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FORMULARY DRUG REVIEWS
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.
Volume 43, June 2008
000 copies/mL and phenotypic resistance to an NNRTI.06 log10 copies/mL reduction with placebo (P < 0.02 log10 copies/mL per day with placebo. without change in time-to-peak concentration or elimination half-life.15 PHARMACOKINETICS Etravirine is a lipophilic compound with low solubility and low permeability. 9 of 10 patients had achieved an undetectable viral load. peak etravirine concentrations are met within 2.1 Gender.3 Etravirine has a half-life of 36 hours.18 Compared with the earlier formulation.19 Following oral administration.89 log10 copies/mL.7 log10 copies/mL. Viral load was reduced from baseline by 1. ed. Patients received etravirine (F060 formulation) 200 mg. Viral load decay rates were 0. race. Absolute oral bioavailability is unknown. monotherapy with etravirine 900 mg twice daily (polyethylene glycol [PEG] 4000 formulation) for 7 days was compared with placebo in 19 patients. creatinine clearance.13 log10 copies/mL per day. darunavir 600 mg. The median reduction in viral load was 2. CYP2C9. age. shortterm etravirine therapy was assessed in antiretroviral-naive and antiretroviral-experienced patients.33 log10 copies/mL per day with etravirine and 0. weight.15 Etravirine is metabolized primarily by CYP3A4. 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. etravirine 900 mg twice daily (PEG 4000 formulation) was administered for 7 days as a substitute for the patients’ regular NNRTI.24 In children 6 to 17 years of age.20 Etravirine (TF035 formulation) was assessed in a randomized.13 In early phase studies.5 to 4 hours. Over 7 days.2 mg/kg twice daily. 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.1. open-label study enrolling 199 patients with genotypic resistance to approved NNRTIs and at least 3 primary protease inhibitor mutations.1 Exposure is reduced when administered in a fasted state. 10 were included in the analysis.14 In an open-label study enrolling 16 patients receiving an NNRTIcontaining antiretroviral regimen (efavirenz.7. nevirapine. and ritonavir 100 mg twice daily in conjunction with 2 or more NRTIs. 13 patients) with an HIV-1 RNA viral load greater than 2. The enrolled patients had a median duration of HIV Hospital Pharmacy 499 .17. Two patients withdrew from the study in the first week. the new formulation produces a substantially greater area under the curve (AUC) and peak concentration. further studies will assess the pharmacokinetics and tolerability of etravirine 5. administration following a meal is recommendLike other NNRTIs. Enfuvirtide use was optional. and use of tenofovir or enfuvirtide in the background regimen were not found to significantly affect etravirine pharmacokinetics. 3 patients. Seven (44%) patients had a reduction of greater than 1 log10 copies/mL.1 The renal clearance of etravirine is less than 1.1 The peak concentration and AUC of etravirine were not significantly altered in volunteers with mild to moderate hepatic function impairment.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).Formulary Drug Reviews logic failure was observed to occur more frequently in patients with increased numbers of nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI mutations.16 In studies with the newer formulation.2%. etravirine was administered twice daily to minimize the pill burden with each administration.20-22 Etravirine metabolites are at least 90% less active than etravirine against wildtype HIV in cell culture.25 Because of concerns related to underdosing of antiretrovirals in children. and CYP2C19 isozymes and induces CYP3A4 and inhibits CYP2C9 and CYP2C19.25 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. With etravirine therapy. primarily to albumin and alpha-1-acid glycoprotein.15 Despite the long half-life. viral load was reduced by a median of 0.20 etravirine is highly protein bound (more than 99%). In naive patients. and particularly in patients with more than 3 baseline etravirine resistance–associated mutations.99 log10 copies/mL with etravirine compared with a 0. viral hepatitis status. At week 24.23 Etravirine pharmacokinetics have not been assessed in patients with severe hepatic function impairment.001). the viral load decay rate was 0. therefore.
