Etravirine (Monograph)

Brand name: Intelence
Drug class: HIV Nonnucleoside Reverse Transcriptase Inhibitors

Medically reviewed by Drugs.com on Feb 10, 2024. Written by ASHP.

[Web]

Introduction

Antiretroviral; HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).

Uses for Etravirine

Treatment of HIV Infection

Treatment of HIV-1 infection in adults and pediatric patients ≥2 years of age who are treatment-experienced; used in conjunction with other antiretrovirals.

Used as part of a fully suppressive antiretroviral regimen in treatment-experienced patients.

Safety and efficacy not systematically evaluated in treatment-naïve patients.

Postexposure Prophylaxis following Occupational Exposure to HIV

Postexposure prophylaxis of HIV infection following occupational exposure^{† [off-label]} (PEP) in health-care personnel and other individuals.

USPHS recommends 3-drug regimen of raltegravir in conjunction with emtricitabine and tenofovir disoproxil fumarate (tenofovir DF) as the preferred regimen for PEP following occupational exposures to HIV. Etravirine and 2 NRTIs is one of several alternative regimens.

Management of occupational exposures to HIV is complex and evolving; consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible. Do not delay initiation of PEP while waiting for expert consultation.

Etravirine Dosage and Administration

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).

Administration

Oral Administration

Administer orally twice daily after a meal.

Swallow tablets whole with a liquid (e.g., water); do not chew.

For patients unable to swallow tablets whole, place dose of etravirine tablets in 5 mL of water (enough to cover tablets) and stir until a uniform, milky dispersion occurs. Add 15 mL (1 tablespoon) of liquid; water may be used, but orange juice or milk may improve taste. Do not use carbonated beverages or warm (>40°C) water. Consume dispersion immediately; rinse glass several times with water, orange juice, or milk and swallow.

Dosage

Pediatric Patients

Treatment of HIV Infection

Antiretroviral-experienced

Oral

Children 2 years to <18 years of age weighing ≥10 kg: Dosage is based on weight and should not exceed recommended adult dosage. (See Table 1.)

Adults

Treatment of HIV Infection

Antiretroviral-experienced

Oral

200 mg twice daily. Give dose as a single 200-mg tablet or two 100-mg tablets.

Postexposure Prophylaxis following Occupational Exposure to HIV† [off-label]

Oral

200 mg twice daily. Use in conjunction with 2 NRTIs.

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.

Special Populations

Hepatic Impairment

Dosage adjustments not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Pharmacokinetics not studied in patients with severe hepatic impairment (Child-Pugh class C).

Dosage adjustments not necessary in HIV-infected adults coinfected with HBV and/or HCV.

Renal Impairment

Dosage adjustments not necessary.

Geriatric Patients

No specific dosage recommendations. Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Cautions for Etravirine

Contraindications

• None.

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, reported. Hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms (DRESS) characterized by rash and systemic symptoms (sometimes involving organ dysfunction such as hepatic failure), also reported.

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, angioedema) occur, immediately discontinue etravirine and initiate appropriate therapy. Monitor clinical status and liver transaminase concentrations.

Rash of mild to moderate intensity also reported; generally occurs within first few weeks of therapy and resolves with continued therapy (median duration 12–16 days).

Manufacturer states that history of rash while receiving other NNRTIs does not appear to increase the risk for etravirine-related rash.

Drug Interactions

Risk of potentially significant drug interactions; may lead to loss of therapeutic effect or clinically significant adverse reactions.

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

Fat Redistribution

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance. Mechanisms and long-term consequences of fat redistribution unknown; causal relationship not established.

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]); may necessitate further evaluation and treatment.

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

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry (APR) at 800-258-4263 or [Web].

Limited human data indicate 1 birth defect in 66 first trimester exposures to etravirine-containing regimens. In animal studies, etravirine was not associated with adverse developmental effects.

Lactation

Based on limited data, etravirine shown to be present in human breast milk. No data on effects on the breastfed infant or the effects on milk production.

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.

Pediatric Use

Safety and efficacy not established in pediatric patients <2 years of age.

Safety, efficacy, and pharmacokinetics evaluated in antiretroviral-experienced pediatric patients 2 years to <18 years of age weighing ≥10 kg; adverse effects similar to those reported in adults, although rash reported more frequently in pediatric patients. Postmarketing cases of Stevens-Johnson syndrome reported.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults. Etravirine pharmacokinetics not considerably different within the age range (18–77 years) evaluated.

