Hospital Pharmacy Volume 43, Number 6, pp 498510 2008 Wolters Kluwer Health, Inc.

FORMULARY DRUG REVIEWS

Etravirine
Dennis J. Cada, PharmD, FASHP, FASCP (Editor),* Terri Levien, PharmD, and Danial E. Baker, PharmD, FASCP, FASHP Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to your Pharmacy & Therapeutics Committee. Subscribers also receive monthly 1-page summary monographs on the agents that are useful for agendas and pharmacy/nursing inservices. A comprehensive target drug utilization evaluation (DUE) is also provided each month. With a subscription, the monographs are sent to you in print and are also available online. Monographs can be customized to meet the needs of your facility. Subscribers to the The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The F.I.X. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. If you would like information about The Formulary Monograph Service or The F.I.X., call The Formulary at 800-322-4349. The June 2008 monograph topics are on sumatriptan succinate and naproxen sodium, diclofenac epolamine topical patch, bendamustine hydrochloride, rotavirus vaccine, and live, oral, levoleucovorin for injection. The DUE is on sumatriptan succinate and naproxen sodium.

Generic Name: ETRAVIRINE Proprietary Name: Intelence (Tibotec) Approval Rating: 1P Therapeutic Class: Antiviral Agents; Nonnucleoside Reverse Transcriptase Inhibitors Similar Drugs: Delavirdine, Efavirenz, Nevirapine Sound- or Look-Alike Names: Efavirenz

ment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to a nonnucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.1 In patients who have experienced virologic failure on a NNRTI-containing regimen, do not use etravirine in combination with only nucleoside/nucleotide reverse transcriptase inhibitors.1 The safety and efficacy of etravirine have not been established in children or treatment-naive adult patients.1 CLINICAL PHARMACOLOGY Etravirine is a diarylpyrimidine NNRTI with activity against both wild-type and NNRTI-resistant HIV-1.2-4 It has exhibited 10-

INDICATIONS Etravirine is indicated for use in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in treat-

fold greater potency than delavirdine and nevirapine against HIV1.3 Development of resistance to etravirine requires multiple mutations. Etravirine retains activity against most viruses exhibiting the signature mutations for efavirenz or nevirapine resistance.2,5 Conformational changes in the etravirine structure are believed to enable the agent to overcome the effects of some resistance mutations to a greater extent than other NNRTIs with more rigid structure.4 Mutations associated with in vitro or clinical resistance to etravirine include V90I, A98G, L100I, K101E/P, V106I, V179D/E/F/I, Y181C/I/V, Y318F, G190A/E/S, M230L, or F277C.5-8 Resistance is believed most likely to occur in patients with one NNRTI mutation plus mutation K101P, Y181I, or Y181V; the Y181C mutation plus mutations V179E, V179F, G190S, or M230L; 2 or more NNRTI mutations plus 1 etravirine mutation; or 3 or more NNRTI mutations.6,7 The most prevalent mutations observed in a clinical populations have included Y181C/I/V and G190A/S, as well as V179D/F/I, L100I, K101E/P, V106I/K, V90I, A98G, E138G, H221Y, and G190S.1,8-12 The mean number of etravirine-associated resistance mutations was greater in patients previously exposed to nevirapine than efavirenz.8 Viro-

*Executive Editor, The Formulary; Clinical Associate Professor of Pharmacotherapy, Drug Information Center, Washington State University Spokane, WA; Director, Drug Information Center and Professor of Pharmacy Practice; College of Pharmacy, Washington State University Spokane, PO Box 1495, Spokane, WA 99210-1495.

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logic failure was observed to occur more frequently in patients with increased numbers of nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI mutations, and particularly in patients with more than 3 baseline etravirine resistanceassociated mutations.7,13 In early phase studies, shortterm etravirine therapy was assessed in antiretroviral-naive and antiretroviral-experienced patients. In naive patients, monotherapy with etravirine 900 mg twice daily (polyethylene glycol [PEG] 4000 formulation) for 7 days was compared with placebo in 19 patients. Viral load was reduced from baseline by 1.99 log10 copies/mL with etravirine compared with a 0.06 log10 copies/mL reduction with placebo (P < 0.001). Viral load decay rates were 0.33 log10 copies/mL per day with etravirine and 0.02 log10 copies/mL per day with placebo.14 In an open-label study enrolling 16 patients receiving an NNRTIcontaining antiretroviral regimen (efavirenz, 3 patients; nevirapine, 13 patients) with an HIV-1 RNA viral load greater than 2,000 copies/mL and phenotypic resistance to an NNRTI, etravirine 900 mg twice daily (PEG 4000 formulation) was administered for 7 days as a substitute for the patients regular NNRTI. With etravirine therapy, the viral load decay rate was 0.13 log10 copies/mL per day. Over 7 days, viral load was reduced by a median of 0.89 log10 copies/mL. Seven (44%) patients had a reduction of greater than 1 log10 copies/mL.15 PHARMACOKINETICS Etravirine is a lipophilic compound with low solubility and low permeability.16 The newly formulated 100 mg tablets (F060 formulation) used in the phase 3 studies

