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brand intelence 200 mg tablet

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Uses

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 antiretroviral-experienced (previously treated) adults, adolescents, and children 6 years of age or older who have evidence of ongoing HIV-1 viral replication and HIV-1 strains resistant to an HIV nonnucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.

The following factors should be considered when initiating etravirine in antiretroviral-experienced patients. Use of etravirine should be guided by the individual's prior antiretroviral treatment and viral resistance testing because of concerns regarding cross-resistance. Administration of etravirine in conjunction with other active antiretroviral agents is associated with a greater likelihood of treatment response. A regimen that includes only etravirine and HIV nucleoside reverse transcriptase inhibitors (NRTIs) is not recommended in patients who experienced virologic failure while receiving a previous NNRTI-containing regimen. Concomitant use of etravirine and another NNRTI (e.g., delavirdine, efavirenz, nevirapine, rilpivirine) is not recommended.

Safety and efficacy of etravirine have not been established in antiretroviral-naive (have not previously received antiretroviral therapy) adults or pediatric patients, and the drug is not recommended by the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents or the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children for initial treatment in antiretroviral-naive adults, adolescents, or pediatric patients.

The most appropriate antiretroviral regimen cannot be defined for each clinical scenario, and selection of specific antiretroviral agents for use in multiple-drug regimens should be individualized based on information regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens,

Antiretroviral-experienced Adults

Clinical Experience

Etravirine has been evaluated in 2 ongoing phase 3, randomized, double-blind, multicenter studies (studies TMC125-C206 [DUET-1], TMC125-C216 [DUET-2]) in antiretroviral-experienced adults with clinically advanced HIV infection (baseline HIV-1 RNA levels greater than 5000 copies/mL) who had received prior therapy and were receiving a stable regimen for at least 8 weeks at study entry. Adults enrolled in these studies had 3 or more primary PI mutations (D30N, V32I, L33F, M46I, M46L, I47A, I47V, G48V, I50L, I50V, V82A, V82F, V82L, V82S, V82T, I84V, N88S, or L90M) at baseline and at least one NNRTI resistance-associated mutation identified at baseline or during prior genotypic analysis. Over 1200 patients (median age 45-46 years, 89-90% male, 70% white, 13% black, 11-12% Hispanic, median baseline plasma HIV-1 RNA level 4.8 log10 copies/mL, median baseline CD4 T-cell count 99-109 cells/mm) 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; these individuals were randomized to receive etravirine 200 mg twice daily in conjunction with an OBR or an OBR alone.

At 48 weeks, 60% of those receiving etravirine and the OBR and 38% of those receiving the OBR alone were virologic responders (achieved plasma HIV-1 RNA levels less than 50 copies/mL); virologic failure (plasma HIV-1 RNA still at levels of 50 copies/mL or greater) was reported in 21 or 33% of those receiving etravirine and the OBR or the OBR alone, respectively. At 48 weeks, 70.8 or 46.4% of those receiving etravirine in conjunction with the OBR or the OBR alone, respectively, had plasma HIV-1 RNA levels less than 400 copies/mL. Analysis at 48 weeks indicated that etravirine added to the OBR resulted in greater decreases in plasma HIV-1 RNA levels (-2.23 log10 copies/mL) than the OBR alone (-1.46 log10 copies/mL). At 48 weeks, mean increases in CD4 T-cell counts were greater in patients receiving etravirine in conjunction with an OBR (increase of 96 cells/mm) than in those receiving the OBR alone (increase of 68 cells/mm). Eighteen percent of those receiving etravirine and the OBR and 25% of those receiving the OBR alone discontinued therapy with these regimens before week 48.

Antiretroviral-experienced Pediatric Patients

Clinical Experience

Safety and efficacy of etravirine in conjunction with other antiretrovirals for the treatment of HIV-1 infection in pediatric patients have been evaluated in a single-arm, phase 2 trial (Study TMC125-C213) in 101 antiretroviral-experienced children and adolescents 6 years to less than 18 years of age weighing at least 16 kg who were receiving antiretroviral therapy and had plasma HIV-1 RNA levels 500 copies/mL or higher (median baseline plasma HIV-1 RNA 3.9 log10 copies/mL and median baseline CD4 T-cell count 385 cells/mm). At 24 weeks, 52% of patients had plasma HIV-1 RNA levels less than 50 copies/mL and 67% had levels less than 400 copies/mL; the mean increase in CD4 T-cell count from baseline was 112 cells/mm.

