Etravirine (Monograph)

Brand name: Intelence
Drug class: HIV Nonnucleoside Reverse Transcriptase Inhibitors
VA class: AM800
Chemical name: 4-{[6-amino-5-bromo-2-((4-cyanophenyl)amino)-4-pyrimidinyl]oxy}-3,5-dimethylbenzonitrile
Molecular formula: C₂₀H₁₅BrN₆O
CAS number: 269055-15-4

Medically reviewed by Drugs.com on Oct 20, 2022. Written by ASHP.

Introduction

Antiretroviral; HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).

Uses for Etravirine

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients ≥6 years of age who are antiretroviral-experienced (previously treated) and have evidence of ongoing HIV-1 replication and HIV-1 resistant to an HIV NNRTI and other antiretrovirals; used in conjunction with other antiretrovirals.

Because of concerns regarding cross-resistance, use individual’s prior antiretroviral treatment and viral resistance testing to guide therapy; use in conjunction with other active antiretrovirals is associated with greater likelihood of treatment response. A regimen that includes only etravirine and HIV nucleoside reverse transcriptase inhibitors (NRTIs) not recommended in those who experienced virologic failure while receiving a previous NNRTI-containing regimen.

Concomitant use of etravirine and another NNRTI (e.g., delavirdine, efavirenz, nevirapine, rilpivirine) not recommended.

Safety and efficacy not established in antiretroviral-naive (have not previously received antiretroviral therapy) adults or pediatric patients; do not use in initial treatment regimens in such patients.

Postexposure Prophylaxis following Occupational Exposure to HIV

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

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. Preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be given as emtricitabine/tenofovir DF; Truvada); alternatives are tenofovir DF and lamivudine, lamivudine and zidovudine (may be given as lamivudine/zidovudine; Combivir), or zidovudine and emtricitabine.

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

Administration

Oral Administration

Administer orally twice daily after a meal. Food enhances bioavailability. (See Food under Pharmacokinetics.)

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

For patients unable to swallow tablets whole, administer as a dispersion. Place dose of tablets in 5 mL of water (enough water to cover the tablets) and stir until a uniform, milky dispersion occurs. If desired, add more water or, alternatively, orange juice or milk; do not use grapefruit juice or carbonated or warm (>40°C) beverage. Consume dispersion promptly; to ensure consumption of entire dose, rinse the glass several times with water, orange juice, or milk and swallow each rinse.

Dosage

Must be used in conjunction with other antiretrovirals.

Pediatric Patients

Treatment of HIV Infection

Antiretroviral-experienced Pediatric Patients

Oral

To avoid medication errors, use extra care in calculating dose, transcribing medication order, dispensing prescription, and providing dosing instructions.

Children 6 years to <18 years of age weighing ≥16 kg: Dosage is based on weight and should not exceed recommended adult dosage. (See Table 1.)

Adults

Treatment of HIV Infection

Antiretroviral-experienced Adults

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 (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).

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 recommendations not available for such patients. (See Special Populations under Pharmacokinetics.)

Dosage adjustments not necessary in HIV-infected adults coinfected with HBV and/or HCV. (See Special Populations under Pharmacokinetics.)

Renal Impairment

Dosage adjustments not necessary. (See Special Populations under Pharmacokinetics.)

Geriatric Patients

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

• Manufacturer states none known.

Warnings/Precautions

Sensitivity 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.

Adipogenic Effects

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]); this may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) 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

Category B.

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

Experts state safety and pharmacokinetic data insufficient to recommend routine use of etravirine for initial treatment regimens in antiretroviral-naive pregnant women.

Lactation

Not known whether distributed into human milk.

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 <6 years of age.

Safety, efficacy, and pharmacokinetics evaluated in antiretroviral-experienced pediatric patients 6 years to <18 years of age weighing ≥16 kg; adverse effects were similar to those reported in adults (e.g., rash, diarrhea), although rash reported more frequently in pediatric patients. Rash generally was mild to moderate and macular/papular rash, occurred the second week of therapy, and generally was self-limiting and resolved within 1 week with continued etravirine therapy.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.

Hepatic Impairment

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

Rash, peripheral neuropathy.

Interactions for Etravirine

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

Drugs Affecting or Metabolized 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-glycoprotein 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.

Not known whether 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 6 years to <18 years of age weighing ≥16 kg: Weight-based dosage (approximately 5.2 mg/kg twice daily) 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 (may be exposed to 15–30°C). Tight 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

• Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician. Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.

• Importance of using in conjunction with other antiretrovirals—not for monotherapy.

• Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.

• Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.

• Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others. Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.

• Importance of reading patient information provided by the manufacturer.

• Importance of taking etravirine twice daily after a meal. 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 of water (enough to cover the tablets); after dispersion in water, orange juice or milk 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 entire dose is ingested.

• 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 missed dose is remembered >6 hours after the scheduled time, the dose should be omitted and the next dose taken at the regularly scheduled time.

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

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

• Advise patients to contact their clinician if signs or symptoms of an infection occur.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John’s wort), and any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise HIV-infected women not to breast-feed.

• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

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

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

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