AHFS Class:

• HIV Nonnucleoside Reverse Transcriptase Inhibitors 8:18.08.16

Generic Name(s):

• Etravirine

Etravirine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI).1

Treatment of HIV Infection

Etravirine is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in treatment-experienced adult and pediatric patients 2 years of age or older.1,2,3,300,301,302,303

Etravirine can be used as part of a fully suppressive antiretroviral regimen in treatment-experienced patients.200,201 It is not recommended for use as part of an initial antiretroviral regimen in treatment-naive patients; safety and efficacy of etravirine have not been systematically evaluated in such patients.200,201,202

Clinical Experience

Antiretroviral-experienced Adults

Etravirine has been evaluated in 2 phase 3, randomized, double-blind, multicenter studies (TMC125-C206 [DUET-1], TMC125-C216 [DUET-2]) in treatment-experienced adults with clinically advanced HIV infection (baseline HIV-1 RNA levels >5000 copies/mL) who had received prior therapy and were receiving a stable regimen for at least 8 weeks at study entry.1,2,3 Adults enrolled in these studies had 1 or more NNRTI resistance-associated substitutions.1

A total of 1203 patients (median age 45-46 years, median baseline plasma HIV-1 RNA level 4.8 log₁₀ copies/mL, median baseline CD4⁺ T-cell count 99-109 cells/mm³) received an optimized background antiretroviral regimen (OBR) that included ritonavir-boosted darunavir, 2 NRTIs selected based on viral resistance testing and the patient's treatment history, and optional enfuvirtide.1,300 Patients were then randomized to receive etravirine 200 mg twice daily in conjunction with an OBR or an OBR alone.1,2,3,300 The primary outcome was the proportion of patients achieving a viral load <50 copies/mL at 24 weeks.2,3

At 24 weeks, 56% of patients receiving etravirine plus an OBR and 39% receiving an OBR alone had a viral load <50 copies/mL in DUET-1; corresponding results for DUET-2 were 62 and 44%, respectively.2,3 At 48 weeks, pooled results for DUET-1 and DUET-2 found that 60% of those receiving etravirine plus an OBR and 38% of those receiving an OBR alone were virologic responders (achieved plasma HIV-1 RNA levels <50 copies/mL); virologic failure (plasma HIV-1 RNA still at levels ≥50 copies/mL) was reported in 21% of those receiving etravirine plus an OBR and in 33% of those receiving an OBR alone.1 Among virologic responders at 24 weeks, 92 or 89% of those treated with etravirine or OBR alone, respectively, achieved sustained viral suppression at 48 weeks.300

At 48 weeks, 70.8 and 46.4% of those receiving etravirine or an OBR alone, respectively, had plasma HIV-1 RNA levels <400 copies/mL.1 Analysis at 48 weeks indicated that etravirine added to an OBR resulted in greater decreases in plasma HIV-1 RNA levels (-2.23 log₁₀ copies/mL) than an OBR alone (-1.46 log₁₀ copies/mL).1 Mean increases in CD4⁺ T-cell counts were greater in patients receiving etravirine in conjunction with an OBR (+96 cells/mm³) than in those receiving the OBR alone (+68 cells/mm³).1 Eighteen percent of those receiving etravirine and an OBR and 25% of those receiving an OBR alone discontinued therapy with these regimens before week 48.1

At 96 weeks, 57% of patients receiving etravirine and an OBR achieved a viral response (viral load <50 copies/mL) versus 36% of those receiving an OBR alone.301 Viral response from week 48 was maintained in 91 and 88% of patients treated with etravirine and OBR alone, respectively.301 The mean increase from baseline in CD4+ T-cell count was 128 cells/mm³ with etravirine compared with 86 cells/mm³ with an OBR alone.301

Antiretroviral-experienced Pediatric Patients

Safety and efficacy of etravirine in conjunction with other antiretrovirals for the treatment of HIV-1 infection in pediatric patients were evaluated in a single-arm, phase 2 trial (Study TMC125-C213, PIANO).1,302 A total of 101 treatment-experienced children and adolescents ≥6 to <18 years of age and weighing at least 16 kg who were receiving antiretroviral therapy were enrolled; patients were required to have plasma HIV-1 RNA levels ≥500 copies/mL.1 All patients were treated with etravirine (5.2 mg/kg, maximum dose 200 mg) twice daily plus an OBR.302 The primary efficacy outcome was virologic response (viral load <50 copies/mL).302 The median patient age was 12 years; median baseline plasma HIV-1 RNA was 3.9 log₁₀ copies/mL and median baseline CD4+ T-cell count was 385 cells/mm³.302 At 24 weeks, 52% of patients had plasma HIV-1 RNA levels <50 copies/mL and 67% had levels <400 copies/mL; the mean increase in CD4+ T-cell count from baseline was 112 cells/mm³.1 At 48 weeks, 56.4% of patients achieved a virologic response, with a mean increase from baseline in CD4+ T-cell count of 156 cells/mm³.302