000 copies/mL) Viral load < 50 copies/mL at 24 weeks (baseline viral load > 100. 98% of patients in the placebo group discontinued therapy because of virologic failure. Patients received etravirine 400 mg (80 patients).5% in the placebo group at week 24.28. DUET-1 and DUET-2 Week 24 Study Results17.1% in the etravirine groups by 24 weeks. Exclusion criteria included life expectancy of less than 6 months.218) compared with 7. acute viral hepatitis.7 log10 copies/mL.27 Etravirine was assessed in 2 multinational. P = 0. b c P < 0.5%). Median baseline viral load was 4.3% and 5. P = 0.0001.000 copies/mL.26.05 for both etravirine doses vs placebo). compared with 9% of patients in both etravirine groups. if female. a reduction in viral load of at least 1 log10 copies/mL was achieved in 36. the mean change from baseline in viral load was −0.8% in the 800 mg group (P < 0.000 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. and 3 or more primary protease inhibitor mutations. or. double-blind. randomized. d e infection of 15 years and received a median of 12 previous antiretroviral agents. and −0.0003. At week 24.32 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 < 100.6% vs 52. More patients in the etravirine groups received at least one drug in their regimen (excluding etravirine) that was scored as active (83.18 log10 copies/mL with etravirine 800 mg. At week 48.4%) and more patients in the etravirine groups received enfuvirtide (62. documented genotypic evidence of NNRTI resistance. By week 48.0001.5% and 64.3% of patients in the 400 mg group (P = 0. NR = not reported.30. 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.001) compared with 7.005. −1.14 log10 copies/mL in the placebo group (P < 0.5% in the placebo group at week 24.Formulary Drug Reviews Table 1. the mean change from baseline in viral load was −1. pregnancy.5% in the placebo group. Viral load less than 400 copies/mL was achieved in 30% of patients in the 400 mg group (P = 0.133) and 17. currently active acquired immune deficiency syndrome (AIDS)-defining illness.01 log10 copies/mL in the 800 mg group.19 log10 copies/mL with placebo (P < 0. and −0.7% in the 800 mg group (P = 0. or of child-bearing potential and not using adequate contraception.018) and 38% in the 800 mg group (P = 0.005) and 41. 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). Viral load less than 50 copies/mL was achieved in 21.88 log10 copies/mL in the 400 mg group. etravirine 800 mg (79 patients). Enrolled patients were randomized to receive etravirine 200 mg or placebo twice daily 500 Volume 43.3% of patients in the 400 mg group (P = 0. viral load more than 5.5% vs 74. At week 24. June 2008 . −1.18. placebo-controlled phase 3 studies (DUET-1 and DUET-2) enrolling treatmentexperienced adult patients with virological failure on stable antiretroviral therapy.002) compared with 7.05 for both etravirine groups vs placebo). Discontinuation of therapy because of virological failure occurred in 75% of placebo-treated patients compared with 6.04 log10 copies/mL with etravirine 400 mg. breast-feeding.
AND PRECAUTIONS The prescribing information for etravirine lists no contraindication to etravirine therapy. The patient population was 86% to 87% male. and erythema multiforme. and 17% were sensitive to 2 or more NRTIs. Randomization was stratified for enfuvirtide use in the background regimen.1% of patients receiving etravirine. The primary end point was confirmed viral load less than 50 copies/mL at week 24 on intentto-treat analysis. and the United States. The patient population was 93% male. 94% maintained a viral load less than 50 copies/mL at 48 weeks with the etravirine regimen compared with 89% with the placebo regimen.6 to achieve 1 more virological response at 24 weeks of therapy.0001). Thailand. with a median baseline viral load of 4. Of patients with a viral load less than 50 copies/mL at week 24. and was infrequent after week 4. the United Kingdom.Formulary Drug Reviews after a meal in conjunction with darunavir (600 mg twice daily) with low-dose ritonavir (100 mg twice daily). 11% to 26%. Italy. Patients in both studies had the option of extending the initial 48-week treatment period by an additional 48 weeks.34 log10 copies/mL in the etravirine group compared with −1. Belgium.9 log10 copies/mL. Mexico. and 66% had 4 or more primary protease inhibitor mutations. 90% of patients had 4 or more NRTI resistance–associated mutations. Germany. P = 0. occurred primarily in the second week of therapy.28. At the time of screening.0001). Hepatitis B and/or C coinfection was present in 13% of patients. Canada. dorsocervical fat enlargement (buffalo hump). and 14% Hispanic. The mean change in viral load at 24 weeks was −2. breast enlargement. Spain. 54% were resistant to all available NRTIs. The absolute difference in attainment of viral load less than 50 copies/mL at 24 weeks was 18% (95% CI. Brazil.17. Such reactions have been reported in less than 0. and investigatorselected NRTIs. hypersensitivity reactions. At the time of screening. The absolute difference in attainment of viral load less than 50 copies/mL at 24 weeks was 17% (95% confidence interval [CI]. primarily because of virological failure.30 DUET-2 enrolled 591 patients (295 in the etravirine group and 296 in the placebo group) in Australia.0003). Poland. and 13% black. France. the Netherlands.8 log10 copies/mL. Results are summarized in Table 1.29. have occurred during etravirine therapy.9 to achieve 1 more virological response at 24 weeks of therapy.8 to 4. 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. were observed in patients receiving antiretroviral therapy.41 log10 copies/mL in the etravirine group compared with −1. 65% white. 65% were sensitive to darunavir.17. and screening viral load. Enfuvirtide was used in 40% of patients in the etravirine group and 41% in the placebo group. Panama. 30% were sensitive to 1 NRTI. primarily because of virological failure. Results are summarized in Table 1. resulting in a number needed to treat of 5. Puerto Rico.0002) at 24 weeks. The mean change in viral load at 24 weeks was −2. By week 24. and the United States. Portugal. 