Hepatic Impairment

Pharmacokinetics not altered in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Pharmacokinetics not studied in patients with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

Minimal renal clearance; decrease in clearance not expected in patients with renal impairment.

Common Adverse Effects

Most common adverse effects (≥2%) of moderate to severe intensity in adults: rash and peripheral neuropathy.

Most common adverse effects (≥2%) in pediatric patients: rash and diarrhea.

Drug Interactions

Metabolized by CYP isoenzymes 3A, 2C9, and 2C19. Induces CYP3A; inhibits 2C9 and 2C19. Inhibits P-glycoprotein (P-gp).

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Potential pharmacokinetic interactions with drugs that induce or inhibit CYP3A, 2C9, or 2C19 with possible altered metabolism of etravirine.

Potential pharmacokinetic interaction with drugs that are substrates for CYP3A, 2C9, or 2C19 with possible altered metabolism of such drugs.

Drugs Affected by P-gp Transport

Potential pharmacokinetic interaction with drugs that are substrates for P-gp.

Specific Drugs

Etravirine Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability is unknown.

Following oral administration in adults, peak plasma concentrations attained within approximately 2.5–4 hours.

Food

Systemic exposure is decreased by about 50% if etravirine is administered under fasting conditions compared with administration after a meal.

Effect of food on etravirine bioavailability was studied using various meals (standard, light, enhanced-fiber, high-fat); magnitude of the food effect is similar with all meal types.

Distribution

Extent

Distribution into compartments other than plasma (e.g., CSF, genital tract secretions) not evaluated.

Crosses the placenta and has been detected in cord blood.

Distributed into human milk.

Plasma Protein Binding

99.9%, principally albumin and alpha 1-acid glycoprotein.

Elimination

Metabolism

Metabolized principally in the liver by CYP isoenzymes 3A, 2C9, and 2C19.

In cell culture, the major metabolites are at least 90% less active than etravirine against wild-type HIV-1.

Elimination Route

Following oral administration of a single dose in adults, the majority (93.7%) is eliminated in feces as unchanged etravirine (81.2–86.4%). Up to 1.2% of the dose is eliminated in urine as metabolites.

Unlikely to be removed by hemodialysis or peritoneal dialysis.

Half-life

Mean terminal elimination half-life in adults is about 41 hours.

Special Populations

Renal impairment: Pharmacokinetics not studied; alterations not expected because renal clearance is minimal.

Hepatic impairment: Pharmacokinetics not altered in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); not studied in patients with severe hepatic impairment (Child-Pugh class C).

HIV-infected individuals coinfected with HBV and/or HCV: Reduced clearance reported.

Geriatric individuals: Studies in those up to 77 years of age indicate no substantial differences in pharmacokinetics relative to younger adults.

Pediatric patients 2 years to <18 years of age weighing ≥10 kg: Weight-based dosage results in systemic etravirine exposures similar to those reported in adults receiving 200 mg twice daily.

Pregnant patients: Pharmacokinetics not studied.

Stability

Storage

Oral

Tablets

25°C (excursions permitted between 15–30°C). Store in tight, closed container; protect from moisture. Dispense and store in original container; do not remove desiccant from bottle.

Actions and Spectrum

• Inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.

• Highly active against wild-type HIV-1; active against some clinical HIV-1 isolates resistant to some other NNRTIs (delavirdine, efavirenz, nevirapine).

• Different resistance profile than other NNRTIs; certain single mutations that result in class resistance to other NNRTIs may not necessarily result in etravirine resistance.

• Cross-resistance may occur between etravirine and other commercially available NNRTIs (delavirdine, etravirine, nevirapine, rilpivirine), and is expected in patients who have virologic failure while receiving a regimen that contains etravirine.

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. Inform patients of the importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting a clinician.

• Advise patients of the importance of using etravirine in conjunction with other antiretrovirals and to not use for monotherapy.

• Advise patients of the importance of taking etravirine twice daily after a meal on a regular dosing schedule. Food enhances absorption of the drug; magnitude of the food effect is similar with all meal types (standard, light, enhanced-fiber, high-fat).

• Advise patients to swallow the tablets whole with liquid (e.g., water) without chewing. 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. 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. Warm water (greater than 40°C) or carbonated beverages should not be used.

• 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. 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.

• Advise patients that a severe and potentially life-threatening rash has occurred (usually within the first few weeks of etravirine therapy). Advise patients on the importance of immediately contacting clinician if rash occurs. 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.

• Inform patients that redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.

• 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.

• 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.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Advise HIV-infected women not to breast-feed.

• Advise patients of other important precautionary information.

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.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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