Intelence

Generic Name: Etravirine
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

Introduction

Antiretroviral; HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).1 2 3 200

Uses for Intelence

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;1 2 3 used in conjunction with other antiretrovirals.1

Because of concerns regarding cross-resistance, use individual’s prior antiretroviral treatment and viral resistance testing to guide therapy;1 use in conjunction with other active antiretrovirals is associated with greater likelihood of treatment response.1 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.1

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Concomitant use of etravirine and another NNRTI (e.g., delavirdine, efavirenz, nevirapine, rilpivirine) not recommended.1 200 226

Safety and efficacy not established in antiretroviral-naive (have not previously received antiretroviral therapy) adults or pediatric patients;1 do not use in initial treatment regimens in such patients.200 201

Postexposure Prophylaxis following Occupational Exposure to HIV

Postexposure prophylaxis of HIV infection following occupational exposure (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.199

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.199 Etravirine and 2 NRTIs is one of several alternative regimens.199 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.199

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.199 Do not delay initiation of PEP while waiting for expert consultation.199

Intelence Dosage and Administration

Administration

Oral Administration

Administer orally twice daily after a meal.1 Food enhances bioavailability.1 11 (See Food under Pharmacokinetics.)

Swallow tablets whole with a liquid (e.g., water);1 do not chew.1

For patients unable to swallow tablets whole, administer as a dispersion.1 Place dose of tablets in 5 mL of water (enough water to cover the tablets) and stir until a uniform, milky dispersion occurs.1 If desired, add more water or, alternatively, orange juice or milk;1 do not use grapefruit juice or carbonated or warm (>40°C) beverage.1 Consume dispersion promptly; to ensure consumption of entire dose, rinse the glass several times with water, orange juice, or milk and swallow each rinse.1

Dosage

Must be used in conjunction with other antiretrovirals.1

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.1

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

Table 1. Dosage of Etravirine for Pediatric Patients 6 Years to <18 Years of Age Weighing ≥16 kg

Body Weight

Dosage

16 to <20 kg

100 mg twice daily

20 to <25 kg

125 mg twice daily

25 to <30 kg

150 mg twice daily

≥30 kg

200 mg twice daily

Adults

Treatment of HIV Infection
Antiretroviral-experienced Adults
Oral

200 mg twice daily.1 Give dose as a single 200-mg tablet or two 100-mg tablets.1

Postexposure Prophylaxis following Occupational Exposure to HIV
Oral

200 mg twice daily.199 Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.199

Special Populations

Hepatic Impairment

Dosage adjustments not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 12 200 Pharmacokinetics not studied in patients with severe hepatic impairment (Child-Pugh class C);1 dosage recommendations not available for such patients.200 (See Special Populations under Pharmacokinetics.)

Dosage adjustments not necessary in HIV-infected adults coinfected with HBV and/or HCV.1 (See Special Populations under Pharmacokinetics.)

Renal Impairment

Dosage adjustments not necessary.1 200 (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.1

Cautions for Intelence

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Sensitivity Reactions

Severe, potentially life-threatening and fatal skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme, reported.1 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.1

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.1 Monitor clinical status and liver transaminase concentrations.1

Rash of mild to moderate intensity also reported;1 2 3 generally occurs within first few weeks of therapy and resolves with continued therapy (median duration 12–16 days).1 2 3

Manufacturer states that history of rash while receiving other NNRTIs does not appear to increase the risk for etravirine-related rash.1

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.1 Mechanisms and long-term consequences of fat redistribution unknown; causal relationship not 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) 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.1

Specific Populations

Pregnancy

Category B.1

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202

Experts state safety and pharmacokinetic data insufficient to recommend routine use of etravirine for initial treatment regimens in antiretroviral-naive pregnant women.202

Lactation

Not known whether distributed into human milk.1

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202

Pediatric Use

Safety and efficacy not established in pediatric patients <6 years of age.1

Safety, efficacy, and pharmacokinetics evaluated in antiretroviral-experienced pediatric patients 6 years to <18 years of age weighing ≥16 kg;1 adverse effects were similar to those reported in adults (e.g., rash, diarrhea), although rash reported more frequently in pediatric patients.1 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.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1