produce exposure at a dose of 2 tablets (200 mg) twice daily comparable with that achieved with 800 mg twice daily dosed with the formulation used in an earlier clinical study (TF035 formulation).17,18 Compared with the earlier formulation, the new formulation produces a substantially greater area under the curve (AUC) and peak concentration, without change in time-to-peak concentration or elimination half-life.16 In studies with the newer formulation, systemic exposure was similar with 100 mg dosed twice daily compared with 200 mg dosed once daily and with 200 mg dosed twice daily compared with 400 mg dosed once daily.19 Following oral administration, peak etravirine concentrations are met within 2.5 to 4 hours. Absolute oral bioavailability is unknown.1 Exposure is reduced when administered in a fasted state; therefore, administration following a meal is recommendLike other NNRTIs, ed.20 etravirine is highly protein bound (more than 99%), primarily to albumin and alpha-1-acid glycoprotein.1,3 Etravirine has a half-life of 36 hours.15 Despite the long half-life, etravirine was administered twice daily to minimize the pill burden with each administration.15 Etravirine is metabolized primarily by CYP3A4, CYP2C9, and CYP2C19 isozymes and induces CYP3A4 and inhibits CYP2C9 and CYP2C19.20-22 Etravirine metabolites are at least 90% less active than etravirine against wildtype HIV in cell culture.1 The renal clearance of etravirine is less than 1.2%.1 The peak concentration and AUC of etravirine were not significantly altered in volunteers with mild to moderate hepatic function

impairment.23 Etravirine pharmacokinetics have not been assessed in patients with severe hepatic function impairment.1 Gender, age, weight, race, creatinine clearance, viral hepatitis status, and use of tenofovir or enfuvirtide in the background regimen were not found to significantly affect etravirine pharmacokinetics.24 In children 6 to 17 years of age, a dose of 4 mg/kg twice daily (administered following a meal with 25 and 100 mg tablets) produced exposure comparable with an adult dose of 200 mg twice daily.25 Because of concerns related to underdosing of antiretrovirals in children, further studies will assess the pharmacokinetics and tolerability of etravirine 5.2 mg/kg twice daily.25 COMPARATIVE EFFICACY The effect of etravirine in conjunction with darunavir/ritonavir was assessed in an open-label study enrolling 12 patients experiencing virological failure on a stable antiretroviral regimen with no other viable treatment options. Patients received etravirine (F060 formulation) 200 mg, darunavir 600 mg, and ritonavir 100 mg twice daily in conjunction with 2 or more NRTIs. Enfuvirtide use was optional. Two patients withdrew from the study in the first week; 10 were included in the analysis. At week 24, 9 of 10 patients had achieved an undetectable viral load. The median reduction in viral load was 2.7 log10 copies/mL.20 Etravirine (TF035 formulation) was assessed in a randomized, open-label study enrolling 199 patients with genotypic resistance to approved NNRTIs and at least 3 primary protease inhibitor mutations. The enrolled patients had a median duration of HIV

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Table 1. DUET-1 and DUET-2 Week 24 Study Results17,28,30,32

Parameter Etravirine Viral load < 50 copies/mL at 24 weeks Viral load < 50 copies/mL at 48 weeks Viral load < 50 copies/mL at 24 weeks (baseline viral load < 100,000 copies/mL) Viral load < 50 copies/mL at 24 weeks (baseline viral load > 100,000 copies/mL) Viral load < 400 copies/mL at 24 weeks Viral load < 400 copies/mL at 48 weeks
a

DUET-1 Placebo 119 (39%) 39% 85 (47%) 34 (27%) 158 (51%) 47% Etravirine 170 (56%)a 60%c 125 (68%) 45 (38%) 224 (74%)e 71%
c

DUET-2 Placebo 129 (44%) 41% NR 22 (24%) 159 (54%) 48% 813 (62%)b 61%c NRd 56 (51%) 221 (75%)e 72%
c

P = 0.005. P = 0.0003. NR = not reported.

b c

P < 0.0001. P = 0.0001.

d e

infection of 15 years and received a median of 12 previous antiretroviral agents. Median baseline viral load was 4.7 log10 copies/mL. Patients received etravirine 400 mg (80 patients), etravirine 800 mg (79 patients), or placebo (40 patients) twice daily in conjunction with an optimized background regimen of at least 2 approved antiretroviral agents (NRTI and/or lopinavir/ritonavir and/or enfuvirtide). More patients in the etravirine groups received at least one drug in their regimen (excluding etravirine) that was scored as active (83.5% vs 74.4%) and more patients in the etravirine groups received enfuvirtide (62.5% and 64.6% vs 52.5%). Discontinuation of therapy because of virological failure occurred in 75% of placebo-treated patients compared with 6.3% and 5.1% in the etravirine groups by 24 weeks. By week 48, 98% of patients in the placebo group discontinued therapy because of virologic failure, compared with 9% of patients in both etravirine groups. At week 24, the mean