51 (17%) patients in the etravirine group and 73 (25%) in the placebo group had discontinued therapy. 42 (14%) patients in the etravirine group and 56 (18%) in the placebo group had discontinued therapy. 65% of patients had 2 or more NNRTI resistance–associated mutations. previous darunavir use. including cases of Stevens-Johnson syndrome.68 log10 copies/mL in the placebo group (P < 0.3692) at week 24. 76% white. P = 0. resulting in a number needed to treat of 5.31.1 Fat redistribution/accumulation. Rash was generally mild to moderate. peripheral wasting. Etravirine therapy should be discontinued if a severe rash develops.7 log10 copies/mL in the placebo group (P < 0.005). CD4 cell count increased by a mean of 89 cells/mcL in the etravirine group and 64 cells/mcL in the placebo group (P = 0.1 Severe and potentially lifethreatening skin reactions. By week 24. Enfuvirtide was used in 52% of patients in the etravirine group and 53% in the placebo group. 44% had 3 or more darunavir resistance–associated mutations. France. 9% to 25%. Chile. and cushingoid appearance. Of patients with a viral load less than 50 copies/mL at 24 weeks. 90% maintained a viral load less than 50 copies/mL at week 48 with etravirine compared with 88% with placebo.28 DUET-1 enrolled 612 patients (304 in the etravirine group and 308 in the placebo group) in Argentina. facial wasting. Rash generally resolved within 1 to 2 weeks with continued therapy.32 CONTRAINDICATIONS. with a median baseline viral load of 4. including central obesity. Enfuvirtide use was optional. A total of 2% of HIV-1–infected patients receiving etravirine in phase 3 clinical trials discontinued therapy because of rash. WARNINGS.1 Hospital Pharmacy 501 .
such as mood swings. and/or CYP2C19 may alter the therapeutic effect or adverse reaction profile of etravirine.1 Etravirine is in Pregnancy Category B.34 Pharmacokinetic interactions were not observed between etravirine and didanosine.1. fosamprenavir/ritonavir. abnormal dreams or nightmares. some earlier studies suggested possible associations between etravirine and some psychiatric adverse reactions. The prevalence of rash was greater in women in DUET-1 (24% vs 18%. abdominal pain.0192).41 When coadministered with atorvastatin.18. etravirine pharmacokinetics were not affected. CYP2C9. fatigue. patients whose immune system responds may develop an anti-inflammatory response to indolent or residual opportunistic infections.3%) and nausea (13. etravirine pharmacokinetics were not affected. atazanavir/ritonavir. and CYP2C19 may alter the therapeutic effect or adverse reaction profile of the coadministered agent. 11 days in DUET-1 and 14 days in DUET2).30. anxiety. Etravirine levels were significantly reduced with this combination.36 When coadministered with the integrase inhibitor raltegravir. 12 days in DUET-1 and 16 days in DUET-2). vomiting.28 Neuropsychiatric adverse reactions were not observed with increased frequency in the etravirine-treatment groups in the DUET-1 and DUET-2 studies.17 In DUET-2. CYP2C9.1.33 In DUET-1.34. Severe rash occurred in 4 (1%) etravirine-treated patients in each trial and 1 placebo-treated patient.20-22 Coadministration of substrates of CYP3A4. possibly because of induction of glucuronidation by etravirine. exposure to the atorvastatin 502 Volume 43.Formulary Drug Reviews Immune reconstitution syndrome was reported in patients treated with combination antiretroviral therapy.17. Atorvastatin exposure was reduced by 37%.38 Etravirine increases fosamprenavir exposure by 69%. an investigational integrase inhibitor. tipranavir. It should be used during pregnancy only if the potential benefit justifies the potential risk.1 To date. saquinavir.17.22. June 2008 .20-22 Coadministration of etravirine with drugs that inhibit or induce CYP3A4.32 Other adverse reactions occurring with similar frequency in etravirineand placebo-treated patients included diarrhea.0001).1 Key drug interactions are summarized in Table 2.35 When coadministered with atazanavir or atazanavir plus ritonavir.28 Grade 1 or 2 rash (mild or moderate) was most common.17 DRUG INTERACTIONS Etravirine is a substrate of CYP3A4. and resolved with continued treatment (median duration.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).37 Pharmacokinetic drug interactions were also not observed when etravirine was administered with the ritonavirboosted elvitegravir. rash occurred in 14% of etravirine-treated patients compared with 9% of placebo recipients. protease inhibitors administered without ritonavir. CYP2C9.39 Etravirine also had no significant effect on the pharmacokinetics of methadone.1 Etravirine should not be administered with tipranavir/ritonavir. Atazanavir trough levels were reduced when etravirine was administered with atazanavir alone but not when ritonavir was coadministered. peripheral neuropathy. including etravirine.1.1 ADVERSE REACTIONS Adverse reactions occurring more frequently with etravirine than placebo have included rash (16. or NNRTIs.34 When coadministered with darunavir/ritonavir. rash occurred in 20% of etravirine-treated patients compared with 10% of placebo recipients (P < 0. P = 0.26 Etravirine had no effect on the pharmacokinetics of lopinavir or tenofovir. Dosage adjustments of either agent do not appear necessary. however. 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. tended to occur within the first few weeks of treatment (median onset. headache.1. Etravirine safety and effectiveness have not been established in children. Etravirine levels were reduced 37%. necessitating further evaluation and treatment. no effects on darunavir pharmacokinetics were observed. Etravirine should not be coadministered with tipranavir/ritonavir. and CYP2C19. Raltegravir levels were slightly reduced. and hypertension. etravirine levels were increased slightly but not to a clinically significant extent. and depression.1%). was generally erythematous or maculopapular in nature. or an oral contraceptive containing ethinylestradiol and norethindrone.40.17.28. During the initial phase of combination therapy.1 It is also an inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19.9% vs 9.9% vs 11.