The IMPAACT trial (TMC125-C234/IMPAACT 1090) was a phase 1/2 open-label trial that evaluated the efficacy of etravirine in 20 treatment-experienced pediatric patients 2 to <6 years of age.1 Enrolled patients had virologic failure after at least 8 weeks of treatment with an antiretroviral regimen or had treatment interrupted for at least 4 weeks, and a confirmed viral load >1000 copies/mL.1 Etravirine (dosed based on weight) was given twice daily with an OBR; virologic success was defined as an HIV-1 RNA level <400 copies/mL or ≥2 log reduction in viral load.303

At week 24, 50% of patients achieved a viral load <50 copies/mL, with 88% having an HIV-1 RNA level <400 copies/mL.1 Median reduction in HIV-1 RNA from baseline was -2.14 log₁₀ copies/mL, with a median CD4+ T-cell count increase from baseline of 298 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 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), an 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 However, etravirine is not recommended for treatment of antiretroviral-naïve patients due to a lack of data in this population.200,201

As an NNRTI, etravirine is used in treatment-experienced patients as part of a fully suppressive antiretrovial regimen in patients with virologic failure.200 In the 2023 HHS adult and adolescent HIV treatment guideline, etravirine is one of several agents recommended for use in patients with virologic failure.200

In the 2023 HHS pediatric HIV treatment guideline, for patients who have failed regimens that included NRTIs, NNRTIs, and PIs, etravirine is listed as an option that may be added to regimens containing an INSTI with or without a ritonavir-boosted PI.201

In the 2023 HHS perinatal HIV treatment guideline, etravirine is not recommended as initial therapy before or during pregnancy, but can be continued as part of a fully suppressive, well-tolerated existing antiretroviral regimen if pregnancy occurs during treatment.202 Etravirine is not recommended for treatment-experienced patients during or before pregnancy, but may be considered under special circumstances when needed to maintain or achieve viral suppression.202

Postexposure Prophylaxis following Occupational Exposure to HIV

Etravirine has been used in alternative regimens in conjunction with other antiretrovirals (NNRTIs or NRTIs) for postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel and other individuals.199

Clinical Perspective

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^®).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 These experts also state that etravirine is one of several alternative agents that may be used in conjunction with other antiretrovirals in PEP regimens.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

General

Patient Monitoring

• Monitor for signs or symptoms of severe skin reactions or hypersensitivity reactions (e.g., severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema).1

Administration

Etravirine is administered orally twice daily following a meal.1

Etravirine tablets should be swallowed whole with a liquid (e.g., water) and should not be chewed.1

For patients unable to swallow tablets whole, the dose of etravirine tablets may be placed in 5 mL of water (enough water to cover the tablets) and stirred until a uniform, milky dispersion occurs.1 Add 15 mL (1 tablespoon) of liquid; water may be used, but orange juice or milk may improve taste.1 Do not use carbonated beverages or warm (>40°C) water.1 The dispersion should be consumed immediately; to ensure consumption of the entire dose, the glass should be rinsed several times with water, orange juice, or milk and each rinse swallowed.1

Store etravirine tablets at 25°C (excursions permitted between 15-30°C).1 Store in the original bottle.1 Keep the bottle tightly closed in order to protect from moisture.1 Do not remove the desiccant pouches.1

Dosage

Adult Dosage

Treatment of HIV Infection

For the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-experienced adults, the recommended dosage of etravirine is 200 mg orally twice daily.1 Each dose can be taken as a single 200-mg tablet or two 100-mg tablets.1

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 etravirine is 200 mg orally twice daily.199 Etravirine is used in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).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

Dosage of etravirine for the treatment of HIV-1 infection in antiretroviral-experienced pediatric patients 2 years to less than 18 years of age weighing at least 10 kg is based on weight and should not exceed the recommended adult dosage.1 (See Table 1.)

Special Populations

Hepatic Impairment

Dosage adjustments are not needed in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 Etravirine pharmacokinetics have not been studied in patients with severe hepatic impairment (Child-Pugh class C).1

Dosage adjustments are not needed in HIV-infected adults coinfected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV).1

Renal Impairment

Dosage adjustments are not needed in patients with renal impairment.1

Geriatric Patients

In general, dosage selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.1

Contraindications

None.1

Warnings/Precautions

Severe Skin and Hypersensitivity Reactions

Severe, potentially life-threatening and fatal skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme, have been reported in patients receiving etravirine.1 Hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), also have been reported and were characterized by rash and systemic symptoms, and sometimes involved organ dysfunction (e.g., hepatic failure).1 Stevens-Johnson syndrome was reported in 1.1% (2/177) of pediatric patients less than 18 years of age treated with etravirine in combination with other HIV-1 antiretroviral agents in an observational study.1