change from baseline in viral load was 1.04 log10 copies/mL with etravirine 400 mg, 1.18 log10 copies/mL with etravirine 800 mg, and 0.19 log10 copies/mL with placebo (P < 0.05 for both etravirine groups vs placebo). At week 48, the mean change from baseline in viral load was 0.88 log10 copies/mL in the 400 mg group, 1.01 log10 copies/mL in the 800 mg group, and 0.14 log10 copies/mL in the placebo group (P < 0.05 for both etravirine doses vs placebo). At week 24, a reduction in viral load of at least 1 log10 copies/mL was achieved in 36.3% of patients in the 400 mg group (P = 0.005) and 41.8% in the 800 mg group (P < 0.001) compared with 7.5% in the placebo group. Viral load less than 400 copies/mL was achieved in 30% of patients in the 400 mg group (P = 0.018) and 38% in the 800 mg group (P = 0.002) compared with 7.5% in the placebo group at week 24. Viral load less than 50 copies/mL was achieved in 21.3% of patients in the 400 mg group (P = 0.133) and 17.7% in the 800 mg

group (P = 0.218) compared with 7.5% in the placebo group at week 24.18,26,27 Etravirine was assessed in 2 multinational, randomized, double-blind, placebo-controlled phase 3 studies (DUET-1 and DUET-2) enrolling treatmentexperienced adult patients with virological failure on stable antiretroviral therapy, documented genotypic evidence of NNRTI resistance, viral load more than 5,000 copies/mL, and 3 or more primary protease inhibitor mutations. Exclusion criteria included life expectancy of less than 6 months, currently active acquired immune deficiency syndrome (AIDS)-defining illness, acute viral hepatitis, or, if female, pregnancy, breast-feeding, or of child-bearing potential and not using adequate contraception. Patients with chronic hepatitis B or C were not excluded as long as aminotransferase concentrations were less than 5 times the upper limit of normal. Enrolled patients were randomized to receive etravirine 200 mg or placebo twice daily

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after a meal in conjunction with darunavir (600 mg twice daily) with low-dose ritonavir (100 mg twice daily), and investigatorselected NRTIs. Enfuvirtide use was optional. Randomization was stratified for enfuvirtide use in the background regimen, previous darunavir use, and screening viral load. The primary end point was confirmed viral load less than 50 copies/mL at week 24 on intentto-treat analysis. Patients in both studies had the option of extending the initial 48-week treatment period by an additional 48 weeks.17,28 DUET-1 enrolled 612 patients (304 in the etravirine group and 308 in the placebo group) in Argentina, Brazil, Chile, France, Mexico, Panama, Puerto Rico, Thailand, and the United States. The patient population was 86% to 87% male, 65% white, and 14% Hispanic, with a median baseline viral load of 4.8 to 4.9 log10 copies/mL. At the time of screening, 54% were resistant to all available NRTIs, 30% were sensitive to 1 NRTI, and 17% were sensitive to 2 or more NRTIs; 65% were sensitive to darunavir. Enfuvirtide was used in 40% of patients in the etravirine group and 41% in the placebo group. By week 24, 42 (14%) patients in the etravirine group and 56 (18%) in the placebo group had discontinued therapy, primarily because of virological failure. Results are summarized in Table 1. The absolute difference in attainment of viral load less than 50 copies/mL at 24 weeks was 17% (95% confidence interval [CI], 9% to 25%; P = 0.005), resulting in a number needed to treat of 5.9 to achieve 1 more virological response at 24 weeks of therapy. Of patients with a viral load less than 50 copies/mL at 24 weeks,

94% maintained a viral load less than 50 copies/mL at 48 weeks with the etravirine regimen compared with 89% with the placebo regimen. The mean change in viral load at 24 weeks was 2.41 log10 copies/mL in the etravirine group compared with 1.7 log10 copies/mL in the placebo group (P < 0.0001). CD4 cell count increased by a mean of 89 cells/mcL in the etravirine group and 64 cells/mcL in the placebo group (P = 0.0002) at 24 weeks.17,29,30 DUET-2 enrolled 591 patients (295 in the etravirine group and 296 in the placebo group) in Australia, Belgium, Canada, France, Germany, Italy, the Netherlands, Poland, Portugal, Spain, the United Kingdom, and the United States. The patient population was 93% male, 76% white, and 13% black, with a median baseline viral load of 4.8 log10 copies/mL. Hepatitis B and/or C coinfection was present in 13% of patients. At the time of screening, 65% of patients had 2 or more NNRTI resistanceassociated mutations, 90% of patients had 4 or more NRTI resistanceassociated mutations, and 66% had 4 or more primary protease inhibitor mutations; 44% had 3 or more darunavir resistanceassociated mutations. Enfuvirtide was used in 52% of patients in the etravirine group and 53% in the placebo group. By week 24, 51 (17%) patients in the etravirine group and 73 (25%) in the placebo group had discontinued therapy, primarily because of virological failure. Results are summarized in Table 1. The absolute difference in attainment of viral load less than 50 copies/mL at 24 weeks was 18% (95% CI, 11% to 26%; P = 0.0003), resulting in a number needed to treat of 5.6 to achieve 1

more virological response at 24 weeks of therapy. Of patients with a viral load less than 50 copies/mL at week 24, 90% maintained a viral load less than 50 copies/mL at week 48 with etravirine compared with 88% with placebo. The mean change in viral load at 24 weeks was 2.34 log10 copies/mL in the etravirine group compared with 1.68 log10 copies/mL in the placebo group (P < 0.0001). CD4 cell count increased by a mean of 78 cells/mcL in the etravirine group and 66 cells/mcL in the placebo group (P = 0.3692) at week 24.28,31,32 CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONS The prescribing information for etravirine lists no contraindication to etravirine therapy.1 Severe and potentially lifethreatening skin reactions, including cases of Stevens-Johnson syndrome, hypersensitivity reactions, and erythema multiforme, have occurred during etravirine therapy. Such reactions have been reported in less than 0.1% of patients receiving etravirine. Etravirine therapy should be discontinued if a severe rash develops. Rash was generally mild to moderate, occurred primarily in the second week of therapy, and was infrequent after week 4. Rash generally resolved within 1 to 2 weeks with continued therapy. A total of 2% of HIV-1infected patients receiving etravirine in phase 3 clinical trials discontinued therapy because of rash.1 Fat redistribution/accumulation, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, were observed in patients receiving antiretroviral therapy.1