combination used in phase 3 studies. indinavir ↓ ↑ ↑ ↓ atazanavir amprenavir nelfinavir indinavir Ritonavir ↓ etravirine May result in loss of etravirine therapeutic effect. Etravirine AUC reduced 33%. mexiletine. phenobarbital. avoid coadministration with ritonavir 600 mg twice daily. May result in loss of etravirine therapeutic effect. nelfinavir. avoid coadministration. itraconazole. avoid coadministration. May alter protease inhibitor concentrations. May result in loss of atazanavir therapeutic effect and 100% increase in etravirine systemic exposure. ↑ anticoagulants Warfarin concentration may be increased. Etravirine AUC increased 85%. Drug Interactions With Etravirine1 Drug Class/Drug NNRTIs Efavirenz. avoid coadministration. coadminister with caution. ketoconazole. Because of significant increase in amprenavir. avoid coadministration. ↓ etravirine May result in loss of etravirine therapeutic effect. appropriate doses for combination therapy have not been established. bepridil. coadminister with caution. avoid coadministration. Combination of 2 NNRTIs not shown beneficial. posaconazole. quinidine Anticoagulants Warfarin Anticonvulsants Carbamazepine. lidocaine (systemic). similar to that with darunavir/ritonavir coadministration. phenytoin Antifungals Fluconazole. nevirapine ↓ etravirine ↑ etravirine Combination of 2 NNRTIs not shown beneficial. ketoconazole. avoid coadministration. disopyramide. however. or voriconazole. ↓ antiarrhythmics Concentrations of these antiarrhythmics may be decreased. coadminister without dose adjustments. flecainide. avoid coadministration. Effect on Etravirine or Concomitant Drug Clinical Considerations Delavirdine Protease Inhibitors Unboosted (Without Low-Dose Ritonavir) Atazanavir. fosamprenavir. propafenone. 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. coadminister without dose adjustments. may result in loss of etravirine therapeutic effect. Etravirine AUC reduced 37%. (continued) Hospital Pharmacy 503 .Formulary Drug Reviews Table 2. voriconazole ↑ ↔ ↓ ↓ ↔ ↑ etravirine fluconazole itraconazole ketoconazole posaconazole voriconazole Dose adjustments may be necessary for itraconazole. monitor international normalized ratio.
sirolimus. dose of sildenafil may need to be altered based on clinical response. Coadminister with caution. May result in loss of etravirine therapeutic effect. if etravirine is coadministered with darunavir/ritonavir or saquinavir/ritonavir. tadalafil ↓ sildenafil ↓ N-desmethyl-sildenafil AUC = area under the curve. Effect on Etravirine or Concomitant Drug Clinical Considerations Antimycobacterials Rifampin. although this difference is not believed to be clinically important and dosage adjustments are not necessary. June 2008 . Can be coadministered without dose adjustments.34. avoid coadministration.21 Etravirine reduces sildenafil exposure by 57% and Ndesmethyl-sildenafil exposure by 41%. monitor for withdrawal symptoms and adjust methadone as needed. dose adjustments with fluvastatin. although atorvastatin dose may need to be altered basedon clinical response.42 Ranitidine had no effect on 504 Volume 43. use with caution or consider alternatives for long-term use. Dosage adjustments of either agent do not appear necessary.) Drug Class/Drug Anti-Infectives Clarithromycin ↑ etravirine ↓ clarithromycin ↑ 14-OH.Formulary Drug Reviews Table 2. such as azithromycin. Decrease diazepam dose if needed. simvastatin ↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin ↓ lovastatin ↓ simvastatin ↓ immunosuppressant ↓ etravirine ↓ etravirine ↑ diazepam Immunosuppressants Cyclosporine. lovastatin.34 Etravirine exposure was increased by 41% when coadmin- istered with omeprazole. should be considered for treatment of Mycobacterium avium complex. Drug Interactions With Etravirine1 (cont. May result in loss of etravirine therapeutic effect. lovastatin. alternatives to clarithromycin. May result in loss of etravirine therapeutic effect. John’s wort HMG-CoA Reductase Inhibitors Atorvastatin. avoid coadministration. Phosphodiesterase Type 5 Inhibitors Sildenafil. and simvastatin may be necessary. NNRTI = nonnucleoside reverse transcriptase inhibitor.desacetylrifabutin ↓ etravirine Benzodiazepines Diazepam Corticosteroids Dexamethasone (systemic) Herbal Products St.clarithromycin Activity against Mycobacterium avium complex may be reduced. tacrolimus Narcotic Analgesics Methadone ↔ etravirine ↔ methadone Can be coadministered without dose adjustments. Can be coadministered with atorvastatin without dose adjustments. fluvastatin. rifapentine Antimycobacterials Rifabutin ↓ etravirine ↓ rifabutin ↓ 25-0. vardenafil. avoid coadministration. active metabolite was increased by 27%. If etravirine is NOT coadministered with a protease inhibitor/ritonavir then rifabutin 300 mg once daily is recommended.