Hepatic Impairment

Not studied in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

Minimal renal clearance; decrease in clearance not expected in patients with renal impairment.1

Common Adverse Effects

Rash, peripheral neuropathy.1

Interactions for Intelence

Metabolized by CYP isoenzymes 3A, 2C9, and 2C19.1 Induces CYP3A;1 inhibits 2C9 and 2C19.1 Inhibits P-glycoprotein (P-gp).1

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.1 200

Potential pharmacokinetic interaction with drugs that are substrates for CYP3A, 2C9, or 2C19 with possible altered metabolism of such drugs.1 200

Drugs Affected by P-glycoprotein Transport

Potential pharmacokinetic interaction with drugs that are substrates for P-gp.1

Specific Drugs

Drug

Interaction

Comments

Abacavir

No in vitro evidence of antagonistic antiretroviral effects 1

Avanafil

Data not available200

Concomitant use not recommended200

Antiarrhythmics (amiodarone, disopyramide, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine)

Possible decreased antiarrhythmic agent concentrations1

Use concomitantly with caution; monitor antiarrhythmic agent concentrations1

Anticoagulants, oral

Possible increased warfarin concentrations1 200

Monitor INR; adjust warfarin dosage if needed1 200

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Possible decreased etravirine concentrations and decreased antiretroviral efficacy;1 200 decreased anticonvulsant concentrations200

Concomitant use not recommended;1 200 consider alternative anticonvulsants200

Antifungals, azoles

Fluconazole: Substantially increased etravirine concentrations and AUC; no clinically important change in fluconazole concentrations or AUC1 200

Itraconazole: Possible increased etravirine concentrations and decreased itraconazole concentrations1 200

Ketoconazole: Possible increased etravirine concentrations and decreased ketoconazole concentrations1 200

Posaconazole: Possible increased etravirine concentrations; no change in posaconazole concentrations1 200

Voriconazole: Substantially increased etravirine concentrations and AUC; increased voriconazole concentration and AUC1 200

Fluconazole: Dosage adjustments not needed for either drug; use caution because of limited safety data regarding increased etravirine concentrations1 200

Itraconazole: Adjustment of itraconazole dosage may be needed depending on other concomitantly administered drugs;1 200 consider monitoring itraconazole concentrations and response to the antifungal200

Ketoconazole: Adjustment of ketoconazole dosage may be needed depending on other concomitantly administered drugs1 200

Posaconazole: Experts state dosage adjustments not needed;200 manufacturer of etravirine states adjustment of posaconazole dosage may be needed depending on other concomitantly administered drugs1

Voriconazole: Use caution because of limited safety data regarding increased etravirine concentrations;1 200 dosage adjustments not needed;1 200 consider monitoring voriconazole concentrations200

Antimalarials

Fixed combination of artemether and lumefantrine (artemether/lumefantrine): Decreased concentrations and AUC of artemether, active metabolite of artemether (dihydroartemisinin), and lumefantrine;1 200 no clinically important effect on etravirine concentrations or AUC1

Artemether/lumefantrine: Dosage adjustments not needed; use concomitantly with caution since effect on antimalarial efficacy not known;1 closely monitor antimalarial efficacy200

Antimycobacterials (rifabutin, rifampin, rifapentine)

Rifabutin: Decreased concentrations of etravirine and rifabutin1 200

Rifampin: Substantially decreased etravirine concentrations possible1 200

Rifapentine: Substantially decreased etravirine concentrations possible1 200

Rifabutin: Recommended rifabutin dosage is 300 mg daily in patients receiving etravirine without a ritonavir-boosted PI;1 200 rifabutin not recommended in patients receiving etravirine with a ritonavir-boosted PI1 200

Rifampin: Concomitant use not recommended1 200

Rifapentine: Concomitant use not recommended1 200

Atazanavir

Atazanavir or ritonavir-boosted atazanavir: Increased etravirine concentrations; decreased atazanavir concentrations and possible decreased antiretroviral efficacy1 200