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Immune reconstitution syndrome was reported in patients treated with combination antiretroviral therapy, including etravirine. During the initial phase of combination therapy, patients whose immune system responds may develop an anti-inflammatory response to indolent or residual opportunistic infections, necessitating further evaluation and treatment.1 To date, etravirine has not been associated with the severe hepatic risk observed with nevirapine or the severe psychiatric and nervous system toxicities and reproductive risk associated with efavirenz. Etravirine safety and effectiveness have not been established in children.1 Etravirine is in Pregnancy Category B. It should be used during pregnancy only if the potential benefit justifies the potential risk.1 ADVERSE REACTIONS Adverse reactions occurring more frequently with etravirine than placebo have included rash (16.9% vs 9.3%) and nausea (13.9% vs 11.1%).1,17,30,32 Other adverse reactions occurring with similar frequency in etravirineand placebo-treated patients included diarrhea, abdominal pain, vomiting, peripheral neuropathy, headache, fatigue, and hypertension.1,17,28 Neuropsychiatric adverse reactions were not observed with increased frequency in the etravirine-treatment groups in the DUET-1 and DUET-2 studies; however, some earlier studies suggested possible associations between etravirine and some psychiatric adverse reactions, such as mood swings, abnormal dreams or nightmares, anxiety, and depression.17,18,28,33 In DUET-1, rash occurred in

20% of etravirine-treated patients compared with 10% of placebo recipients (P < 0.0001).17 In DUET-2, rash occurred in 14% of etravirine-treated patients compared with 9% of placebo recipients.28 Grade 1 or 2 rash (mild or moderate) was most common, was generally erythematous or maculopapular in nature, tended to occur within the first few weeks of treatment (median onset, 11 days in DUET-1 and 14 days in DUET2), and resolved with continued treatment (median duration, 12 days in DUET-1 and 16 days in DUET-2). Severe rash occurred in 4 (1%) etravirine-treated patients in each trial and 1 placebo-treated patient. The prevalence of rash was greater in women in DUET-1 (24% vs 18%; P = 0.0192).17 DRUG INTERACTIONS Etravirine is a substrate of CYP3A4, CYP2C9, and CYP2C19.1,20-22 Coadministration of etravirine with drugs that inhibit or induce CYP3A4, CYP2C9, and/or CYP2C19 may alter the therapeutic effect or adverse reaction profile of etravirine.1 It is also an inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19.1,20-22 Coadministration of substrates of CYP3A4, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of the coadministered agent.1 Key drug interactions are summarized in Table 2. Etravirine should not be coadministered with tipranavir/ritonavir, fosamprenavir/ritonavir, atazanavir/ritonavir, protease inhibitors administered without ritonavir, or NNRTIs.1 Etravirine should not be administered with tipranavir/ritonavir. Etravirine levels were significantly reduced with this combination.17 Concomitant use of either lopinavir/ritonavir or

tenofovir was also associated with reduced etravirine exposure with the 400 mg twice-daily dose but not the 800 mg twice-daily dose (TF035 formulation).26 Etravirine had no effect on the pharmacokinetics of lopinavir or tenofovir.34 When coadministered with darunavir/ritonavir, no effects on darunavir pharmacokinetics were observed. Etravirine levels were reduced 37%.35 When coadministered with atazanavir or atazanavir plus ritonavir, etravirine levels were increased slightly but not to a clinically significant extent. Atazanavir trough levels were reduced when etravirine was administered with atazanavir alone but not when ritonavir was coadministered.36 When coadministered with the integrase inhibitor raltegravir, etravirine pharmacokinetics were not affected. Raltegravir levels were slightly reduced, possibly because of induction of glucuronidation by etravirine. Dosage adjustments of either agent do not appear necessary.37 Pharmacokinetic drug interactions were also not observed when etravirine was administered with the ritonavirboosted elvitegravir, an investigational integrase inhibitor.38 Etravirine increases fosamprenavir exposure by 69%.34 Pharmacokinetic interactions were not observed between etravirine and didanosine.39 Etravirine also had no significant effect on the pharmacokinetics of methadone, saquinavir, tipranavir, or an oral contraceptive containing ethinylestradiol and norethindrone.22,34,40,41 When coadministered with atorvastatin, etravirine pharmacokinetics were not affected. Atorvastatin exposure was reduced by 37%; exposure to the atorvastatin

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Table 2. Drug Interactions With Etravirine1

Drug Class/Drug NNRTIs Efavirenz, nevirapine etravirine etravirine Combination of 2 NNRTIs not shown beneficial; may result in loss of etravirine therapeutic effect; avoid coadministration. Combination of 2 NNRTIs not shown beneficial; avoid coadministration. May alter protease inhibitor concentrations; avoid coadministration. Effect on Etravirine or Concomitant Drug Clinical Considerations