Andries K. 3rd International AIDS Society Conference on HIV Pathogenesis. Staes M. 15th Conference on Retroviruses and Opportunistic Infections. et al. 2005. AIDS. Boston. TMC125. Antivir Ther.48(12):4680-4686. Antimicrob Agents Chemother. Brazil. February 3-6. Rosenbaum W. 2.1 CONCLUSION Etravirine is regarded as a second generation NNRTI with fewer propensities for the development of resistance. Evaluating the role of etravirine in the second-line ART after failing an initial NNRTI-based regimens in a resource-limited setting [abstract]. Tardy JC. Piyavong B. et al. Drug regimens must be carefully considered because of the potential for drug interactions. July 2427. Hoetelmans R. Pozniak AL. Raritan. REFERENCES 1. 4th International AIDS Society Conference on HIV Pathogenesis. Thielemans T. Peeter M. Abstract 866. An open-label assessment of TMC 125—a new. MA. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6. 2004. 10. J Antimicrob Chemother. NJ: Tibotec. 16. placebo-controlled trial of TMC125 as 7-day monotherapy in antiretroviral naive. It is available as 100 mg tablets packaged in bottles of 120 tablets. 2003.1. Santos J. Abstract 867. November 12-16. 2006. 14. July 22-25. J Virol. Ruiz I. 15. et al. et al. Molto J. Prevalence of mutations with effect on virological response to etravirine in routine clinical samples [abstract]. 77°F) in the original bottle tightly closed to protect from moisture and without removing the desiccant pouches. Madruga JV.12:S34. Chantratita W. MA. Vingerhoets J. 8. 7. patients should stir the dispersion well and drink it immediately. 2008. Llibre J. Azijn H. Antivir Ther. 2005. de Mendoza C. 5. Fransen E. Grinsztejn B. 15th Conference on Retroviruses and Opportunistic Infections. Azijn H. 2004. Efficacy and safety of TMC125 (etravirine) in treatment-experienced Hospital Pharmacy 505 . for 7 days in HIV-1 infected individuals with NNRTI resistance. Boston. Lewi PJ. Prevalence of TMC125 resistanceassociated mutations in a large panel of clinical isolates [abstract]. et al. Chaplin B. MA. 2007. Vingerhoets J. 13. 11. Impact of NNRTI and NRTI resistance on the response to the regimen of TMC125 plus two NRTIs in Study TMC125-C227 [abstract]. double-blind. Inc. 2003. et al. Treatment and Prevention. Llibre JM. Cotte L. Substantial improvement of oral bioavailability of TMC125 using new tablet formulations in healthy volunteers [abstract]. Trabaud MA. a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Puig T.1 Dose adjustments are not necessary in patients with mild to moderate hepatic function impairment or renal function impairment. 3. 2007.1 Patients unable to swallow the tablets whole may disperse the tablets in a glass of water. HIV 8. Doubovskaya E. Vingerhoets J. Santos JR. Abstract TUPEB033. et al.Formulary Drug Reviews etravirine bioavailability. 2008. Treatment and Prevention. Glasgow. Rakhmanova A. Gazzard BG.17(17):2487-2494. etravirine should be stored at room temperature (25°C. Intelence [package insert].1B11. 2008. et al. Puig T. J Med Chem.17(18):F49-F54. et al. Vingerhoets J. 6. Boston. Scholler M. Abstract TuPe3. HIV-1 NNRTI mutation profiles in clinical practice: implications for TMC125 use [abstract].12:S74. 12. Prevalence of etravirine-associated mutations in clinical samples with resistance to nevirapine and efavirenz [abstract]. Abstract 483. Prevalence of etravirine (TMC125) resistance mutations in HIV-infected patients with prior experience of nonnucleoside reverse transcriptase inhibitors [letter]. et al. Rio De Janeiro. February 3-6. Clark AD Jr. Beets G. Buelens A. MA. Manosuthi W. Abstract 865. Sungkanuparph S. Scotland. 9. A randomized. Picchio G. Abstract 868. All patients receiving antiretroviral therapy should have periodic viral load testing. Kiertiburanakul S. Taiwo B. AIDS. Once dispersed. Das K.60(6):1409-1410.23 PRODUCT AVAILABILITY AND STORAGE Etravirine received Food and Drug Administration approval in January 2008 following a priority review. February 3-6. Eighth International Congress on Drug Therapy in HIV Infection.47(10):2550-2560. et al. 2008. Garrido C. next-generation NNRTI. Australia. 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. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. Woodfall B. et al. Etravirine-resistance mutations in patients with virologic failure on nevirapine or efavirenz-based HAART [abstract]. Gruzdev B. Sydney. 2007. Each bottle contains 3 desiccant pouches. et al. DOSING The recommended etravirine dose is 200 mg (two 100 mg tablets) twice daily following a meal. 4. 2008.42 RECOMMENDED MONITORING Specific monitoring recommendations have not been established. Peeters M. It appears effective and well tolerated in a heavily pretreated population and should be reserved for use in the treatmentexperienced population. 17. Clotet B. 2007. Stanton J.79(20):1277312782. Impact of baseline NNRTI mutations on the virological response to TMC125 in the phase III clinical trials DUET-1 and DUET-2 [abstract]. Cahn P. Boston. 15th Conference on Retroviruses and Opportunistic Infections. et al. HIV-1 infected subjects. Poveda E.
