrations and may lead to decreased antiretroviral efficacy and development of resistance.1

An alternative corticosteroid should be considered in patients receiving EVG/c/FTC/TDF.1

Ergot Alkaloids

Potential for serious and/or life-threatening adverse effects (e.g., peripheral vasospasm, ischemia of the extremities and other tissues) if EVG/c/FTC/TDF is used concomitantly with ergot alkaloids (e.g., dihydroergotamine, ergotamine, methylergonovine).1

Concomitant use of ergot alkaloids and EVG/c/FTC/TDF is contraindicated.1

Estrogens and Progestins

Pharmacokinetic interactions with oral contraceptives containing ethinyl estradiol and norgestimate or drospirenone (decreased ethinyl estradiol plasma concentrations and AUC and increased norgestimate plasma concentrations and AUC).1

Possible effects of increased norgestimate plasma concentrations are not established, but may include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis.1 The potential risks and benefits of concomitant use of EVG/c/FTC/TDF and oral contraceptives containing ethinyl estradiol and norgestimate should be considered, particularly in women with risk factors for these effects.1

If ethinyl estradiol and drospirenone are given concomitantly with EVG/c/FTC/TDF, clinical monitoring for hyperkalemia is recommended.1

Concomitant use of EVG/c/FTC/TDF with oral contraceptives containing progestins other than drospirenone, levonorgestrel, or norgestimate or with other hormonal contraceptives (e.g., patch, vaginal ring, injections) has not been studied; alternative nonhormonal methods of contraception should be considered.1

Additional or nonhormonal methods of contraception should be used when estrogen-based contraceptives are used concomitantly with EVG/c/FTC/TDF.1

GI Drugs

Antacids

Pharmacokinetic interaction with antacids containing aluminum, calcium, and/or magnesium hydroxide (decreased plasma concentrations and AUC of elvitegravir).1

EVG/c/FTC/TDF should be given at least 2 hours before or at least 2 hours after antacids containing aluminum, calcium, or magnesium.1

Histamine H2-receptor Antagonists

Concomitant use of famotidine and cobicistat-boosted elvitegravir did not have a clinically important effect on elvitegravir plasma concentrations or AUC.1

Concomitant use of EVG/c/FTC/TDF and famotidine is not expected to result in clinically important drug interactions.1

Proton-pump Inhibitors

Concomitant use of omeprazole and cobicistat-boosted elvitegravir did not result in clinically important alterations in elvitegravir pharmacokinetics.1

Concomitant use of EVG/c/FTC/TDF and proton-pump inhibitors is not expected to result in clinically important drug interactions.1

Sucralfate

Sucralfate may decrease plasma concentrations of elvitegravir if used concomitantly with EVG/c/FTC/TDF.1

EVG/c/FTC/TDF should be administered at least 2 hours before or at least 2 hours after sucralfate.1

HCV Antivirals

HCV Polymerase Inhibitors

Sofosbuvir and Velpatasvir

Concomitant use of the fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) with EVG/c/FTC/TDF results in increased tenofovir exposures.1

If sofosbuvir/velpatasvir and EVG/c/FTC/TDF are used concomitantly, the patient should be monitored for tenofovir-associated adverse effects.1

Sofosbuvir, Velpatasvir, and Voxilaprevir

Concomitant use of the fixed combination of sofosbuvir, velpatasvir and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir) with EVG/c/FTC/TDF results in increased tenofovir exposures.1 If sofosbuvir/velpatasvir/voxilaprevir and EVG/c/FTC/TDF are used concomitantly, the patient should be monitored for tenofovir-associated adverse effects.1

HCV Replication Complex Inhibitors

Ledipasvir and Sofosbuvir

Concomitant use of the fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) and EVG/c/FTC/TDF results in increased ledipasvir plasma concentrations and is expected to result in increased tenofovir plasma concentrations.1 Safety of increased tenofovir plasma concentrations in patients receiving ledipasvir/sofosbuvir and EVG/c/FTC/TDF concomitantly has not been established.1