Etravirine should be discontinued immediately and appropriate therapy initiated if severe hypersensitivity reactions (e.g., severe rash or rash with fever, malaise, fatigue, muscle or joint pain, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, or angioedema) occur.1 Clinical status and liver transaminase concentrations should be monitored.1 Delay in discontinuing etravirine after the onset of severe rash can result in a life-threatening reaction.1

Rash of mild to moderate intensity has been reported in etravirine-treated patients in clinical studies.1,2,3 Rash generally occurred within the first few weeks of therapy1 and resolved with continued therapy (median duration 12-16 days).1,2,3 In phase 3 studies in adults, 2.2% of etravirine-treated patients discontinued therapy because of rash.1,2,3

The manufacturer states that individuals with a history of rash related to other HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) do not appear to be at increased risk for etravirine-related rash compared to those without a history of NNRTI-associated rash.1

Drug Interactions

Concomitant use of etravirine and other drugs may result in potentially significant drug interactions, some of which may lead to loss of therapeutic effect of the concomitant drug or etravirine and possible development of resistance.1 Such drug interactions may also result in potentially clinically significant adverse reactions from greater exposure of etravirine or other concomitant drugs.1

Consider the potential for drug interactions prior to and during etravirine therapy and review concomitant medications during therapy.1

Fat Redistribution

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance have been reported in patients receiving antiretroviral therapy.1 The mechanisms and long-term consequences of fat redistribution are unknown; a causal relationship has not been established.1

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium , M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]); this may necessitate further evaluation and treatment.1

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

Specific Populations

Pregnancy

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to etravirine during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting [Web].1,202

Etravirine has been evaluated in a limited number of women during pregnancy.1 In animal studies, etravirine was not associated with adverse developmental effects at exposures equivalent to those at the maximum recommended human dose.1

Based on prospective reports from the APR of 116 live births following exposure to etravirine-containing antiretroviral regimens during pregnancy, the number of birth defects in live births for etravirine was 1 out of 66 with first trimester exposure and 0 out of 38 with second/third trimester exposure.1

Lactation

Based on limited data, etravirine has been shown to be present in human breast milk.1 There are no data on the effects on the breastfed infant or the effects of etravirine on milk production.1

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

Pediatric Use

Safety and efficacy of etravirine have not been established in pediatric patients younger than 2 years of age.1 Five HIV-infected subjects from 1 year to less than 2 years of age were enrolled in the TMC125-C234/IMPAACT P1090 study.1 Etravirine exposure in these pediatric subjects was lower than that reported in HIV-infected adults.1

Safety, efficacy, and pharmacokinetics of etravirine have been evaluated in antiretroviral-experienced pediatric patients 2 years to less than 18 years of age weighing at least 10 kg.1 Adverse effects reported in pediatric patients in a clinical study after 24 weeks of etravirine therapy were similar to those reported in adults (e.g., rash, diarrhea), although rash was reported more frequently in pediatric patients than in adults.1 Postmarketing cases of Stevens-Johnson syndrome have been reported in pediatric patients treated with etravirine.1

Geriatric Use

Insufficient experience in patients 65 years of age and older to determine whether they respond differently than younger adults.1 Population pharmacokinetic analysis in HIV-infected subjects showed that etravirine pharmacokinetics are not considerably different within the age range (18-77 years) evaluated.1

Hepatic Impairment

Pharmacokinetics of etravirine are not altered in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1,12 Pharmacokinetics of the drug have not been studied in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

Renal clearance of etravirine is minimal; decrease in clearance of the drug is not expected in patients with renal impairment.1 Etravirine is not expected to be significantly removed by hemodialysis or peritoneal dialysis due to the high rate of plasma protein binding.1

Common Adverse Effects

The most common adverse effects (≥2%) of moderate to severe intensity occurring at a higher rate than placebo in adults are rash and peripheral neuropathy.1

The most common adverse effects (≥2%) of pediatric patients are rash and diarrhea.1

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Etravirine is metabolized by the cytochrome P-450 (CYP) isoenzymes 3A, 2C9, and 2C19; potential pharmacokinetic interactions exist with drugs that induce or inhibit these isoenzymes (altered metabolism of etravirine).1

Etravirine induces CYP3A and inhibits CYP2C9 and 2C19; potential pharmacokinetic interactions exist with drugs that are substrates for these isoenzymes (altered metabolism of the drug that is a substrate).1

Drugs Affected by P-glycoprotein Transport

Etravirine is an inhibitor of the P-glycoprotein (P-gp) transport system; potential pharmacokinetic interactions exist with drugs that are substrates for P-gp.1

Antiarrhythmic Agents

Potential pharmacokinetic interaction exists with amiodarone, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, and quinidine (decreased plasma concentrations of the antiarrhythmic agent).1 The drugs should be used concomitantly with caution; plasma concentrations of the antiarrhythmic agent should be monitored.1