Grinsztejn B. et al. Berger DS. 15th Conference on Retroviruses and Opportunistic Infections. Abstract 472. Lack of 506 Volume 43. June 2008 . Scholler-Gyure M. J Clin Pharmacol. placebo-controlled trial. Los Angeles. Glasgow. Nadler JP. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. 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]. Abstract L131. Kakuda T. et al. Pharmacokinetic and pharmacodynamic study of the concomitant administration of methadone and TMC125 in HIV-negative volunteers.21(11):1449-1455. Kakuda T. 28. 2007. November 12-16. Johnson M. Canada. Lancet. Abstract 578. Boston. Peeters M. De Smedt G. Glasgow. Woodfall B. Boston. 2007. Pharmacokinetics of TMC125. 4th International AIDS Society Conference on HIV Pathogenesis. et al. Eighth International Congress on Drug Therapy in HIV Infection. 2008. Cahn P. Scholler-Gyure M. et al. Campbell T. 18. et al. MA. August 13-18. 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]. Treatment and Prevention. double-blind. Schöller-Gyure M. 19. Scholler-Gyure M. 34. Glasgow. Australia. Sydney. 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]. IL. Cahn P.370(9581):39-48. and impact of baseline resistance on the virologic response in study TMC125-C223 [abstract]. 24. West S. 27. Steinhart C. Haubrich R. Woodfall B. Campbell T. 22. Treatment and Prevention. 2006. Boston. No frequent reporting of neurological or psychiatric events during TMC125 treatment [abstract]. Miller JL.Formulary Drug Reviews HIV-1-infected patients in DUET-1: 24week results from a randomized. Kakuda T. Woodfall B. Peeters M. Ramanathan S. Clotet B. 2006. Abstract WESS204-2. July 22-25. Konigs C. 15th Conference on Retroviruses and Opportunistic Infections. Kakuda TN. Kakuda TN. MA. Pharmacokinetics (PK) of TMC125 in QD and BID regimens in HIV-1 negative volunteers [abstract]. Efficacy and safety results at 48 weeks with the novel NNRTI. Sydney. Cohen C. 21. Holmes C. AIDS. Mack R. Pharmacokinetic interaction between the non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125 and atorvastatin in HIV-negative volunteers [abstract]. et al. Peeterss M. September 17-20. Pharmacokinetics of TMC125 in HIV-negative volunteers with mild and moderate hepatic impairment [abstract]. 29. TMC125 in combination with other medications: summary of drug-drug interaction studies [abstract].21(6):F1-F10. Toronto. AIDS 2006 XVI International AIDS Conference. 4th International AIDS Society Conference on HIV Pathogenesis. De Smedt G. Abstract 791. 2008. Pharmacokinetics of the next-generation NNRTI TMC125 in HIV-infected children between 6 and 17 years of age [abstract]. et al. Scotland. Abstract 762. Efficacy and safety of TMC125 (etravirine) in treatment experienced HIV-1-infected patients in DUET-2: 24-week results from a randomized. 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]. 35. 2007. with atazanavir (ATV) and atazanavir/ritonavir (ATV/r) [abstract]. CA. De Smedt G. Mills A. November 12-16. Scholler-Gyure M. et al. 2006. Australia. et al. Scotland. 2008. Australia. 26. 2007. 2007. August 13-18. Abstract A-1427. Blick G. Eighth International Congress on Drug Therapy in HIV Infection. Boston. 2007. Toronto. July 22-25. Scholler-Gyure M. 2006. DUET-2 Study Group. 31. Abstract 485. Kakuda TN. Australia. et al. 2006 XVI International AIDS Conference. Scholler-Gyure M. Grinsztejn B. Snoeck E. 32. 