No in vitro evidence of antagonistic antiretroviral effects1

Atazanavir (with or without low-dose ritonavir): Do not use concomitantly1 200

Benzodiazepines (alprazolam, diazepam)

Alprazolam: Data not available200

Diazepam: Possible increased diazepam concentrations1 200

Alprazolam: Monitor for alprazolam therapeutic effects200

Diazepam: Decreased diazepam dosage may be needed1 200

Boceprevir

Decreased etravirine AUC; increased boceprevir concentrations and AUC200

Dosage adjustments not needed200

Buprenorphine, buprenorphine/naloxone

Decreased buprenorphine concentrations and AUC; no effect on norbuprenorphine or etravirine concentrations1 200

Routine buprenorphine or buprenorphine/naloxone dosage adjustments not needed;1 200 monitor for withdrawal symptoms since buprenorphine or buprenorphine/naloxone maintenance dosage adjustment may be needed in some patients1

Clarithromycin

Increased etravirine concentrations; decreased clarithromycin concentrations and increased concentrations of the major metabolite (14-hydroxyclarithromycin)1 200

Consider an alternative to clarithromycin (e.g., azithromycin) for treatment or prophylaxis of MAC1 200

Clopidogrel

Possible decreased concentrations of the active metabolite of clopidogrel1

Avoid concomitant use if possible;200 consider alternatives to clopidogrel1

Corticosteroids (dexamethasone)

Dexamethasone: Possible decreased etravirine concentrations and decreased antiretroviral efficacy1 200

Use concomitantly with caution; consider alternatives to dexamethasone, especially when long-term corticosteroid use anticipated1 200

Darunavir

Ritonavir-boosted darunavir: Decreased etravirine AUC; no change in darunavir concentrations; safety and efficacy of concomitant use established in phase 3 clinical studies1 2 3 200

No in vitro evidence of antagonistic antiretroviral effects1

Ritonavir-boosted darunavir: Dosage adjustments not needed1 200

Delavirdine

Possible increased etravirine concentrations1

Do not use concomitantly1

Didanosine

No effect on didanosine or etravirine concentrations1

No in vitro evidence of antagonistic antiretroviral effects1

Dosage adjustments not needed1

Digoxin

Possible increased digoxin concentrations; no change in etravirine concentrations1

If digoxin and etravirine are initiated at the same time, initiate digoxin at the lowest dosage1

If etravirine is initiated in a patient already receiving digoxin, dosage adjustments not needed for either drug1

Monitor serum digoxin concentrations and adjust digoxin dosage to achieve desired clinical effect1

Dolutegravir

Substantially decreased dolutegravir concentrations and AUC;200 236 no apparent effect on etravirine pharmacokinetics236

Effect on dolutegravir pharmacokinetics is mitigated if etravirine and dolutegravir used concomitantly with lopinavir/ritonavir or ritonavir-boosted darunavir;200 236 effect expected to be mitigated if etravirine and dolutegravir used concomitantly with ritonavir-boosted atazanavir200 236

Do not use etravirine and dolutegravir concomitantly unless ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir also included in the regimen200 236

HIV integrase strand transference inhibitor-naive (INSTI-naive) or INSTI-experienced without INSTI resistance: Use dolutegravir 50 mg once daily with etravirine and with ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir200

INSTI-experienced with documented or suspected INSTI resistance: Use dolutegravir 50 mg twice daily with etravirine and with ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir200

Efavirenz

Decreased etravirine concentrations1 200 and loss of antiretroviral efficacy1

Do not use concomitantly1 200

Elvitegravir and cobicistat

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/COBI/TDF/FTC): Possible altered concentrations of elvitegravir, cobicistat, and/or etravirine200

EVG/COBI/TDF/FTC: Do not use concomitantly200

Emtricitabine

No in vitro evidence of antagonistic antiretroviral effects1

Enfuvirtide

No in vitro evidence of antagonistic antiretroviral effects1

Dosage adjustments not needed1

Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine)

Possible decreased ergot alkaloid concentrations; possible inadequate treatment effect202

If methylergonovine used to treat postpartum hemorrhage in a woman receiving etravirine, additional uterotonic agents may be needed202

