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Etravirine

Pronunciation

(et ra VIR een)

Index Terms

  • ETR
  • TMC125

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Intelence: 25 mg [scored]

Intelence: 100 mg, 200 mg

Brand Names: U.S.

  • Intelence

Pharmacologic Category

  • Antiretroviral, Reverse Transcriptase Inhibitor, Non-nucleoside (Anti-HIV)

Pharmacology

As a non-nucleoside reverse transcriptase inhibitor, etravirine has activity against HIV-1 by binding to reverse transcriptase. It consequently blocks the RNA-dependent and DNA-dependent DNA polymerase activities, including HIV-1 replication. It does not require intracellular phosphorylation for antiviral activity.

Absorption

Increased 50% with food

Metabolism

Hepatic, primarily by CYP3A4, 2C9, and 2C19; major metabolites exhibit ~10% of parent drug activity against wild-type HIV

Excretion

Feces (94%, up to 86% as unchanged drug); urine (1%)

Time to Peak

2.5 to 4 hours

Half-Life Elimination

41 hours (± 20 hours)

Protein Binding

99.9%; primarily to albumin and alpha1-acid glycoprotein

Use: Labeled Indications

Treatment of HIV-1 infection in combination with at least two additional antiretroviral agents in treatment-experienced patients exhibiting viral replication with documented non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance

Contraindications

There are no contraindications listed in the manufacturer's U.S. labeling.

Canadian labeling: Hypersensitivity to etravirine or any component of the formulation.

Dosing: Adult

Treatment of HIV-1 infection: Oral: 200 mg twice daily

Dosing: Pediatric

Treatment of HIV-1 infection: Oral: Children 6 to <18 years:

≥16 kg to <20 kg: 100 mg twice daily

≥20 kg to <25 kg: 125 mg twice daily

≥25 kg to <30 kg: 150 mg twice daily

≥30 kg: 200 mg twice daily

Dosing: Renal Impairment

No dosage adjustment necessary.

Due to extensive protein binding, significant removal by hemodialysis or peritoneal dialysis is unlikely.

Dosing: Hepatic Impairment

Mild-to-moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Administration

Administer after meals. If unable to swallow tablets, may disperse tablets in water (≥1 teaspoonful [enough to cover tablets]); stir well (until milky), add additional water (or may add milk or orange juice), and drink immediately. Rinse glass several times (with water, milk or orange juice) and swallow entire contents to ensure administration of dose. Do not use grapefruit juice, carbonated beverages or warm (>40°C) water.

Dietary Considerations

Take after meals.

Storage

Store at USP controlled room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture.

Drug Interactions

Amiodarone: Etravirine may decrease the serum concentration of Amiodarone. Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May increase the serum concentration of Etravirine. Applicable Isavuconazonium considerations are addressed in separate monographs. Etravirine may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). This would be anticipated with itraconazole or ketoconazole. Etravirine may increase the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). This would be anticipated with voriconazole. Management: Monitor for increased effects/toxicity of etravirine. Antifungal dose adjustment may be needed for ketoconazole, itraconazole, or posaconazole but specific dosing guidelines are lacking. Exceptions: Isavuconazonium Sulfate. Consider therapy modification

Antihepaciviral Combination Products: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Antihepaciviral Combination Products. Avoid combination

Apixaban: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Apixaban. Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification

Artemether: Etravirine may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, concentrations of dihydroartemisinin may be decreased. Artemether may increase the serum concentration of Etravirine. Etravirine may increase the serum concentration of Artemether. Monitor therapy

Asunaprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Asunaprevir. Avoid combination

Asunaprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Asunaprevir. Avoid combination

Atazanavir: May increase the serum concentration of Etravirine. Etravirine may decrease the serum concentration of Atazanavir. Management: The combination of etravirine and atazanavir should be avoided unless atazanavir is boosted with ritonavir. The use of cobicistat instead of ritonavir has not been evaluated and is not recommended. Consider therapy modification

Avanafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Avanafil. Management: The maximum avanafil adult dose is 50 mg per 24-hour period when used together with a moderate CYP3A4 inhibitor. Patients receiving such a combination should also be monitored more closely for evidence of adverse effects. Consider therapy modification

Axitinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Axitinib. Avoid combination

Bedaquiline: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bedaquiline. Avoid combination

Bepridil: Etravirine may decrease the serum concentration of Bepridil. Monitor therapy

Blonanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Blonanserin. Monitor therapy

Boceprevir: May decrease the serum concentration of Etravirine. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosentan: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bosutinib. Avoid combination

Bosutinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Bosutinib. Avoid combination

Brexpiprazole: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Bromocriptine. Management: The bromocriptine dose should not exceed 1.6 mg daily with use of a moderate CYP3A4 inhibitor. The Cycloset brand specifically recommends this dose limitation, but other bromocriptine products do not make such specific recommendations. Consider therapy modification