2007. Abstract WESS204-1. Kakuda TN. 2007. double-blind. Lancet. Treatment and Prevention. Sydney. TMC125-C223 Writing Group. 37. 20. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. Efficacy and safety of etravirine (TMC125) in patients with highly resistant HIV-1: primary 24-week analysis. Pharmacokinetics and pharmacodynamics of TMC125 in HIVinfected patients with NNRTI and PI resistance: TMC125-C223 [abstract]. et al. 2007. 33. Scotland. Kearney BP. et al. Ward D. February 3-6. 38. HIV 8. Chicago. Abstract 790.370(9581):29-38. 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]. et al. Scholler-Gyure M. February 3-6. 2007. Kakuda TN. Winston A. AIDS. 4th International AIDS Society Conference on HIV Pathogenesis. Lazzarin A. MA. 2008. Clotet B. Abstract WEPEA106. TMC125. Anderson MS. et al. November 12-16. Treatment and Prevention. February 3-6. Clotet B. Pharmacokinetic evaluation of non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125 and integrase inhibitor (InSTI) Raltegravir (RAL) in healthy subjects [abstract]. Abstract TUPE0061. Chicago. 2008. Eighth International Congress on Drug Therapy in HIV Infection. MA. Abstract TUPE0086. 14th Conference on Retroviruses and Opportunistic Infections. et al. February 2528. Abstract 56. July 22-25. et al. 36. Jackson A. De Marez T. Abstract A-1428. 2007. placebo-controlled trial. Kakuda T.48(3):322-329. Wade J. Baeten B. February 3-6. et al. Pharmacokinetic interaction study with TMC125 and TMC114/rtv in HIV-negative volunteers [abstract]. Feiterna-Sperling C. 25. Sydney. Boffito M. 2006. 30. AIDS. 23. 4th International AIDS Society Conference on HIV Pathogenesis. Pharmacokinetics and antiretroviral response to darunavir/ritonavir and etravirine combination in patients with high-level viral resistance. van den Brink W. IL. Campbell T. HIV 8. 15th Conference on Retroviruses and Opportunistic Infections. September 17-20. Canada. HIV 8. July 22-25. 15th Conference on Retroviruses and Opportunistic Infections. et al. Kakuda TN. et al. Kakuda T. Katlama C. Berckmans C. De Smedt G. Abstract TUPDB02.
et al. No significant interaction between TMC125 and didanosine (ddI) in healthy volunteers [abstract]. Scholler-Gyure M. 2005. HIV 8. Scotland. Aharchi F. August 13-18. AIDS 2006 XVI International AIDS Conference. Rio De Janerio. Abstract H1049. Scholler M. 2007. August 13-18. No effect of TMC125 on the pharmacokinetics of oral contraceptives [abstract]. July 24-27. De Smedt G. Chicago. Hoetelmans R. et al. Toronto. Treatment and Prevention. Abstract WePe3. 2006. Brazil. 39. November 12-16. et al. et al. 42. Abstract TUPE0084. IL. Abstract 57. Abstract TUPE0082. Eighth International Congress on Drug Therapy in HIV Infection. Debroye C. 40.3C16. Hospital Pharmacy 507 . 2006. Vanakaen H. Canada. TMC125 bioavailability is not affected by ranitidine and omeprazole [abstract]. AIDS 2006 XVI International AIDS Conference. Vanaken H. Woodfall B. 3rd International AIDS Society Conference on HIV Pathogenesis. Lack of interaction between TMC125 and methadone [abstract]. 41. 2006. Canada. Glasgow. September 17-20. Bollen S. Scholler-Gyure M. Scholler-Gyure M. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto.Formulary Drug Reviews clinically relevant drug interactions between ritonavir-boosted elvitegravir and TMC125 [abstract].