Potential pharmacokinetic interaction exists with digoxin (increased digoxin plasma concentrations; no change in etravirine plasma concentrations).1 If digoxin and etravirine therapy are initiated at the same time, digoxin should be initiated at the lowest dosa if etravirine is initiated in a patient already receiving stable dosages of digoxin, dosage adjustment is not needed for either drug.1 Serum digoxin concentrations should be monitored and digoxin dosage adjusted to achieve the desired clinical effect in patients receiving concomitant etravirine.1

Anticoagulants

Potential pharmacokinetic interaction exists with warfarin (increased plasma concentrations of warfarin).1 International normalized ratio (INR) should be monitored if warfarin is used concomitantly with etravirine; warfarin dosage should be adjusted if needed.1

Anticonvulsants

Potential pharmacokinetic interaction exists with carbamazepine, phenobarbital, and phenytoin (decreased etravirine plasma concentrations with possible decreased antiretroviral efficacy).1 Concomitant use of these anticonvulsants with etravirine is not recommended.1

Antifungal Agents

Fluconazole

Potential pharmacokinetic interaction exists with fluconazole (substantially increased etravirine plasma concentrations and area under the plasma concentration-time curve [AUC], no clinically important change in fluconazole plasma concentrations or AUC).1 Although dosage adjustments are not needed for either drug, caution is advised because only limited data are available regarding the safety of increased etravirine concentrations.1

Itraconazole and Ketoconazole

Potential pharmacokinetic interaction exists with itraconazole or ketoconazole (increased etravirine plasma concentrations; decreased plasma concentrations of the antifungal agent).1 Adjustment of itraconazole or ketoconazole dosage may be needed depending on other concomitantly administered drugs.1

Posaconazole

Potential pharmacokinetic interaction exists with posaconazole (increased etravirine plasma concentrations; no change in posaconazole concentrations).1 The manufacturer of etravirine states that dosage adjustment of posaconazole may be needed depending on other concomitantly administered drugs.1

Voriconazole

Potential pharmacokinetic interaction exists with voriconazole (substantially increased etravirine plasma concentrations and AUC; increased voriconazole plasma concentrations and AUC).1 Because of limited data regarding the safety of increased etravirine concentrations, caution is advised when etravirine is administered concomitantly with voriconazole.1 Dosage adjustments are not needed for either drug.1

Antimalarial Agents

Concomitant use of the fixed combination of artemether and lumefantrine (artemether/lumefantrine) and etravirine decreases plasma concentrations and AUC of artemether, the active metabolite of artemether (dihydroartemisinin), and lumefantrine, but does not have a clinically important effect on etravirine plasma concentrations or AUC.1 Although dosage adjustments are not needed, artemether/lumefantrine and etravirine should be used concomitantly with caution since it is unknown whether the decreased artemether or dihydroartemisinin exposure results in decreased antimalarial efficacy.1

Antimycobacterial Agents

Potential pharmacokinetic interaction exists with rifabutin (decreased etravirine plasma concentrations; decreased rifabutin plasma concentrations).1 The recommended rifabutin dosage is 300 mg once daily in patients receiving etravirine, provided a ritonavir-boosted HIV protease inhibitor (PI) is not included in the regimen.1 Rifabutin is not recommended in patients receiving etravirine with a ritonavir-boosted PI (e.g., ritonavir-boosted darunavir, fixed combination of lopinavir and ritonavir [lopinavir/ritonavir], ritonavir-boosted saquinavir).1

Potential pharmacokinetic interaction exists with rifampin or rifapentine (substantially decreased etravirine plasma concentrations); this may result in decreased antiretroviral efficacy.1 Concomitant use of etravirine and rifampin or rifapentine is not recommended.1

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Enfuvirtide

Dosage adjustments are not needed if etravirine is used concomitantly with enfuvirtide.1

No in vitro evidence of antagonistic antiretroviral effects between etravirine and enfuvirtide.1

Maraviroc

Potential pharmacokinetic interaction exists with maraviroc (decreased maraviroc plasma concentrations and AUC; no clinically important effects on etravirine plasma concentrations or AUC).1

If maraviroc is used concomitantly with etravirine, the recommended maraviroc dosage is 600 mg twice daily with the usual etravirine dosage, provided the regimen does not include a potent CYP3A inhibitor (e.g., a ritonavir-boosted PI).1

If etravirine is used in a regimen that contains maraviroc and a ritonavir-boosted PI, the recommended maraviroc dosage is 150 mg twice daily with the usual etravirine dosage.1

No in vitro evidence of antagonistic antiretroviral effects between etravirine and maraviroc.1

HIV Integrase Inhibitors (INSTIs)