Delavirdine

Protease Inhibitors Unboosted (Without Low-Dose Ritonavir) Atazanavir, fosamprenavir, nelfinavir, indinavir atazanavir amprenavir nelfinavir indinavir

Ritonavir

etravirine

May result in loss of etravirine therapeutic effect; avoid coadministration with ritonavir 600 mg twice daily. May result in loss of etravirine therapeutic effect; avoid coadministration. Because of significant increase in amprenavir, appropriate doses for combination therapy have not been established; avoid coadministration. May result in loss of atazanavir therapeutic effect and 100% increase in etravirine systemic exposure; avoid coadministration. Etravirine AUC reduced 37%; however, combination used in phase 3 studies; coadminister without dose adjustments. Etravirine AUC increased 85%, coadminister with caution. Etravirine AUC reduced 33%; similar to that with darunavir/ritonavir coadministration; coadminister without dose adjustments.

Protease Inhibitors Boosted (With Low-Dose Ritonavir) Tipranavir/ritonavir Fosamprenavir/ritonavir etravirine amprenavir atazanavir etravirine etravirine etravirine etravirine

Atazanavir/ritonavir

Darunavir/ritonavir

Lopinavir/ritonavir Saquinavir/ritonavir

Other Agents Antiarrhythmics Amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine Anticoagulants Warfarin Anticonvulsants Carbamazepine, phenobarbital, phenytoin Antifungals Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole etravirine fluconazole itraconazole ketoconazole posaconazole voriconazole Dose adjustments may be necessary for itraconazole, ketoconazole, or voriconazole. etravirine May result in loss of etravirine therapeutic effect; avoid coadministration. anticoagulants Warfarin concentration may be increased; monitor international normalized ratio. antiarrhythmics Concentrations of these antiarrhythmics may be decreased; coadminister with caution.

(continued)

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Table 2. Drug Interactions With Etravirine1 (cont.)

Drug Class/Drug Anti-Infectives Clarithromycin etravirine clarithromycin 14-OH- clarithromycin Activity against Mycobacterium avium complex may be reduced; alternatives to clarithromycin, such as azithromycin, should be considered for treatment of Mycobacterium avium complex. May result in loss of etravirine therapeutic effect; avoid coadministration. If etravirine is NOT coadministered with a protease inhibitor/ritonavir then rifabutin 300 mg once daily is recommended; if etravirine is coadministered with darunavir/ritonavir or saquinavir/ritonavir, avoid coadministration. Decrease diazepam dose if needed. May result in loss of etravirine therapeutic effect; use with caution or consider alternatives for long-term use. May result in loss of etravirine therapeutic effect; avoid coadministration. Can be coadministered with atorvastatin without dose adjustments; although atorvastatin dose may need to be altered basedon clinical response; dose adjustments with fluvastatin, lovastatin, and simvastatin may be necessary. Effect on Etravirine or Concomitant Drug Clinical Considerations

Antimycobacterials Rifampin, rifapentine Antimycobacterials Rifabutin etravirine rifabutin 25-0- desacetylrifabutin etravirine

Benzodiazepines Diazepam Corticosteroids Dexamethasone (systemic) Herbal Products St. Johns wort HMG-CoA Reductase Inhibitors Atorvastatin, fluvastatin, lovastatin, simvastatin etravirine atorvastatin 2-OH-atorvastatin etravirine fluvastatin lovastatin simvastatin immunosuppressant etravirine etravirine diazepam

Immunosuppressants Cyclosporine, sirolimus, tacrolimus Narcotic Analgesics Methadone etravirine methadone Can be coadministered without dose adjustments; monitor for withdrawal symptoms and adjust methadone as needed. Can be coadministered without dose adjustments; dose of sildenafil may need to be altered based on clinical response. Coadminister with caution.

Phosphodiesterase Type 5 Inhibitors Sildenafil, vardenafil, tadalafil sildenafil N-desmethyl-sildenafil

AUC = area under the curve; NNRTI = nonnucleoside reverse transcriptase inhibitor.

active metabolite was increased by 27%. Dosage adjustments of either agent do not appear necessary.21 Etravirine reduces sildenafil

exposure by 57% and Ndesmethyl-sildenafil exposure by 41%.34 Etravirine exposure was increased by 41% when coadmin-

istered with omeprazole; although this difference is not believed to be clinically important and dosage adjustments are not necessary.34,42 Ranitidine had no effect on

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etravirine bioavailability.42 RECOMMENDED MONITORING Specific monitoring recommendations have not been established. All patients receiving antiretroviral therapy should have periodic viral load testing. DOSING The recommended etravirine dose is 200 mg (two 100 mg tablets) twice daily following a meal.1 Patients unable to swallow the tablets whole may disperse the tablets in a glass of water. Once dispersed, patients should stir the dispersion well and drink it immediately.1 Dose adjustments are not necessary in patients with mild to moderate hepatic function impairment or renal function impairment.1,23 PRODUCT AVAILABILITY AND STORAGE Etravirine received Food and Drug Administration approval in January 2008 following a priority review. It is available as 100 mg tablets packaged in bottles of 120 tablets. Each bottle contains 3 desiccant pouches; etravirine should be stored at room temperature (25C; 77F) in the original bottle tightly closed to protect from moisture and without removing the desiccant pouches.1 CONCLUSION Etravirine is regarded as a second generation NNRTI with fewer propensities for the development of resistance. It appears effective and well tolerated in a heavily pretreated population and should be reserved for use in the treatmentexperienced population. Drug regimens must be carefully considered because of the potential for drug interactions.