Postexposure Prophylaxis following Occupational Exposure to HIV

Etravirine is used in conjunction with 2 NRTIs for postexposure prophylaxis of HIV infection following occupational exposure (PEP) in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.

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 disoproxil fumarate (tenofovir DF) (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada). Etravirine and 2 NRTIs is one of several alternative regimens recommended when the preferred regimen cannot be used. The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as 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.

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. However, initiation of PEP should not be delayed while waiting for expert consultation.

For information on types of occupational exposure to HIV and associated risk of infection, management of occupational exposure to HIV, efficacy and safety of postexposure prophylaxis, and recommendations regarding PEP,

Dosage and Administration

Administration

Etravirine is administered orally twice daily following a meal. Food enhances etravirine bioavailability; systemic exposure is 50% lower if the drug is administered under fasting conditions compared with following a meal.

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

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. If desired, more water or, alternatively, orange juice or milk may be added to the dispersion. Grapefruit juice or carbonated or warm (greater than 40°C) beverages should not be used. The dispersion should be consumed promptly; to ensure consumption of the entire dose, the glass should be rinsed several times with water, orange juice, or milk and each rinse swallowed.

Dosage

Adult Dosage

Treatment of HIV-1 Infection in Antiretroviral-experienced Adults

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

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 twice daily. Etravirine is used in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).(See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.)

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

Pediatric Dosage

Treatment of HIV-1 Infection in Antiretroviral-experienced Pediatric Patients

To avoid medication errors, extra care should be used in calculating the dose, transcribing the medication order, dispensing the prescription, and providing dosing instructions.

Dosage of etravirine for the treatment of HIV-1 infection in antiretroviral-experienced pediatric patients 6 years to less than 18 years of age weighing at least 16 kg is based on weight and should not exceed the recommended adult dosage.(See Table 1.)

Table 1. Dosage of Etravirine for Pediatric Patients 6 Years to Less than 18 Years of Age Weighing at Least 16 kg
Body Weight Dosage
16 to less than 20 kg 100 mg twice daily
20 to less than 25 kg 125 mg twice daily
25 to less than 30 kg 150 mg twice daily
30 or greater 200 mg twice daily

Special Populations

Hepatic Impairment

Dosage adjustments are not needed in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Etravirine pharmacokinetics have not been studied in patients with severe hepatic impairment (Child-Pugh class C), and dosage recommendations are not available for such patients.

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

Renal Impairment

Dosage adjustments are not needed in patients with renal impairment.

Cautions

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, have been reported in patients receiving etravirine. 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).

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. Clinical status and liver transaminase concentrations should be monitored. Delay in discontinuing etravirine after the onset of severe rash can result in a life-threatening reaction.

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

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.

Adipogenic Effects

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. The mechanisms and long-term consequences of fat redistribution are unknown; a causal relationship has not been 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-Barre syndrome) 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.

Specific Populations

Pregnancy

Category B.

Antiretroviral Pregnancy Registry at 800-258-4263 or http://www.APRegistry.com.

The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that safety and pharmacokinetic data are insufficient to recommend routine use of etravirine for initial treatment regimens in antiretroviral-naive pregnant women.

Lactation

Not known whether etravirine is distributed into human milk.

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

Pediatric Use

Safety and efficacy of etravirine have not been established in pediatric patients younger than 6 years of age.

Safety, efficacy, and pharmacokinetics of etravirine have been evaluated in antiretroviral-experienced pediatric patients 6 years to less than 18 years of age weighing at least 16 kg. 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 (15%) than in adults (10%) and more frequently in female than male patients (20.3 and 5.4%, respectively). In most cases, rash was mild to moderate and macular/papular, occurred in the second week of treatment, and generally was self-limiting and resolved within 1 week with continued etravirine treatment. A similar safety profile was reported for pediatric patients after 48 weeks of treatment.