Dolutegravir

Concomitant use of etravirine and dolutegravir results in substantially decreased plasma concentrations and AUC of dolutegravir, but does not appear to affect the pharmacokinetics of etravirine.1 The effect on dolutegravir pharmacokinetics is mitigated if ritonavir-boosted darunavir or lopinavir/ritonavir is used concomitantly with etravirine and dolutegravir and may also be mitigated if ritonavir-boosted atazanavir is used concomitantly with etravirine and dolutegravir.1

The manufacturer states that dolutegravir and etravirine should not be used concomitantly unless ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir is included in the regimen.1

Raltegravir

Potential pharmacokinetic interaction exists with raltegravir (decreased raltegravir plasma concentrations and AUC; no clinically important effect on etravirine pharmacokinetics).1 Dosage adjustments are not necessary if raltegravir is used concomitantly with etravirine.1

No in vitro evidence of antagonistic antiretroviral effects between etravirine and raltegravir.1

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Concomitant use of etravirine and other NNRTIs is not recommended.1

Delavirdine

Possible pharmacokinetic interaction with delavirdine (increased etravirine plasma concentrations).1 Etravirine and delavirdine should not be used concomitantly.1

Efavirenz

Pharmacokinetic interaction with efavirenz (decreased etravirine plasma concentrations) and loss of antiretroviral efficacy.1 Etravirine and efavirenz should not be used concomitantly.1

Nevirapine

Pharmacokinetic interaction with nevirapine (decreased etravirine plasma concentrations) and loss of antiretroviral efficacy.1 Etravirine and nevirapine should not be used concomitantly.1

Rilpivirine

Possible pharmacokinetic interaction with rilpivirine (decreased rilpivirine plasma concentrations; no change in etravirine concentrations).1 Rilpivirine and etravirine should not be used concomitantly.1

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

No in vitro evidence of antagonism between etravirine and NRTIs (abacavir, didanosine, emtricitabine, lamivudine, tenofovir, zidovudine).1

Didanosine

Concomitant use of etravirine and didanosine does not have a clinically important effect on the plasma concentrations or AUC of either drug.1 Dosage adjustments are not needed if the drugs are used concomitantly.1

Tenofovir

Potential pharmacokinetic interaction exists with tenofovir disoproxil fumarate (decreased etravirine plasma concentrations; no change in tenofovir plasma concentrations).1 Dosage adjustments are not needed.1

HIV Protease Inhibitors

There is no in vitro evidence of antagonism between etravirine and PIs (amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir).1

Use of etravirine in a PI-based regimen that does not include low-dose ritonavir is not recommended.1 Etravirine may be used concomitantly with ritonavir-boosted darunavir, lopinavir/ritonavir, or ritonavir-boosted saquinavir.1 However, concomitant use of etravirine and atazanavir (with or without low-dose ritonavir), fosamprenavir (with or without low-dose ritonavir), or ritonavir-boosted tipranavir is not recommended.1

Atazanavir

Potential pharmacokinetic interaction exists between atazanavir (with or without low-dose ritonavir) and etravirine (increased etravirine plasma concentrations and AUC; decreased atazanavir plasma concentrations and possible decreased antiretroviral efficacy).1

Etravirine and atazanavir should not be used concomitantly without low-dose ritonavir.1 Dose adjustments are not needed if etravirine is used concomitantly with ritonavir-boosted atazanavir.1 Co-administration of etravirine with atazanavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to atazanavir.1

Darunavir

Potential pharmacokinetic interaction exists with ritonavir-boosted darunavir (decreased etravirine plasma concentrations and AUC; no clinically important effect on darunavir plasma concentrations and AUC).1 Safety and efficacy of concomitant use of etravirine and ritonavir-boosted darunavir were established in phase 3 clinical studies.1,2,3 Co-administration of etravirine with darunavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir.1

Dosage adjustments are not needed if etravirine is used concomitantly with ritonavir-boosted darunavir.1

Fosamprenavir

Potential pharmacokinetic interaction exists with fosamprenavir or ritonavir-boosted fosamprenavir (substantially increased plasma concentrations of amprenavir [active metabolite of fosamprenavir]).1

Etravirine and fosamprenavir (with or without low-dose ritonavir) should not be used concomitantly.1

Indinavir

Potential pharmacokinetic interaction exists with indinavir (without low-dose ritonavir) (decreased indinavir plasma concentrations).1

Etravirine and indinavir should not be used concomitantly without low-dose ritonavir.1

Lopinavir

Potential pharmacokinetic interaction exists with lopinavir/ritonavir (decreased etravirine plasma concentrations and AUC; decreased lopinavir plasma concentrations and AUC).1 Because the decrease in etravirine systemic exposure reported with concomitant lopinavir/ritonavir is similar to that reported in patients receiving etravirine concomitantly with ritonavir-boosted darunavir (a combination that has been found to be safe and effective), the manufacturer and some experts state that the usual etravirine dosage can be used with the usual lopinavir/ritonavir dosage.1