Ledipasvir/sofosbuvir and EVG/c/FTC/TDF should not be used concomitantly.1

HMG-CoA Reductase Inhibitors

Concomitant use of certain hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) metabolized by CYP3A (e.g., atorvastatin, lovastatin, simvastatin) and EVG/c/FTC/TDF may increase plasma concentrations of the HMG-CoA reductase inhibitor resulting in increased effects and increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis.1

Atorvastatin

If atorvastatin is used concomitantly with EVG/c/FTC/TDF, the statin should be initiated at the lowest dosage and titrated carefully while monitoring for atorvastatin-associated adverse effects.1 Do not exceed a dosage of atorvastatin 20 mg daily with concomitant EVG/c/FTC/TDF therapy.1

Lovastatin

Concomitant use of lovastatin and EVG/c/FTC/TDF is contraindicated.1

Rosuvastatin

Pharmacokinetic interaction when rosuvastatin is used concomitantly with cobicistat-boosted elvitegravir (increased rosuvastatin plasma concentrations and AUC; no clinically important effect on elvitegravir pharmacokinetics).1

Simvastatin

Concomitant use of simvastatin and EVG/c/FTC/TDF is contraindicated.1

Immunosuppressive Agents

Potential pharmacokinetic interactions with cyclosporine, everolimus, sirolimus, or tacrolimus (increased plasma concentrations of the immunosuppressive agent).1

If EVG/c/FTC/TDF is used concomitantly with cyclosporine, sirolimus, or tacrolimus, plasma concentrations of the immunosuppressive agent should be monitored and the patient monitored for toxicities.1

Lomitapide

Concomitant use of lomitapide and EVG/c/FTC/TDF is contraindicated due to the potential for marked increases in transaminase levels.1

Macrolides

Clarithromycin

Potential pharmacokinetic interactions (increased plasma concentrations of clarithromycin and cobicistat).1

Modification of the usual dosage of clarithromycin is not necessary in those with a creatinine clearance of 60 mL/minute or greater; however, clarithromycin dosage should be reduced by 50% in those with a creatinine clearance of 50-60 mL/minute.1 EVG/c/FTC/TDF should not be used in those with a creatinine clearance less than 50 mL/minute.1

Nucleoside and Nucleotide Antivirals

Potential pharmacokinetic interactions if EVG/c/FTC/TDF is used concomitantly with drugs that compete for active tubular secretion, including acyclovir, cidofovir, ganciclovir, valacyclovir, and valganciclovir; increased plasma concentrations of some of the components of EVG/c/FTC/TDF (i.e., emtricitabine, tenofovir) or the concomitant drug may occur and increase the risk of adverse effects.1

Adefovir

EVG/c/FTC/TDF should not be used concomitantly with adefovir.1

Entecavir or Famciclovir

Clinically important interactions are not expected if EVG/c/FTC/TDF is used concomitantly with entecavir or famciclovir.1

Ribavirin

Clinically important interactions are not expected if EVG/c/FTC/TDF is used concomitantly with ribavirin.1

Opiates Agonists, Opiate Partial Agonists, and Opiate Antagonists

Buprenorphine

Concomitant use of the fixed combination of buprenorphine and naloxone (buprenorphine/naloxone) with cobicistat-boosted elvitegravir increased plasma concentrations and AUC of buprenorphine and norbuprenorphine and decreased peak plasma concentrations and AUC of naloxone.1

If buprenorphine/naloxone is used concomitantly with EVG/c/FTC/TDF, dosage adjustments are not necessary; however, patients should be monitored closely for sedation and adverse cognitive effects.1

Fentanyl

Potential pharmacokinetic interactions with fentanyl (increased fentanyl plasma concentrations).1 If fentanyl and EVG/c/FTC/TDF are used concomitantly, carefully monitor for therapeutic and adverse effects of fentanyl.1

Methadone

Concomitant use of methadone and cobicistat-boosted elvitegravir did not result in clinically important alterations in methadone pharmacokinetics.1