REFERENCES
1. Intelence [package insert]. Raritan, NJ: Tibotec, Inc; 2008. 2. 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(20):1277312782. 3. Andries K, Azijn H, Thielemans T, et al. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2004;48(12):4680-4686. 4. Das K, Clark AD Jr, Lewi PJ, et al. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drugresistant HIV-1 variants. J Med Chem. 2004;47(10):2550-2560. 5. Llibre JM, Santos JR, Puig T, Molto J, Ruiz I, Clotet B. Prevalence of etravirine-associated mutations in clinical samples with resistance to nevirapine and efavirenz [abstract]. Antivir Ther. 2007;12:S74. 6. Cotte L, Trabaud MA, Tardy JC, et al. HIV-1 NNRTI mutation profiles in clinical practice: implications for TMC125 use [abstract]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUPEB033. 7. Vingerhoets J, Buelens A, Peeter M, et al. Impact of baseline NNRTI mutations on the virological response to TMC125 in the phase III clinical trials DUET-1 and DUET-2 [abstract]. Antivir Ther. 2007;12:S34. 8. Poveda E, Garrido C, de Mendoza C, et al. Prevalence of etravirine (TMC125) resistance mutations in HIV-infected patients with prior experience of nonnucleoside reverse transcriptase inhibitors [letter]. J Antimicrob Chemother. 2007;60(6):1409-1410. 9. Sungkanuparph S, Manosuthi W, Kiertiburanakul S, Piyavong B, Chantratita W. Evaluating the role of etravirine in the second-line ART after failing an initial NNRTI-based regimens

in a resource-limited setting [abstract]. 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, MA. Abstract 865. 10. Picchio G, Vingerhoets J, Staes M, et al. Prevalence of TMC125 resistanceassociated mutations in a large panel of clinical isolates [abstract]. 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, MA. Abstract 866. 11. Taiwo B, Chaplin B, Stanton J, et al. Etravirine-resistance mutations in patients with virologic failure on nevirapine or efavirenz-based HAART [abstract]. 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, MA. Abstract 867. 12. Llibre J, Santos J, Puig T, et al. Prevalence of mutations with effect on virological response to etravirine in routine clinical samples [abstract]. 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, MA. Abstract 868. 13. Woodfall B, Vingerhoets J, Peeters M, et al. Impact of NNRTI and NRTI resistance on the response to the regimen of TMC125 plus two NRTIs in Study TMC125-C227 [abstract]. HIV 8, Eighth International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract 483. 14. Gruzdev B, Rakhmanova A, Doubovskaya E, et al. A randomized, double-blind, placebo-controlled trial of TMC125 as 7-day monotherapy in antiretroviral naive, HIV-1 infected subjects. AIDS. 2003;17(17):2487-2494. 15. Gazzard BG, Pozniak AL, Rosenbaum W, et al. An open-label assessment of TMC 125a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance. AIDS. 2003;17(18):F49-F54. 16. Scholler M, Hoetelmans R, Beets G, et al. Substantial improvement of oral bioavailability of TMC125 using new tablet formulations in healthy volunteers [abstract]. 3rd International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 2427, 2005; Rio De Janeiro, Brazil. Abstract TuPe3.1B11. 17. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced

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HIV-1-infected patients in DUET-1: 24week results from a randomized, double-blind, placebo-controlled trial. Lancet. 2007;370(9581):29-38. 18. Nadler JP, Berger DS, Blick G, et al; TMC125-C223 Writing Group. Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis. AIDS. 2007;21(6):F1-F10. 19. Scholler-Gyure M, Kakuda TN, De Smedt G, et al. Pharmacokinetics (PK) of TMC125 in QD and BID regimens in HIV-1 negative volunteers [abstract]. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago, IL. Abstract A-1427. 20. Boffito M, Winston A, Jackson A, et al. Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level viral resistance. AIDS. 2007;21(11):1449-1455. 21. Schller-Gyure M, Kakuda TN, De Smedt G, et al. Pharmacokinetic interaction between the non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125 and atorvastatin in HIV-negative volunteers [abstract]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEPEA106. 22. Scholler-Gyure 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(3):322-329. 23. Scholler-Gyure M, Kakuda TN, De Smedt G, et al. Pharmacokinetics of TMC125 in HIV-negative volunteers with mild and moderate hepatic impairment [abstract]. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago, IL. Abstract A-1428. 24. Kakuda T, Wade J, Snoeck E, et al. Pharmacokinetics and pharmacodynamics of the NNRTI TMC125 in treatment experienced HIV-1 infected patients: pooled 24-week results of DUET-1 and DUET-2 [abstract]. 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, MA. Abstract 762.