Geriatric Use

Experience in those 65 years of age and older is insufficient to determine whether they respond differently than younger adults. Dosage should be selected with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Hepatic Impairment

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

Renal Impairment

Renal clearance of etravirine is minimal; decrease in clearance of the drug is not expected in patients with renal impairment.

Common Adverse Effects

Adverse effects of moderate intensity or greater reported in 2% or more of adults receiving etravirine and at an incidence higher than that reported with placebo include rash (10%) and peripheral neuropathy (4%).

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

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

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

Drugs Affected by P-glycoprotein Transport

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

Antiarrhythmic Agents

Possible pharmacokinetic interaction with amiodarone, bepridil (no longer commercially available in the US), disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, and quinidine (decreased plasma concentrations of the antiarrhythmic agent). The drugs should be used concomitantly with caution; plasma concentrations of the antiarrhythmic agent should be monitored.

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

Anticoagulants

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

Anticonvulsants

Possible pharmacokinetic interaction with carbamazepine, phenobarbital, and phenytoin (decreased etravirine plasma concentrations with possible decreased antiretroviral efficacy; decreased anticonvulsant concentrations). Concomitant use of these anticonvulsants with etravirine is not recommended. Alternative anticonvulsants should be considered in patients receiving etravirine.

Antifungal Agents

Fluconazole

Pharmacokinetic interaction 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). 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.

Itraconazole and Ketoconazole

Possible pharmacokinetic interaction with itraconazole or ketoconazole (increased etravirine plasma concentrations; decreased plasma concentrations of the antifungal agent). Adjustment of itraconazole or ketoconazole dosage may be needed depending on other concomitantly administered drugs. Consideration should be given to monitoring plasma concentrations of itraconazole and response to the antifungal.

Posaconazole

Possible pharmacokinetic interaction with posaconazole (increased etravirine plasma concentrations; no change in posaconazole concentrations). Some experts state that dosage adjustments are not needed if posaconazole is used concomitantly with etravirine; the manufacturer of etravirine states that dosage adjustment of posaconazole may be needed depending on other concomitantly administered drugs.

Voriconazole

Pharmacokinetic interaction with voriconazole (substantially increased etravirine plasma concentrations and AUC; increased voriconazole plasma concentrations and AUC). Because of limited data regarding the safety of increased etravirine concentrations, caution is advised when etravirine is administered concomitantly with voriconazole. Dosage adjustments are not needed for either drug, but some experts state that consideration should be given to monitoring plasma concentrations of voriconazole.

Antimalarial Agents

Concomitant use of the fixed combination of artemether and lumefantrine (artemether/lumefantrine) and etravirine decreases plasma concentrations and AUC of artemether, active metabolite of artemether (dihydroartemisinin), and lumefantrine, but does not have a clinically important effect on etravirine plasma concentrations or AUC. 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; antimalarial efficacy of artemether/lumefantrine should be closely monitored.

Antimycobacterial Agents

Pharmacokinetic interaction with rifabutin (decreased etravirine plasma concentrations; decreased rifabutin plasma concentrations). 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. 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).

Possible pharmacokinetic interaction with rifampin or rifapentine (substantially decreased etravirine plasma concentrations); possible decreased antiretroviral efficacy. Concomitant use of etravirine and rifampin or rifapentine is not recommended.

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Enfuvirtide

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

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

Maraviroc

Pharmacokinetic interaction with maraviroc (decreased maraviroc plasma concentrations and AUC; no clinically important effects on etravirine plasma concentrations or AUC).

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).

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.

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

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. 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.

The manufacturer of dolutegravir and some experts state that dolutegravir and etravirine should not be used concomitantly unless ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir is included in the regimen. However, concomitant use of etravirine and ritonavir-boosted atazanavir is not usually recommended.

If etravirine is used concomitantly with dolutegravir in patients who are antiretroviral-naive or antiretroviral-experienced without INSTI resistance, some experts state that dolutegravir should be given in a dosage of 50 mg once daily and ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir should also be included in the regimen.

If etravirine is used concomitantly with dolutegravir in patients who are INSTI-experienced and have documented or suspected INSTI resistance, some experts state that dolutegravir should be given in a dosage of 50 mg twice daily and ritonavir-boosted atazanavir, ritonavir-boosted darunavir, or lopinavir/ritonavir should also be included in the regimen.