Concomitant use of methadone and EVG/c/FTC/TDF is not expected to result in clinically important drug interactions.1

Tramadol

Potential pharmacokinetic interactions with tramadol (increased tramadol plasma concentrations).1 Decreased doses of tramadol may be necessary if used concomitantly with EVG/c/FTC/TDF.1

Phosphodiesterase Type 5 Inhibitors

Concomitant use of EVG/c/FTC/TDF and selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil) is expected to result in increased plasma concentrations of the PDE5 inhibitor and increase the risk of adverse effects (e.g., hypotension, syncope, visual disturbances, priapism) associated with these agents.1

Sildenafil

Concomitant use of EVG/c/FTC/TDF is contraindicated in patients receiving sildenafil for treatment of pulmonary arterial hypertension (PAH).1

If sildenafil is used for treatment of erectile dysfunction in a patient receiving EVG/c/FTC/TDF, sildenafil dosage should not exceed 25 mg once every 48 hours and the patient should be monitored for sildenafil-related adverse effects.1

Tadalafil

If tadalafil is used for treatment of PAH in a patient who has been receiving EVG/c/FTC/TDF for at least 1 week, tadalafil should be initiated at a dosage of 20 mg once daily and, if tolerated, dosage may be increased to 40 mg once daily.1 EVG/c/FTC/TDF should not be initiated in patients receiving tadalafil for treatment of PAH; tadalafil should be discontinued for at least 24 hours prior to initiating EVG/c/FTC/TDF.1 After at least 1 week, tadalafil may be resumed at a dosage of 20 mg once daily and, if tolerated, dosage may be increased to 40 mg once daily.1

If tadalafil is used for treatment of erectile dysfunction in a patient receiving EVG/c/FTC/TDF, tadalafil dosage should not exceed 10 mg once every 72 hours and the patient should be monitored for tadalafil-related adverse effects.1

Vardenafil

If vardenafil is used for treatment of erectile dysfunction in a patient receiving EVG/c/FTC/TDF, vardenafil dosage should not exceed 2.5 mg once every 72 hours and the patient should be monitored for vardenafil-related adverse effects.1

Salmeterol

Potential pharmacokinetic interaction with salmeterol (increased salmeterol plasma concentrations) may result in increased risk of salmeterol-associated adverse cardiovascular effects, including QT interval prolongation, palpitations, and sinus tachycardia.1

Concomitant use of salmeterol and EVG/c/FTC/TDF is not recommended.1

Selective Serotonin-reuptake Inhibitors

Potential pharmacokinetic interactions with certain selective serotonin-reuptake inhibitors (SSRIs), including citalopram, escitalopram, fluoxetine, and paroxetine (increased SSRI plasma concentrations).1

If citalopram, escitalopram, fluoxetine, or paroxetine is used concomitantly with EVG/c/FTC/TDF, the lowest initial dosage of the SSRI should be used and dosage carefully titrated based on clinical response.1

Trazodone

Potential pharmacokinetic interaction with trazodone (increased trazodone plasma concentrations).1

If trazodone is initiated in a patient receiving EVG/c/FTC/TDF, the lowest initial dosage of the antidepressant should be used and dosage carefully titrated according to response.1

Tricyclic Antidepressants

Potential pharmacokinetic interactions with tricyclic antidepressants, including amitriptyline, desipramine, imipramine, and nortriptyline (increased tricyclic antidepressant plasma concentrations and AUC).1 Increased desipramine plasma concentrations and AUC reported when used concomitantly with cobicistat or EVG/c/FTC/TDF.1

If a tricyclic antidepressant is initiated in a patient receiving EVG/c/FTC/TDF, the lowest initial dosage of the antidepressant should be used and dosage carefully titrated based on clinical response and/or plasma concentrations of the antidepressant.1

Zolpidem

Pharmacokinetic interaction with zolpidem expected (increased zolpidem plasma concentrations).1