Nelfinavir

Potential pharmacokinetic interaction exists with nelfinavir (without low-dose ritonavir) (increased nelfinavir plasma concentrations).1

Etravirine and nelfinavir should not be used concomitantly without low-dose ritonavir.1

Ritonavir

Potential pharmacokinetic interaction exists with full-dose ritonavir (substantially decreased etravirine plasma concentrations); possible decreased antiretroviral efficacy.1 Etravirine and full-dose ritonavir (600 mg twice daily) should not be used concomitantly.1

Etravirine can be used in conjunction with low-dose ritonavir (usually 100 mg once or twice daily) in certain ritonavir-boosted PI regimens (i.e., ritonavir-boosted darunavir, lopinavir/ritonavir, ritonavir-boosted saquinavir).1 Etravirine and ritonavir-boosted fosamprenavir or ritonavir-boosted tipranavir should not be used concomitantly.1

Saquinavir

Potential pharmacokinetic interaction exists with ritonavir-boosted saquinavir (saquinavir 1 g twice daily and ritonavir 100 mg twice daily) (decreased etravirine AUC; no change in saquinavir plasma concentrations).1 The decrease in systemic exposure to etravirine was similar to that reported in patients receiving etravirine in conjunction with ritonavir-boosted darunavir, a combination that has been found to be safe and effective.1

Dosage adjustments are not needed if etravirine is used concomitantly with ritonavir-boosted saquinavir (saquinavir 1 g twice daily with ritonavir 100 mg twice daily).1

Tipranavir

Potential pharmacokinetic interaction exists with ritonavir-boosted tipranavir (decreased etravirine plasma concentrations and possible decreased antiretroviral efficacy; increased tipranavir plasma concentrations).1

Etravirine and ritonavir-boosted tipranavir should not be used concomitantly.1

Benzodiazepines

Potential pharmacokinetic interaction exists with diazepam (increased plasma concentrations of diazepam).1 Decrease in diazepam dosage may be needed.1

Clarithromycin

Potential pharmacokinetic interaction exists with clarithromycin (increased etravirine plasma concentrations, decreased plasma concentrations of clarithromycin and increased concentrations of its major metabolite [14-hydroxyclarithromycin]).1 Because the clarithromycin metabolite has reduced activity against Mycobacterium avium complex (MAC), an alternative to clarithromycin (e.g., azithromycin) should be used for the treatment or prophylaxis of MAC in patients receiving etravirine.1

Clopidogrel

Potential pharmacokinetic interaction exists with clopidogrel (decreased concentrations of the active metabolite of clopidogrel).1 Concomitant use of clopidogrel and etravirine should be avoided, if possible; consider alternatives to clopidogrel.1

Corticosteroids

Potential pharmacokinetic interaction exists with dexamethasone (decreased etravirine plasma concentrations); possible decreased antiretroviral efficacy.1 Systemic dexamethasone therapy should be used with caution in patients receiving etravirine; an alternative to dexamethasone should be considered, especially when long-term use of the corticosteroid is anticipated.1

Estrogens/Progestins

Dosage adjustments are not needed if etravirine is used concomitantly with oral contraceptives containing ethinyl estradiol and norethindrone.1

GI Drugs

Potential pharmacokinetic interaction exists with omeprazole (increased etravirine plasma concentrations).1 Dosage adjustments are not needed.1

HCV Antivirals

HCV Direct-Acting Antivirals

Daclastavir

Coadministration of etravirine with daclatasvir may decrease daclatasvir concentrations.1 Increase the dosage of daclatasvir to 90 mg once daily.1

Elbasvir/grazoprevir

Coadministration of etravirine with elbasvir/grazoprevir may decrease concentrations of elbasvir and grazoprevir, leading to reduced therapeutic effect of elbasvir/grazoprevir.1 Avoid coadministration.1

HMG-CoA Reductase Inhibitors

Pharmacokinetic interactions are possible between efavirenz and certain hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins), including atorvastatin, fluvastatin, lovastatin, pitavastatin, and simvastatin.1

Atorvastatin

Potential pharmacokinetic interaction exists with atorvastatin (decreased atorvastatin plasma concentrations; no change in etravirine plasma concentrations).1 Usual atorvastatin dosage can be used with usual etravirine dosa dosage of atorvastatin may need to be adjusted based on clinical response.1

Fluvastatin

Potential pharmacokinetic interaction exists with fluvastatin (increased fluvastatin plasma concentrations; no change in etravirine plasma concentrations).1 Fluvastatin dosage adjustments may be needed.1

Lovastatin

Potential pharmacokinetic interaction exists with lovastatin (decreased lovastatin plasma concentrations).1 Lovastatin dosage may need to be adjusted based on clinical response.1