25. Kakuda T, Konigs C, Feiterna-Sperling C, et al. Pharmacokinetics of the next-generation NNRTI TMC125 in HIV-infected children between 6 and 17 years of age [abstract]. 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, MA. Abstract 578. 26. Kakuda T, Scholler-Gyure M, Peeters M, et al. Pharmacokinetics and pharmacodynamics of TMC125 in HIVinfected patients with NNRTI and PI resistance: TMC125-C223 [abstract]. 14th Conference on Retroviruses and Opportunistic Infections; February 2528, 2007; Los Angeles, CA. Abstract L131. 27. Cohen C, Steinhart C, Ward D, et al. Efficacy and safety results at 48 weeks with the novel NNRTI, TMC125, and impact of baseline resistance on the virologic response in study TMC125-C223 [abstract]. AIDS. 2006 XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0061. 28. Lazzarin A, Campbell T, Clotet B, et al; DUET-2 Study Group. Efficacy and safety of TMC125 (etravirine) in treatment experienced HIV-1-infected patients in DUET-2: 24-week results from a randomized, double-blind, placebo-controlled trial. Lancet. 2007;370(9581):39-48. 29. Mills A, Cahn P, Grinsztejn B, et al. DUET-1: 24 week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 612 treatment-experienced HIV-1 infected patients [abstract]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS204-1. 30. Haubrich R, Cahn P, Grinsztejn B, et al. DUET-1: week-48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 612 treatmentexperienced HIV-1-infected patients [abstract]. 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, MA. Abstract 790. 31. Katlama C, Campbell T, Clotet B, et al. DUET-2: 24 week results of a phase III randomised double-blind trial to evaluate the efficacy and safety of TMC125 versus placebo in 591 treat-

ment-experienced HIV-1 infected patients [abstract]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007. Sydney, Australia. Abstract WESS204-2. 32. Johnson M, Campbell T, Clotet B, et al. DUET-2: week-48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 591 treatmentexperienced HIV-1-infected patients [abstract]. 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, MA. Abstract 791. 33. Woodfall B, De Smedt G, Berckmans C, Baeten B, Peeterss M. No frequent reporting of neurological or psychiatric events during TMC125 treatment [abstract]. HIV 8, Eighth International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract 485. 34. Kakuda T, Scholler-Gyure M, Woodfall B, et al. TMC125 in combination with other medications: summary of drug-drug interaction studies [abstract]. HIV 8, Eighth International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract 472. 35. Kakuda T, Scholler-Gyure M, Peeters M, et al. Pharmacokinetic interaction study with TMC125 and TMC114/rtv in HIV-negative volunteers [abstract]. AIDS 2006 XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0086. 36. Scholler-Gyure M, Woodfall B, De Marez T, et al. Pharmacokinetics of TMC125, with atazanavir (ATV) and atazanavir/ritonavir (ATV/r) [abstract]. HIV 8, Eighth International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract 56. 37. Anderson MS, Kakuda TN, Miller JL, et al. Pharmacokinetic evaluation of non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125 and integrase inhibitor (InSTI) Raltegravir (RAL) in healthy subjects [abstract]. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract TUPDB02. 38. Ramanathan S, West S, Kakuda TN, Mack R, Holmes C, Kearney BP. Lack of

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clinically relevant drug interactions between ritonavir-boosted elvitegravir and TMC125 [abstract]. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2007; Chicago, IL. Abstract H1049. 39. Scholler M, Hoetelmans R, Bollen S, et al. No significant interaction between TMC125 and didanosine (ddI) in healthy volunteers [abstract]. 3rd International AIDS Society Conference on

HIV Pathogenesis, Treatment and Prevention; July 24-27, 2005; Rio De Janerio, Brazil. Abstract WePe3.3C16. 40. Scholler-Gyure M, Debroye C, Aharchi F, et al. No effect of TMC125 on the pharmacokinetics of oral contraceptives [abstract]. HIV 8, Eighth International Congress on Drug Therapy in HIV Infection; November 12-16, 2006; Glasgow, Scotland. Abstract 57. 41. Scholler-Gyure M, Woodfall B,

Vanaken H, et al. Lack of interaction between TMC125 and methadone [abstract]. AIDS 2006 XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0084. 42. Scholler-Gyure M, De Smedt G, Vanakaen H, et al. TMC125 bioavailability is not affected by ranitidine and omeprazole [abstract]. AIDS 2006 XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0082.

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Continuing Education Case Study Quiz

Goal The goal of this program is to educate the reader about the use of etravirine in patients with human immunodeficiency virus (HIV)-1 infection. Objectives At the completion of this program, the reader will be able to: 1. Describe the pharmacology and pharmacokinetics of etravirine. 2. Discuss the risks associated with etravirine use. 3. Discuss the potential benefit of etravirine for an individual patient. 4. Apply the information on etravirine use to a case study. Key Words new drugs; acquired immune deficiency syndrome; human immunodeficiency virus; antiviral agents