If zolpidem is used concomitantly with EVG/c/FTC/TDF, patients should be monitored clinically; reduced zolpidem dosage may be necessary.1

Dietary and Herbal Supplements

St. John's Wort

Potential pharmacokinetic interactions with St. John's wort ( Hypericum perforatum ) (decreased elvitegravir and/or cobicistat plasma concentrations); possible decreased antiretroviral efficacy and development of resistance.1

Concomitant use of St. John's wort and EVG/c/FTC/TDF is contraindicated.1

Other Information ⬆ ⬇

Description

The fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/c/FTC/TDF) contains elvitegravir (a human immunodeficiency virus [HIV] integrase strand transfer inhibitor [INSTI]), cobicistat (a pharmacokinetic enhancer), emtricitabine (an HIV nucleoside reverse transcriptase inhibitor [NRTI]), and tenofovir disoproxil fumarate (an HIV nucleotide reverse transcriptase inhibitor).1 Cobicistat, a potent cytochrome P-450 (CYP) 3A inhibitor, is included in the fixed combination to increase plasma concentrations of elvitegravir ( cobicistat-boosted elvitegravir).1

Elvitegravir inhibits the activity of HIV-1 integrase, an enzyme that is required for viral replication.1 This results in the inhibition of integration of HIV-1 DNA into host genomic DNA, which is required for maintenance of the viral genome and for efficient viral gene expression and replication.1 Inhibition of integration prevents propagation of viral infection.1 Elvitegravir is active against HIV-1 and also has some in vitro activity against HIV type 2 (HIV-2); the drug does not have activity against hepatitis B virus (HBV) or hepatitis C virus (HCV).1

Cobicistat is a selective mechanism-based inhibitor of CYP3A that decreases metabolism and increases plasma concentrations of CYP3A substrates; cobicistat also is a weak inhibitor of CYP2D6, but does not inhibit CYP1A2, 2C9, or 2C19.1 Cobicistat is included in EVG/c/FTC/TDF for therapeutic advantage and acts as a pharmacokinetic enhancer (also known as a booster) to increase systemic exposure of elvitegravir sufficient to allow for once-daily dosing ( cobicistat-boosted elvitegravir).1,200 Cobicistat does not have any antiretroviral or antiviral activity and is not active against HIV-1, HBV, or HCV; cobicistat does not antagonize the antiretroviral activity of elvitegravir, emtricitabine, or tenofovir.1

Emtricitabine, a synthetic nucleoside analog of cytidine, is a prodrug that is inactive until converted intracellularly to an active 5'-triphosphate metabolite.1 After conversion to the pharmacologically active metabolite, the drug acts as a reverse transcriptase inhibitor antiretroviral.1 Emtricitabine is active against HIV-1 and also has some in vitro activity against HIV-2.1

Tenofovir DF is a tenofovir prodrug and is inactive until it undergoes diester hydrolysis in vivo to tenofovir and is subsequently metabolized to the active metabolite (tenofovir diphosphate).1 After conversion to the pharmacologically active metabolite, the drug act as a reverse transcriptase inhibitor antiretroviral.200 Tenofovir is active against HIV-1 and also has some in vitro activity against HIV-2; the drug also is active against HBV.1

HIV-1 resistant to elvitegravir, emtricitabine, or tenofovir has been produced in vitro and has emerged during EVG/c/FTC/TDF therapy.1 In clinical trials evaluating EVG/c/FTC/TDF in antiretroviral-naïve patients, 1 or more primary mutations associated with resistance to elvitegravir, emtricitabine, and/or tenofovir were identified in HIV-1 isolates from 51% of patients who received EVG/c/FTC/TDF and were considered to be virologic treatment failures.1 Cross-resistance between elvitegravir and other HIV INSTIs (e.g., dolutegravir, raltegravir) has been reported.1 Cross-resistance also occurs among the HIV NRTIs.1