Pitavastatin

Potential pharmacokinetic interaction exists with pitavastatin (increased pitavastatin plasma concentrations).1 Pitavastatin dosage adjustments may be needed.1

Simvastatin

Potential pharmacokinetic interaction exists with simvastatin (decreased simvastatin plasma concentrations).1 Simvastatin dosage may need to be adjusted based on clinical response.1

Immunosuppressive Agents

Possible pharmacokinetic interaction with cyclosporine, sirolimus, and tacrolimus (decreased plasma concentrations of the immunosuppressive agent).1 The drugs should be used concomitantly with caution.1

Opiates and Opiate Partial Agonists

Buprenorphine

Concomitant use of buprenorphine or fixed combination of buprenorphine and naloxone (buprenorphine/naloxone) and etravirine results in decreased buprenorphine concentrations and AUC but does not affect norbuprenorphine or etravirine concentrations.1 Dosage adjustments are not needed if buprenorphine or buprenorphine/naloxone are used concomitantly with etravirine; however, monitor patients for withdrawal symptoms since adjustment of buprenorphine or buprenorphine/naloxone maintenance dosage may be needed in some patients.1

Methadone

Concomitant use with methadone does not appear to have a clinically important effect on plasma concentrations of etravirine or methadone; dosage adjustments are not needed.1 However, monitor patients for withdrawal symptoms since adjustments of methadone maintenance dosage may be needed in some patients.1

Paroxetine

Concomitant use with paroxetine does not appear to affect plasma concentrations of etravirine or paroxetine.1 Dosage adjustments are not needed.1

Phosphodiesterase Type 5 Inhibitors

Pharmacokinetic interaction with sildenafil (decreased plasma concentrations of sildenafil and its active N -desmethyl metabolite).1 Usual etravirine dosages can be used with usual sildenafil dosages; however, dosage of sildenafil may need to be increased based on clinical effect.1

Possible pharmacokinetic interaction with tadalafil or vardenafil.1

St. John's Wort ( Hypericum perforatum )

Potential pharmacokinetic interaction with St. John's wort ( Hypericum perforatum ) (substantially decreased plasma concentrations of etravirine); possible decreased antiretroviral efficacy.1 Concomitant use is not recommended.1

Description

Etravirine, a diarylpyrimidine human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI), inhibits replication of HIV type 1 (HIV-1) by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.1,4 Etravirine is highly active against wild-type HIV-1 and has been active against some clinical HIV-1 isolates resistant to some other commercially available NNRTIs (delavirdine, efavirenz, nevirapine).1,3,4 Etravirine appears to have a different resistance profile than other NNRTIs and certain single mutations that result in class resistance to other NNRTIs may not necessarily result in resistance to etravirine.2,3,4 However, cross-resistance can occur between etravirine and other commercially available NNRTIs (delavirdine, etravirine, nevirapine, rilpivirine),1,4 and is expected in patients who have virologic failure while receiving a regimen that contains etravirine.1

The absolute oral bioavailability of etravirine is unknown.1 Following oral administration in adults, peak plasma concentrations are attained within approximately 2.5-4 hours.1,11 Food enhances etravirine bioavailability;1,11 systemic exposure is 50% lower if the drug is administered under fasting conditions compared with following a meal.1 The effect of food on etravirine bioavailability was studied using various meals (standard, light, enhanced-fiber, high-fat);11 the magnitude of the food effect is similar with all meal types.1,11 Distribution of etravirine into compartments other than plasma (e.g., CSF, genital tract secretions) has not been evaluated.1 Etravirine crosses the placenta and has been detected in cord blood.202 Based on limited data, etravirine has been shown to be present in human breast milk.1 Etravirine is 99.9% bound to protein, principally albumin and alpha 1-acid glycoprotein.1

Etravirine is metabolized principally in the liver by cytochrome P-450 (CYP) isoenzymes 3A, 2C9, and 2C19.1 In cell culture, the major metabolites of etravirine are at least 90% less active than the parent drug against wild-type HIV.1 Following oral administration of a single etravirine dose in adults, the majority (93.7%) of the dose is eliminated in feces as unchanged etravirine (81.2-86.4%).1 Up to 1.2% of the dose is eliminated in urine as metabolites.1 Etravirine is not likely to be removed by hemodialysis or peritoneal dialysis.1 The mean terminal elimination half-life of etravirine in adults is about 41 hours.1

The pharmacokinetics of etravirine have not been studied in patients with renal impairment; alterations are not expected because renal clearance is minimal.1 The pharmacokinetics of etravirine are not altered in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B);1,12 data are not available regarding patients with severe hepatic impairment (Child-Pugh Class C).1 Clearance of etravirine may be reduced in HIV-infected patients coinfected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV).1 Studies in geriatric individuals up to 77 years of age did not identify any substantial differences in etravirine pharmacokinetics relative to younger adults.1 In pediatric patients 2 years to less than 18 years of age weighing at least 10 kg, weight-based etravirine dosage results in etravirine systemic exposures similar to those reported in adults receiving 200 mg twice daily.1