antiviral agents D. D. 1 to 2 hours. low C. C. D. A. human immunodeficiency virus. B. Almost exclusively renally. Following metabolism via CYP 3A4. Etravirine should be taken following a meal to increase absorption. June 2008 . 3. Lipophilic.Formulary Drug Reviews 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. B. Etravirine is a(n): A. the reader will be able to: 1. C. The etravirine half-life. etravirine: A. peak-etravirine concentrations are reached within: A. and 2C19. 400 mg once daily 10. B. 200 mg once daily C. 4. 7.5 to 4 hours.e x p e r i e n c e d adults with HIV-2 strains resistant to a nucleoside reverse transcriptase inhibitor. Tr e a t m e n t . The recommended frequency of etravirine administration was initially determined by: A. Etravirine should be taken 1. D. Case History KC is a 41-year-old man with HIV-1 infection who is about to initiate a new regimen consisting of etravirine. 2. Following oral administration. and ritonavir. B. high B. What instructions should be given to KC regarding timing of the etravirine dose? A. B. Describe the pharmacology and pharmacokinetics of etravirine. Should be used with extreme caution and a reduced initial dose. Hydrophilic. 9. Etravirine gastrointestinal tolerability. Nucleotide reverse transcriptase inhibitor. Extensively in the bile. Key Words — new drugs.e x p e r i e n c e d adults with HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor. 36 hours. Tr e a t m e n t . D. Lipophilic. 11. Etravirine has a half-life of: A. Objectives — At the completion of this program. Occurs in all HIV-1 resistant to efavirenz. 2. 2C9. What is the recommended etravirine dose for KC? A. Hydrophilic. Integrase inhibitor. 200 mg twice daily D. B. D. Should be used with extreme caution and frequent monitoring of liver function tests.e x p e r i e n c e d adults and children. Requires multiple mutations. C. C. Saturable etravirine absorption pharmacokinetics. B. C. Nonnucleoside reverse transcriptase inhibitor. 12 hours. 4. C. Discuss the risks associated with etravirine use. darunavir. Tr e a t m e n t . high D. Is promoted by its rigid structure. Is contraindicated. 6. 6 hours.5 to 6 hours. low 5. Etravirine is eliminated: A. May be used without dosage adjustment. Occurs rapidly when used in a multidrug regimen. Apply the information on etravirine use to a case study. 508 Volume 43. 8. C. 100 mg twice daily B. 4. B. The etravirine pill burden. Development of etravirine resistance: A. D. Etravirine is a _______ compound with ______ solubility. 6. Discuss the potential benefit of etravirine for an individual patient.5 to 8 hours. D. 2. 24 hours. Pediatric patients with HIV1 strains resistant to multiple antiretroviral agents. Nucleoside reverse transcriptase inhibitor. C. 3. Etravirine is indicated for the treatment of HIV-1 infection in: A. B. acquired immune deficiency syndrome. As unchanged drug. In a patient with a history of hepatitis and moderate hepatic impairment.
Diarrhea and peripheral neuropathy B. and rifampin D. B. and rifabutin 14. Etravirine tablets should be stored at room temperature. and retaining the 3 desiccant pouches. atazanavir. Headache and hypertension D. D. Etravirine should be taken on an empty stomach to minimize drug interactions. Hospital Pharmacy 509 . D. 13. and clarithromycin C. The tablets can be dispersed in a glass of water. B. stirred well. What are the most common side effects associated with etravirine therapy? A. Edema and fatigue C. Etravirine tablets should be transferred to a pill box to aid adherence. Rash and nausea 15. Which medications that are commonly used in patients with HIV infection should not be coadministered with etravirine? A. and immedi- ately consumed. tightly closed in the original container. Etravirine tablets should be stored in the refrigerator. What storage instructions should KC be given? A. An oral suspension is available. itraconazole. azithromycin. Only the tablets are available and they must be swallowed intact. indinavir. Delavirdine. KC reports difficulty swallowing tablets and asks if a liquid form of etravirine is available. and fluconazole B.Formulary Drug Reviews following a meal to increase tolerability. 12. phenytoin. Etravirine tablets can be dispersed in water and the resulting solution stored in the refrigerator. C. C. Etravirine should be taken on an empty stomach to increase absorption. Ritonavir. atazanavir/ritonavir. C. You inform KC that: A. tightly closed in the original container. The tablets can be crushed and mixed with a soft food such as applesauce. and protected from moisture. Efavirenz. nelfinavir. D. Nevirapine. itraconazole.
I was able to discuss the potential benefit of etravirine for an individual patient: completely fairly well not at all 5. 1. WA 99210–1495 Print clearly or type. Washington State University Spokane PO Box 1495 Spokane. Name__________________________________________ Address: _______________________________________ City:_______________ State: _______ Zip: __________ Note: Your answer sheet will be graded confidentially and you will receive prompt notification of your score. 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. A B 6. 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. PROGRAM EVALUATION Please rate our continuing education offering by responding to the following questions. A B 11. Was the content of this article relevant to the practice of pharmacy? excellent good fair poor 7. you need a minimum correct response rate of 70%.15 CEU Program Expires: June 1. After this program. 2011 To receive continuing education credit. A B 8. complete this form and mail with your $7 processing fee (made payable to WSU College of Pharmacy) to: College of Pharmacy. A B 5. How long did it take you to complete this continuing education program? _______ hours 8. A B 3. A B 15. In order to receive continuing education credit for this program. Allow 4 weeks for processing. A B C D C D C D C D C D C D C D C D 9.Formulary Drug Reviews Drug Evaluation: Etravirine ACPE # 071-999-08-006-H02-P 0. The program discussed the risks associated with the use of etravirine: completely fairly well not at all 4. A B 7. 510 Volume 43. This program described the pharmacology and pharmacokinetics of etravirine: completely fairly well not at all 2. A B 2. A B 14. What other continuing education programs or topics would you like to see? ____________________________________________ _________________________________________ _________________________________________ Answer Form 1. A B 13. A B 10. Continuing Education Dept. June 2008 . A B 12. A B 4. The overall quality of the program was: excellent good fair poor 6.
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