Following an oral dose of EVG/c/FTC/TDF given 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 Administration of EVG/c/FTC/TDF with a high-fat meal (approximately 800 kcal, 50% fat) increases mean systemic exposures of elvitegravir and tenofovir by 87 and 23%, respectively, compared with administration in the fasting state; mean systemic exposures of cobicistat and emtricitabine are decreased by 17 and 4%, respectively, compared with administration in the fasting state.1 Elvitegravir is approximately 99% and cobicistat is approximately 98% bound to plasma proteins; emtricitabine is less than 4% and tenofovir is less than 1% bound to plasma proteins.1 Elvitegravir is metabolized principally by CYP3A isoenzymes, but also undergoes glucuronidation via uridine diphosphate-glucuronsyltransferase (UGT) 1A1/3 enzymes.1 Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6.1 Although the cobicistat component of EVG/c/FTC/TDF acts as a pharmacokinetic enhancer for elvitegravir,1,200 cobicistat does not have any clinically important effects on the pharmacokinetics of emtricitabine or tenofovir DF.1 Elvitegravir and cobicistat are principally excreted in feces (94.8 and 86.2% of a dose, respectively) and to a lesser extent in urine (6.7 and 8.2% of a dose, respectively).1 Emtricitabine is principally excreted in urine (70% of a dose) and to a lesser extent in feces (13.7% of a dose); approximately 70-80% of a dose of TDF is excreted in urine.1 The median terminal plasma half-lives of elvitegravir, cobicistat, emtricitabine, and tenofovir are 12.9, 3.5, 10, and 12-18 hours, respectively.1 No clinically significant differences in the pharmacokinetics of EVG/c/FTC/TDF have been identified based on race or gender.1

Advice to Patients

Advise patients of the critical nature of compliance with HIV therapy and the importance of remaining under the care of a clinician.1 Importance of taking EVG/c/FTC/TDF as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1
Advise patients that EVG/c/FTC/TDF is a complete regimen for treatment of HIV-1 infection and should not be used in conjunction with other antiretroviral agents.1
Advise patients on the importance of taking EVG/c/FTC/TDF with food.1
If a dose is missed, take the dose as soon as it is remembered and take next dose at regularly scheduled time.1 If a dose is skipped, do not take a double dose to make up for the missed dose.1
Inform patients that testing for hepatitis B virus (HBV) infection is recommended before antiretroviral therapy is initiated.1 Also advise patients that severe acute exacerbations of HBV infection have been reported following discontinuance of emtricitabine or tenofovir DF in HIV-infected patients coinfected with HBV.1
Advise patients that renal impairment, including cases of acute renal failure or Fanconi syndrome, has occurred.1 Advise patients on the importance of not using EVG/c/FTC/TDF concomitantly with or shortly after nephrotoxic agents (e.g., high-dose or multiple nonsteroidal anti-inflammatory agents [NSAIAs]).1
Advise patients of reproductive potential that additional or nonhormonal methods of contraception should be used when estrogen-based contraceptives are used concomitantly with EVG/c/FTC/TDF.1
Advise patients that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have occurred with emtricitabine and tenofovir (components of EVG/c/FTC/TDF).1 Advise patients on the importance of contacting a clinician if symptoms suggestive of lactic acidosis or hepatotoxicity (e.g., nausea, vomiting, unusual/unexpected stomach discomfort, weakness) occur.1
Advise patients that decreased bone mineral density (BMD) has occurred and that assessment of BMD should be considered in those with a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.1
Advise patients that signs and symptoms of inflammation from previous infections may occur soon after initiation of antiretroviral therapy in some individuals with advanced HIV infection (AIDS).1 These symptoms may be due to an improvement in immune response, enabling the body to fight infections that may have been present with no obvious symptoms.1 Advise patients on the importance of immediately informing a healthcare provider if any symptoms of infection occur.1
Advise patients to inform their clinician 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
Advise women to inform clinician if they are or plan to become pregnant or plan to breast-feed.1 Due to the risk of HIV transmission, HIV-infected women should not breast-feed infants.1
Advise patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Disoproxil Fumarate

Copyright ⬆ ⬇

References ⬆