Advice to Patients

• Advise patients of the critical nature of compliance with human immunodeficiency virus (HIV) therapy and importance of remaining under the care of a clinician.1 Inform patients of the importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting a clinician.1
• Advise patients of the importance of using etravirine in conjunction with other antiretrovirals and to not use for monotherapy.1
• Advise patients of the importance of taking etravirine twice daily after a meal on a regular dosing schedule.1 Food enhances absorption of the drug; magnitude of the food effect is similar with all meal types (standard, light, enhanced-fiber, high-fat).1,11
• Advise patients to swallow the tablets whole with liquid (e.g., water) without chewing.1 Patients unable to swallow tablets whole may disperse the tablets in 5 mL (1 teaspoon) of water (enough to cover the tablets); after dispersion in water, orange juice, milk, or water (approximately 15 mL, 1 tablespoon) may be added to the mixture.1 Ingest the liquid containing the dispersed etravirine tablets immediately, then rinse the glass several times with water, orange juice, or milk and drink the rinse each time to ensure that the entire dose is ingested.1 Warm water (greater than 40°C) or carbonated beverages should not be used.1
• Inform patients that if a missed dose is remembered within 6 hours of the usually scheduled time, it should be taken after a meal as soon as possible and the next dose taken at the regularly scheduled time.1 If the missed dose is remembered more than 6 hours after the scheduled time, the dose should be omitted and the next dose taken at the regularly scheduled time.1
• Advise patients that a severe and potentially life-threatening rash has occurred (usually within the first few weeks of etravirine therapy).1 Advise patients on the importance of immediately contacting clinician if rash occurs.1 Advise patients on the importance of immediately discontinuing etravirine and seeking medical care if rash associated with systemic symptoms (e.g., fever, generally ill feeling, extreme tiredness, muscle or joint aches, blisters, oral lesions, eye inflammation, swelling of the face, eyes, lips, or mouth, breathing difficulties, yellowing of the eyes or skin, dark or tea colored urine, pale colored stools, nausea, vomiting, loss of appetite, or right upper quadrant tenderness/pain) occurs.1
• Inform patients that redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1
• Advise patients to inform their healthcare provider immediately of any symptoms of infection, since in some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started.1
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses.1
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1 Advise HIV-infected women not to breast-feed.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.

1. Janssen. Intelence^® (etravirine) tablets prescribing information. Titusville, NJ; 2023 Mar.

2. Madruga JV, Cahn P, Grinsztejn B et al; DUET-1 Study Group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1 infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet . 2007; 370:29-38. [PubMed 17617270]

3. Lazzarin A, Campbell T, Clotet B et al; DUET-2 Study Group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1 infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet . 2007; 370:39-48. [PubMed 17617271]

4. Vingerhoets J, Azijn H, Fransen E et al. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J Virol . 2005; 79:12773-82. [PubMed 16188980]

8. Schöller-Gyüre M, van den Brink W, Kakuda TN et al. Pharmacokinetic and pharmacodynamic study of the concomitant administration of methadone and TMC125 in HIV-negative volunteers. J Clin Pharmacol . 2008; 48:322-9.

11. Schöller-Gyüre M, Boffito M, Pozniak AL et al. Effects of different meal compositions and fasted state on the oral bioavailability of etravirine. Pharmacotherapy . 2008; 28:1215-22. [PubMed 18823217]

12. Schöller-Gyüre M, Kakuda TN, De Smedt G et al. Effects of hepatic impairment on the steady-state pharmacokinetics of etravirine 200 mg BID: an open-label, multiple-dose, controlled Phase I study in adults. Clin Ther . 2010; 32:328-37. [PubMed 20206790]

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

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (March 23, 2023). Updates may be available at HIV.gov website. [Web]

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 (April 11, 2023). Updates may be available at HIV.gov website. [Web]

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 (January 31, 2023). Updates may be available at HIV.gov website. [Web]

300. Katlama C, Haubrich R, Lalezari J et al; DUET-1, DUET-2 Study Groups. Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials. AIDS. 2009;23:2289-2300.

301. Katlama C, Clotet B, Mills A, et al. Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials. Antivir Ther. 2010;15:1045-1052.

302. Tudor-Williams G, Cahn P, Chokephaibulkit K et al; PIANO Study Group. Etravirine in treatment-experienced, HIV-1 infected children and adolescents: 48-week safety, efficacy and resistance analysis of the phase II PIANO study. HIV Med. 2014;15:513-524.

303. MacBrayne C, Rutstein R, Wiznia A et al; and the IMPACT P1090 Protocol Team. Etravirine in treatment-experienced HIV-infected children 1 year to less than 6 years of age. AIDS. 2021;35:1413-1421.