D. Following metabolism via CYP 3A4, 2C9, and 2C19. 8. In a patient with a history of hepatitis and moderate hepatic impairment, etravirine: A. Is contraindicated. B. Should be used with extreme caution and frequent monitoring of liver function tests. C. Should be used with extreme caution and a reduced initial dose. D. May be used without dosage adjustment. Case History KC is a 41-year-old man with HIV-1 infection who is about to initiate a new regimen consisting of etravirine, darunavir, and ritonavir. 9. What is the recommended etravirine dose for KC? A. 100 mg twice daily B. 200 mg once daily C. 200 mg twice daily D. 400 mg once daily 10. The recommended frequency of etravirine administration was initially determined by: A. Etravirine gastrointestinal tolerability. B. Saturable etravirine absorption pharmacokinetics. C. The etravirine half-life. D. The etravirine pill burden. 11. What instructions should be given to KC regarding timing of the etravirine dose? A. Etravirine should be taken following a meal to increase absorption. B. Etravirine should be taken

1. Etravirine is indicated for the treatment of HIV-1 infection in: A. Tr e a t m e n t - e x p e r i e n c e d adults with HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor. B. Pediatric patients with HIV1 strains resistant to multiple antiretroviral agents. C. Tr e a t m e n t - e x p e r i e n c e d adults and children. D. Tr e a t m e n t - e x p e r i e n c e d adults with HIV-2 strains resistant to a nucleoside reverse transcriptase inhibitor. 2. Etravirine is a(n): A. Integrase inhibitor. B. Nonnucleoside reverse transcriptase inhibitor. C. Nucleoside reverse transcriptase inhibitor. D. Nucleotide reverse transcriptase inhibitor. 3. Development of etravirine resistance: A. Is promoted by its rigid structure.

B. Occurs in all HIV-1 resistant to efavirenz. C. Occurs rapidly when used in a multidrug regimen. D. Requires multiple mutations. 4. Etravirine is a _______ compound with ______ solubility. A. Lipophilic, high B. Lipophilic, low C. Hydrophilic, high D. Hydrophilic, low 5. Following oral administration, peak-etravirine concentrations are reached within: A. 1 to 2 hours. B. 2.5 to 4 hours. C. 4.5 to 6 hours. D. 6.5 to 8 hours. 6. Etravirine has a half-life of: A. 6 hours. B. 12 hours. C. 24 hours. D. 36 hours. 7. Etravirine is eliminated: A. Almost exclusively renally. B. As unchanged drug. C. Extensively in the bile.

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following a meal to increase tolerability. C. Etravirine should be taken on an empty stomach to increase absorption. D. Etravirine should be taken on an empty stomach to minimize drug interactions. 12. KC reports difficulty swallowing tablets and asks if a liquid form of etravirine is available. You inform KC that: A. An oral suspension is available. B. Only the tablets are available and they must be swallowed intact. C. The tablets can be crushed and mixed with a soft food such as applesauce. D. The tablets can be dispersed in a glass of water, stirred well, and immedi-

ately consumed. 13. Which medications that are commonly used in patients with HIV infection should not be coadministered with etravirine? A. Efavirenz, atazanavir, phenytoin, and fluconazole B. Delavirdine, nelfinavir, itraconazole, and clarithromycin C. Nevirapine, indinavir, atazanavir/ritonavir, and rifampin D. Ritonavir, itraconazole, azithromycin, and rifabutin 14. What are the most common side effects associated with etravirine therapy? A. Diarrhea and peripheral neuropathy B. Edema and fatigue

C. Headache and hypertension D. Rash and nausea 15. What storage instructions should KC be given? A. Etravirine tablets can be dispersed in water and the resulting solution stored in the refrigerator. B. Etravirine tablets should be stored at room temperature, tightly closed in the original container, and retaining the 3 desiccant pouches. C. Etravirine tablets should be stored in the refrigerator, tightly closed in the original container, and protected from moisture. D. Etravirine tablets should be transferred to a pill box to aid adherence.

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Drug Evaluation: Etravirine ACPE # 071-999-08-006-H02-P 0.15 CEU Program Expires: June 1, 2011 To receive continuing education credit, complete this form and mail with your $7 processing fee (made payable to WSU College of Pharmacy) to: College of Pharmacy, Continuing Education Dept. Washington State University Spokane PO Box 1495 Spokane, WA 992101495
Print clearly or type. Allow 4 weeks for processing. Name__________________________________________ Address: _______________________________________ City:_______________ State: _______ Zip: __________ Note: Your answer sheet will be graded confidentially and you will receive prompt notification of your score. In order to receive continuing education credit for this program, you need a minimum correct response rate of 70%. PROGRAM EVALUATION Please rate our continuing education offering by responding to the following questions. 1. This program described the pharmacology and pharmacokinetics of etravirine: completely fairly well not at all

2. I was able to apply the knowledge from this educational program and other resources to answer questions associated with the case study: completely fairly well not at all 3. The program discussed the risks associated with the use of etravirine: completely fairly well not at all 4. After this program, I was able to discuss the potential benefit of etravirine for an individual patient: completely fairly well not at all 5. The overall quality of the program was: excellent good fair poor

6. Was the content of this article relevant to the practice of pharmacy? excellent good fair poor 7. How long did it take you to complete this continuing education program? _______ hours 8. What other continuing education programs or topics would you like to see? ____________________________________________

_________________________________________ _________________________________________

Answer Form
1. A B 2. A B 3. A B 4. A B 5. A B 6. A B 7. A B 8. A B C D C D C D C D C D C D C D C D 9. A B 10. A B 11. A B 12. A B 13. A B 14. A B 15. A B C D C D C D C D C D C D C D
The Washington State University College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmaceutical education.

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