Estrogens/progestins

Hormonal contraceptives: Slight increase in ethinyl estradiol concentrations; no change in norethindrone concentrations1 200

Dosage adjustments not needed with oral contraceptives containing ethinyl estradiol and norethindrone1 200

Fosamprenavir

Fosamprenavir or ritonavir-boosted fosamprenavir: Substantially increased concentrations of amprenavir (active metabolite of fosamprenavir)1 200

No in vitro evidence of antagonistic antiretroviral effects1

Fosamprenavir (with or without low-dose ritonavir): Do not use concomitantly1 200

Histamine H2-receptor antagonists

Ranitidine: Decreased etravirine concentrations1

Ranitidine: Dosage adjustments not needed1

HMG-CoA reductase inhibitors (statins)

Atorvastatin: Decreased atorvastatin concentrations; no change in etravirine concentrations1 200

Fluvastatin: Possible increased fluvastatin concentrations; no change in etravirine concentrations1 200

Lovastatin: Possible decreased lovastatin concentrations1 200

Pitavastatin: Possible increased pitavastatin concentrations1

Pravastatin: Pharmacokinetic interaction not expected1 200

Rosuvastatin: Pharmacokinetic interaction not expected1 200

Simvastatin: Possible decreased simvastatin concentrations1 200

Atorvastatin: Usual etravirine and atorvastatin dosages can be used; however, may need to adjust atorvastatin dosage based on clinical response1 200 (do not exceed maximum recommended atorvastatin dosage)200

Fluvastatin: May need to adjust fluvastatin dosage1 200

Lovastatin: May need to adjust lovastatin dosage based on clinical response1 200 (do not exceed maximum recommended lovastatin dosage);200 if a ritonavir-boosted PI is included in the regimen, avoid use of lovastatin200

Pitavastatin: May need to adjust pitavastatin dosage1

Pravastatin: Dosage adjustments not needed200

Rosuvastatin: Dosage adjustments not needed200

Simvastatin: May need to adjust simvastatin dosage based on clinical response1 200 (do not exceed maximum recommended simvastatin dosage);200 if a ritonavir-boosted PI is included in the regimen, avoid use of simvastatin200

Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)

Potential for decreased immunosuppressive agent concentrations1

Use concomitantly with caution;1 therapeutic drug monitoring of immunosuppressive agent recommended;200 consultation with a specialist may be needed200

Indinavir

Indinavir (without low-dose ritonavir): Possible decreased indinavir concentrations1

No in vitro evidence of antagonistic antiretroviral effects1

Do not use concomitantly without low-dose ritonavir1

Lamivudine

No in vitro evidence of antagonistic antiretroviral effects 1

Lopinavir/ritonavir

Decreased etravirine concentrations and AUC; decreased lopinavir concentrations and AUC1 200

No in vitro evidence of antagonistic antiretroviral effects1

Because decrease in etravirine systemic exposure in patients receiving concomitant lopinavir/ritonavir is similar to that in patients receiving etravirine and concomitant ritonavir-boosted darunavir (a combination found to be safe and effective), manufacturer and experts state that dosage adjustments not needed for either drug1 200

Maraviroc

Decreased maraviroc concentrations and AUC;1 200 224 no clinically important effect on etravirine concentrations or AUC1

No in vitro evidence of antagonistic antiretroviral effects1

Recommended maraviroc dosage is 600 mg twice daily with usual etravirine dosage, provided regimen does not include a potent CYP3A inhibitor1 200 224

Methadone

No clinically important change in methadone or etravirine concentrations1 8 200

Dosage adjustments not needed1 8 200

Nelfinavir

Nelfinavir (without low-dose ritonavir): Possible increased nelfinavir concentrations1

No in vitro evidence of antagonistic antiretroviral effects1

Do not use concomitantly with etravirine without low-dose ritonavir1

Nevirapine

Decreased etravirine concentrations1 200 and loss of antiretroviral efficacy1

Do not use concomitantly with etravirine1

Paroxetine

No change in etravirine or paroxetine concentrations1

Dosage adjustments not needed1

Proton pump inhibitors

Omeprazole: Increased etravirine concentrations1

Omeprazole: Dosage adjustments not needed1

Raltegravir

Decreased raltegravir concentrations and AUC;1 225 no clinically important effect on etravirine pharmacokinetics;1 225 clinical importance unknown225