Elvitegravir and Cobicistat

Possible pharmacokinetic interaction with the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF) (EVG/COBI/TDF/FTC) (altered concentrations of elvitegravir, cobicistat, and/or etravirine). EVG/COBI/TDF/FTC should not be used concomitantly with etravirine.

Raltegravir

Pharmacokinetic interaction with raltegravir (decreased raltegravir plasma concentrations and AUC; no clinically important effect on etravirine pharmacokinetics). Clinical importance of this interaction is unknown. Dosage adjustments are not necessary if raltegravir is used concomitantly with etravirine.

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

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Concomitant use of etravirine and other NNRTIs is not recommended.

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

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

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

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

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

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

Didanosine

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

Tenofovir

Pharmacokinetic interaction with tenofovir DF (decreased etravirine plasma concentrations; no change in tenofovir plasma concentrations). Dosage adjustments are not needed.

HIV Protease Inhibitors

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

Use of etravirine in a PI-based regimen that does not include low-dose ritonavir is not recommended. Etravirine may be used concomitantly with ritonavir-boosted darunavir, lopinavir/ritonavir, or ritonavir-boosted saquinavir. 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.

Atazanavir

Pharmacokinetic interaction 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).

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

Darunavir

Pharmacokinetic interaction with ritonavir-boosted darunavir (decreased etravirine plasma concentrations and AUC; no clinically important effect on darunavir plasma concentrations and AUC). Safety and efficacy of concomitant use of etravirine and ritonavir-boosted darunavir were established in phase 3 clinical studies.

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

Fosamprenavir

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

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

Indinavir

Possible pharmacokinetic interaction with indinavir (without low-dose ritonavir) (decreased indinavir plasma concentrations).

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

Lopinavir

Pharmacokinetic interaction with lopinavir/ritonavir (decreased etravirine plasma concentrations and AUC; decreased lopinavir plasma concentrations and AUC). 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.

Nelfinavir

Possible pharmacokinetic interaction with nelfinavir (without low-dose ritonavir) (increased nelfinavir plasma concentrations).

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

Ritonavir

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

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). Etravirine and ritonavir-boosted atazanavir, ritonavir-boosted fosamprenavir, or ritonavir-boosted tipranavir should not be used concomitantly.

Saquinavir

Pharmacokinetic interaction with ritonavir-boosted saquinavir (saquinavir 1 g twice daily and ritonavir 100 mg twice daily) (decreased etravirine AUC; no change in saquinavir plasma concentrations). 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.

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).

Tipranavir

Pharmacokinetic interaction with ritonavir-boosted tipranavir (decreased etravirine plasma concentrations and possible decreased antiretroviral efficacy; increased tipranavir plasma concentrations).

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

Benzodiazepines

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

Data are not available regarding concomitant use with alprazolam; monitor for therapeutic effects of alprazolam if used concomitantly.

Clarithromycin

Pharmacokinetic interaction (increased etravirine plasma concentrations, decreased plasma concentrations of clarithromycin and increased concentrations of its major metabolite [14-hydroxyclarithromycin]). 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.

Clopidogrel

Possible pharmacokinetic interaction (decreased concentrations of the active metabolite of clopidogrel). Concomitant use of clopidogrel and etravirine should be avoided, if possible; alternatives to clopidogrel should be considered.

Corticosteroids

Possible pharmacokinetic interaction with dexamethasone (decreased etravirine plasma concentrations); possible decreased antiretroviral efficacy. 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.

Ergot Alkaloids

If methylergonovine maleate is used to treat postpartum hemorrhage in a woman receiving etravirine, additional uterotonic agents may be needed since etravirine potentially could decrease methylergonovine concentrations resulting in an inadequate treatment effect.

Estrogens/Progestins

Pharmacokinetic interaction with oral contraceptives (slight increase in plasma concentrations of ethinyl estradiol, no change in plasma concentrations of norethindrone). Dosage adjustments are not needed if etravirine is used concomitantly with oral contraceptives containing ethinyl estradiol and norethindrone.

GI Drugs

Pharmacokinetic interaction with omeprazole (increased etravirine plasma concentrations). Dosage adjustments are not needed.