No in vitro evidence of antagonistic antiretroviral effects1

Dosage adjustments not needed1 200

Rilpivirine

Possible decreased rilpivirine concentrations; no change in etravirine concentrations226

No in vitro evidence of antagonistic antiretroviral effects 226

Do not use concomitantly226

Ritonavir

Full-dose ritonavir (600 mg twice daily): Substantial decrease in etravirine concentrations and possible loss of antiretroviral efficacy1

No in vitro evidence of antagonistic antiretroviral effects 1

Full-dose ritonavir (600 mg twice daily): Do not use concomitantly with etravirine1

Low-dose ritonavir (usually 100 mg once or twice daily): Etravirine may be used concomitantly with certain ritonavir-boosted PI regimens (i.e., ritonavir-boosted darunavir, lopinavir/ritonavir, ritonavir-boosted saquinavir);1 concomitant use with ritonavir-boosted atazanavir, ritonavir-boosted fosamprenavir, or ritonavir-boosted tipranavir not recommended1 200

Saquinavir

Ritonavir-boosted saquinavir: Decreased etravirine AUC; no change in saquinavir concentrations1 200

Decrease in systemic exposure to etravirine is similar to that in patients receiving etravirine in conjunction with ritonavir-boosted darunavir (a combination found to be safe and effective)1 200

No in vitro evidence of antagonistic antiretroviral effects1

Ritonavir-boosted saquinavir: Dosage adjustments not needed1 200

Sildenafil

Decreased sildenafil concentrations1 200

Usual etravirine and sildenafil dosages can be used; sildenafil dosage may need to be increased based on clinical effect1 200

Simeprevir

Possible decreased simeprevir concentrations187 200

Concomitant use not recommended187 200

Stavudine

No in vitro evidence of antagonistic antiretroviral effects1

St. John’s wort (Hypericum perforatum)

Possible substantially decreased etravirine concentrations and loss of antiretroviral efficacy1 200

Concomitant use not recommended1 200

Tadalafil

Possible decreased tadalafil concentrations200

Tadalafil dosage may need to be increased based on clinical effect200

Telaprevir

Decreased telaprevir concentrations and AUC; no clinically important effect on etravirine concentrations or AUC1 200

Insufficient data to make telaprevir dosage recommendations1 200

Tenofovir

Decreased etravirine concentrations; no change in tenofovir concentrations1

No in vitro evidence of antagonistic antiretroviral effects1

Dosage adjustments not needed1

Tipranavir

Ritonavir-boosted tipranavir: Decreased etravirine concentrations and possible decreased antiretroviral efficacy; increased tipranavir concentrations1 200

No in vitro evidence of antagonistic antiretroviral effects1

Ritonavir-boosted tipranavir: Do not use concomitantly1 200

Vardenafil

Possible decreased vardenafil concentrations200

Vardenafil dosage may need to be increased based on clinical effect200

Zidovudine

No in vitro evidence of antagonistic antiretroviral effects1

Intelence Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability is unknown.1

Following oral administration in adults, peak plasma concentrations attained within approximately 2.5–4 hours.1 11

Food

Systemic exposure is decreased by about 50% if etravirine is administered under fasting conditions compared with administration after a meal.1 11

Effect of food on etravirine bioavailability was studied using various meals (standard, light, enhanced-fiber, high-fat);11 magnitude of the food effect is similar with all meal types.1 11

Distribution

Extent

Distribution into compartments other than plasma (e.g., CSF, genital tract secretions) not evaluated.1

Crosses the placenta and has been detected in cord blood.202

Not known whether distributed into human milk.1 202

Plasma Protein Binding

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

Elimination

Metabolism

Metabolized principally in the liver by CYP isoenzymes 3A, 2C9, and 2C19.1

In cell culture, the major metabolites are at least 90% less active than etravirine against wild-type HIV-1.1

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%).1 Up to 1.2% of the dose is eliminated in urine as metabolites.1

Unlikely to be removed by hemodialysis or peritoneal dialysis.1

Half-life

Mean terminal elimination half-life in adults is about 41 hours.1

Special Populations

Renal impairment: Pharmacokinetics not studied; alterations not expected because renal clearance is minimal.1

Hepatic impairment: Pharmacokinetics not altered in patients with mild or moderate hepatic impairment (Child-Pugh class A or B);1 12 not studied in patients with severe hepatic impairment (Child-Pugh class C).1

HIV-infected individuals coinfected with HBV and/or HCV: Reduced clearance reported.1

Geriatric individuals: Studies in those up to 77 years of age indicate no substantial differences in pharmacokinetics relative to younger adults.1

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.1

Pregnant patients: Pharmacokinetics not studied.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1 Tight container; protect from moisture.1 Dispense and store in original container; do not remove desiccant from bottle.1

Actions and Spectrum

  • Inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.1 4

  • Highly active against wild-type HIV-1; active against some clinical HIV-1 isolates resistant to some other NNRTIs (delavirdine, efavirenz, nevirapine).1 3 4 200

  • Different resistance profile than other NNRTIs; certain single mutations that result in class resistance to other NNRTIs may not necessarily result in etravirine resistance.2 3 4

  • Cross-resistance may occur between etravirine and other commercially available NNRTIs (delavirdine, etravirine, nevirapine, rilpivirine),1 4 200 226 and is expected in patients who have virologic failure while receiving a regimen that contains etravirine.1

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 200 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1

  • Importance of using in conjunction with other antiretrovirals—not for monotherapy.1 200

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1

  • Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.1

  • Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200

  • Importance of reading patient information provided by the manufacturer.1

  • Importance of taking etravirine twice daily after a meal.1 Food enhances absorption of the drug;1 11 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 of water (enough to cover the tablets); after dispersion in water, orange juice or milk 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 entire dose is ingested.1

  • 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 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.1

  • Advise patients that severe and potentially life-threatening rash has occurred (usually within the first few weeks of etravirine therapy).1 Importance of immediately contacting clinician if rash occurs.1 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

  • Advise patients that redistribution/accumulation of body fat may occur with antiretroviral therapy, with as yet unknown long-term health effects.1

  • Advise patients to contact their clinician if signs or symptoms of an infection occur.1

  • 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.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise HIV-infected women not to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Etravirine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

25 mg

Intelence

Janssen

100 mg

Intelence

Janssen

200 mg

Intelence

Janssen

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Intelence 100MG Tablets (JANSSEN PRODUCTS): 120/$876.00 or 360/$2,519.00

Intelence 200MG Tablets (JANSSEN PRODUCTS): 60/$871.03 or 180/$2,567.01

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 30, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Janssen. Intelence (etravirine) tablets prescribing information. Titusville, NJ; 2013 Feb.

2. Madruga JV, Cahn P, Grinsztejn B et al. 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. 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]

6. Tibotec Therapeutics, Bridgewater, NJ: Personal communication.

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.

10. Anderson MS, Kakuda TN, Hanley W et al. Minimal pharmacokinetic interaction between the human immunodeficiency virus nonnucleoside reverse transcriptase inhibitor etravirine and the integrase inhibitor raltegravir in healthy subjects. Antimicrob Agents Chemother. 2008; 52:4228-32. [PubMed 18838586]

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]

187. Janssen Products LP. Olysio (simeprevir) capsules prescribing information. Titusville, NJ; 2013 Nov.

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 (May 1, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website.

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (February 12, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website.

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (March 28, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website.

224. ViiV Healthcare. Selzentry (maraviroc) tablets prescribing information. Research Triangle Park, NC; 2012 Aug.

225. Merck Sharp & Dohme. Isentress (raltegravir) film-coated tablets and chewable tablets prescribing information. Whitehouse Station, NJ; 2012 Aug.

226. Tibotec Therapeutics. Edurant (rilpivirine) tablets prescribing information. Raritan, NJ; 2012 Aug.

236. ViiV Healthcare. Tivicay (dolutegravir) tablets prescribing information. Research Triangle Park, NC; 2014 May.

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