Pharmacokinetic interaction with ranitidine (decreased etravirine plasma concentrations). Dosage adjustments are not needed.

HCV Antivirals

HCV Protease Inhibitors

Boceprevir

Pharmacokinetic interaction with boceprevir (decreased etravirine AUC and increased boceprevir plasma concentrations and AUC). Dosage adjustments are not necessary.

Simeprevir

Possible pharmacokinetic interaction with simeprevir (decreased simeprevir plasma concentrations). Concomitant use of simeprevir and etravirine is not recommended.

Telaprevir

Pharmacokinetic interaction with telaprevir (decreased telaprevir plasma concentrations and AUC); no clinically important effect on etravirine plasma concentrations or AUC. Data are insufficient to make dosage recommendations for telaprevir when used concomitantly with etravirine.

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.

Atorvastatin

Pharmacokinetic interaction with atorvastatin (decreased atorvastatin plasma concentrations; no change in etravirine plasma concentrations). Usual atorvastatin dosage can be used with usual etravirine dosage; dosage of atorvastatin may need to be adjusted based on clinical response, but should not exceed the maximum recommended dosage.

Fluvastatin

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

Lovastatin

Possible pharmacokinetic interaction with lovastatin (decreased lovastatin plasma concentrations). Lovastatin dosage may need to be adjusted based on clinical response, but should not exceed the maximum recommended dosage. If etravirine is used with a ritonavir-boosted PI, use of lovastatin should be avoided.

Pitavastatin

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

Pravastatin

Pharmacokinetic interaction not expected with pravastatin; dosage adjustments are not needed.

Rosuvastatin

Pharmacokinetic interaction not expected with rosuvastatin; dosage adjustments are not needed.

Simvastatin

Possible pharmacokinetic interaction with simvastatin (decreased simvastatin plasma concentrations). Simvastatin dosage may need to be adjusted based on clinical response, but should not exceed the maximum recommended dosage. If etravirine is used with a ritonavir-boosted PI, use of simvastatin should be avoided.

Immunosuppressive Agents

Possible pharmacokinetic interaction with cyclosporine, sirolimus, and tacrolimus (decreased plasma concentrations of the immunosuppressive agent). The drugs should be used concomitantly with caution. Therapeutic drug monitoring of the immunosuppressive agent is recommended; consultation with a specialist may be necessary.

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. 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.

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.

Paroxetine

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

Phosphodiesterase Type 5 Inhibitors

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

Possible pharmacokinetic interaction with tadalafil or vardenafil (decreased tadalafil or vardenafil concentrations). Dosage of tadalafil or vardenafil may need to be increased based on clinical effect.

Data are not available regarding concomitant use of avanafil and etravirine; concomitant use is not recommended.

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. Concomitant use is not recommended.

Pharmacokinetics

Absorption

Absolute oral bioavailability of etravirine is unknown.

Following oral administration in adults, peak plasma concentrations are 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.

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

Distribution

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

Etravirine crosses the placenta and has been detected in cord blood.

It is not known whether etravirine is distributed into human milk.

Etravirine is 99.9% bound to protein, principally albumin and alpha 1-acid glycoprotein.

Elimination

Etravirine is metabolized principally in the liver by cytochrome P-450 (CYP) isoenzymes 3A, 2C9, and 2C19.

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

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

Etravirine is not likely to be removed by hemodialysis or peritoneal dialysis.

The mean terminal elimination half-life of etravirine in adults is about 41 hours.

Special Populations

The pharmacokinetics of etravirine have not been studied in patients with renal impairment; alterations are not expected because renal clearance is minimal.

The pharmacokinetics of etravirine are not altered in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); data are not available regarding patients with severe hepatic impairment (Child-Pugh class C).

Clearance of etravirine may be reduced in HIV-infected patients coinfected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV).

Studies in geriatric individuals up to 77 years of age did not identify any substantial differences in etravirine pharmacokinetics relative to younger adults.

In pediatric patients 6 years to less than 18 years of age weighing at least 16 kg, weight-based etravirine dosage (approximately 5.2 mg/kg twice daily) results in etravirine systemic exposures similar to those reported in adults receiving 200 mg twice daily.

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