Budesonide (Systemic): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic). Management: Consider reducing the oral budesonide dose when used together with a CYP3A4 inhibitor or temporarily stopping budesonide therapy during CYP3A4 inhibitor use. Monitor patients closely for signs/symptoms of corticosteroid excess. Consider therapy modification

Budesonide (Topical): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Buprenorphine: Etravirine may decrease the serum concentration of Buprenorphine. Monitor therapy

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Cannabis: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Reverse Transcriptase Inhibitors (Non-Nucleoside). Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of CarBAMazepine. This mechanism applies specifically to efavirenz. Avoid combination

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

Cilostazol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving moderate inhibitors of CYP3A4. Consider therapy modification

Cilostazol: CYP2C19 Inhibitors may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

Citalopram: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a moderate CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (e.g., serotonin syndrome, QT prolongation, etc.). Consider therapy modification

Clarithromycin: CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Clarithromycin. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and impair its efficacy. Consider therapy modification

Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a moderate CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

Cobimetinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Cobimetinib. Management: Avoid the concomitant use of cobimetinib and moderate CYP3A4 inhibitors. If concurrent short term (14 days or less) use cannot be avoided, reduce the cobimetinib dose to 20 mg daily. Avoid combination

Cobimetinib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Cobimetinib. Avoid combination

Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Consider therapy modification

CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Substrates: CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Substrates: CYP3A4 Inducers (Moderate) may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates. Management: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Daclatasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Daclatasvir. Management: Increase the daclatasvir dose to 90 mg once daily if used with a moderate CYP3A4 inducer. Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dapoxetine. Management: The dose of dapoxetine should be limited to 30 mg/day when used together with a moderate inhibitor of CYP3A4. Consider therapy modification

Darunavir: May decrease the serum concentration of Etravirine. Management: No action is required if etravirine is combined with darunavir/ritonavir. The combination of etravirine and darunavir/cobicistat should be avoided. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Diazepam: Etravirine may decrease the serum concentration of Diazepam. Etravirine may increase the serum concentration of Diazepam. Monitor therapy

Digoxin: Etravirine may increase the serum concentration of Digoxin. Management: Monitor serum digoxin concentrations and adjust dose as needed. In patients initiating a regimen of digoxin with etravirine, digoxin should be initiated at the lowest dose. Monitor therapy

Disopyramide: Etravirine may decrease the serum concentration of Disopyramide. Monitor therapy

Dofetilide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dofetilide. Monitor therapy

Dolutegravir: Etravirine may decrease the serum concentration of Dolutegravir. Management: US recommends avoiding the use of etravirine with dolutegravir unless used with atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir. Canada recommends increasing dolutegravir to 50 mg twice daily when used with etravirine without a boosted PI Consider therapy modification

Domperidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Domperidone. Avoid combination

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to moderate CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Dronabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Efavirenz: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Efavirenz. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Efavirenz. Avoid combination

Elbasvir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Elbasvir. Avoid combination

Eletriptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eletriptan. Management: The use of eletriptan within 72 hours of a moderate CYP3A4 inhibitor should be avoided. Consider therapy modification

Eliglustat: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates. Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C19 Substrates. Conversely, concentrations of active metabolites may be increased for those drugs activated by CYP2C19. Management: Concurrent use of enzalutamide with CYP2C19 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C19 substrate should be performed with caution and close monitoring. Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: When used concomitantly with moderate inhibitors of CYP3A4, eplerenone dosing recommendations may vary depending on international labeling. Consult appropriate labeling for specific recommendations. Consider therapy modification

Ergonovine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Ergonovine. Specifically, this would be most likely with delavrdine, while other Non-Nucleoside Reverse Transcriptase Inhibitors may be more likely to decrease the concentration of Ergonovine. Avoid combination

Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Flecainide: Etravirine may decrease the serum concentration of Flecainide. Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Flibanserin. Avoid combination

Flibanserin: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Flibanserin. Avoid combination

Fosamprenavir: Etravirine may increase serum concentrations of the active metabolite(s) of Fosamprenavir. Specifically, amprenavir concentrations may increase. Avoid combination

Fosphenytoin: May decrease the serum concentration of Etravirine. Avoid combination

Grazoprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of GuanFACINE. Management: Canadian labeling recommends an initial 50% reduction in guanfacine dose with further dose titration as needed. However, US labeling does not call for any specific guanfacine dose reduction with this combination. Monitor therapy

Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Consider therapy modification

HMG-CoA Reductase Inhibitors: Etravirine may decrease the serum concentration of HMG-CoA Reductase Inhibitors. This applies to atorvastatin, lovastatin and simvastatin. Conversely, levels of fluvastatin may be increased. Management: Dose adjustment of the HMG-CoA reductase inhibitor may be warranted. No interaction is expected with rosuvastatin, pravastatin, or pitavastatin. Exceptions: Pitavastatin; Pravastatin; Rosuvastatin. Monitor therapy

Hydrocodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Hydrocodone. Monitor therapy

Hydrocodone: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Hydrocodone. Monitor therapy

Ibrutinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ibrutinib. Management: If a moderate CYP3A inhibitor must be used, consider reducing the dose of ibrutinib to 140mg daily and monitor closely for signs of toxicity. Avoid combination

Ifosfamide: CYP3A4 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Ifosfamide: CYP3A4 Inducers (Moderate) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Imatinib. Monitor therapy

Ivabradine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivabradine. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult prescribing information for specific age- and weight-based recommendations. Consider therapy modification

Lidocaine (Systemic): Etravirine may decrease the serum concentration of Lidocaine (Systemic). Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lomitapide. Avoid combination

Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Management: U.S. labeling: start at 20 mg/day and limit to max of 80 mg/day with moderate CYP3A4 inhibitor. Canadian labeling: limit to max of 40 mg/day with moderate CYP3A4 inhibitor; avoid concomitant use of grapefruit products. Consider therapy modification

Macrolide Antibiotics: Etravirine may decrease the serum concentration of Macrolide Antibiotics. Clarithromycin AUC is reduced and levels of the active metabolite (14-hydroxy-clarithromycin) are modestly increased. Management: For the treatment of Mycobacterium avium complex, consider changing to alternative agent, such as azithromycin. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin. Consider therapy modification

Maraviroc: Etravirine may decrease the serum concentration of Maraviroc. Of note, this effect only applies in the absence of a strong CYP3A4 inhibitor Management: Increase maraviroc adult dose to 600 mg twice daily if used with etravirine. This does not apply to patients also receiving strong CYP3A4 inhibitors. This combination is contraindicated in patients with CrCl less than 30 mL/min. Consider therapy modification

Methadone: Etravirine may decrease the serum concentration of Methadone. Monitor therapy

Mexiletine: Etravirine may decrease the serum concentration of Mexiletine. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Naloxegol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Naloxegol. Avoid combination

NiMODipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of NiMODipine. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of NiMODipine. Monitor therapy

Nisoldipine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 200 mg twice daily. Avoid combination

Olaparib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Olaparib. Avoid combination

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

OxyCODONE: CYP3A4 Inhibitors (Moderate) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite Oxymorphone may also be increased. Consider therapy modification

Palbociclib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Palbociclib. Management: The US label does not provide specific recommendations concerning use with moderate CYP3A4 inducers, but the Canadian label recommends avoiding use of moderate CYP3A4 inducers. Consider therapy modification

PHENobarbital: May decrease the serum concentration of Etravirine. Avoid combination

Phenytoin: May decrease the serum concentration of Etravirine. Management: The manufacturer of etravirine states these drugs should not be used in combination Avoid combination

Phosphodiesterase 5 Inhibitors: Etravirine may decrease the serum concentration of Phosphodiesterase 5 Inhibitors. Management: No empiric dosage adjustments are recommended with concomitant therapy; however, dose of the phosphodiesterase inhibitor may need to be altered based on clinical response. Monitor therapy

Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Pimozide. Avoid combination

Primidone: May decrease the serum concentration of Etravirine. Avoid combination

Propafenone: Etravirine may decrease the serum concentration of Propafenone. Monitor therapy

Protease Inhibitors: May decrease the serum concentration of Etravirine. This effect is anticipated with darunavir, saquinavir, and lopinavir (with low-dose ritonavir). Etravirine may increase the serum concentration of Protease Inhibitors. This effect is anticipated with nelfinavir. Management: Low-dose ritonavir boosting must be used when any protease inhibitor is used with etravirine. Avoid use of etravirine in combination with atazanavir, fosamprenavir, full-dose ritonavir (600 mg twice daily, in adults), or tipranavir. Exceptions: Atazanavir; Fosamprenavir; Ritonavir; Tipranavir. Monitor therapy

QuiNIDine: Etravirine may decrease the serum concentration of QuiNIDine. Monitor therapy

Ranolazine: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Ranolazine. Avoid combination

Reverse Transcriptase Inhibitors (Non-Nucleoside): May decrease the serum concentration of Etravirine. This has been observed with the NNRTIs efavirenz and nevirapine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Etravirine. This has been observed with delavirdine. Avoid combination

Rifabutin: May decrease the serum concentration of Etravirine. Management: Avoid concomitant use with rifabutin if a protease inhibitor/ritonavir combination is also used. Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Etravirine. Exceptions: Rifabutin. Avoid combination

Rilpivirine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Rilpivirine. This mechanism applies to coadministration of delavirdine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Rilpivirine. This mechanism applies to coadministration of efavirenz, etravirine, and nevirapine. Avoid combination

Ritonavir: May decrease the serum concentration of Etravirine. Management: Avoid concomitant use of etravirine with antiviral doses of ritonavir; use with ritonavir-boosted fosamprenavir or with ritonavir-boosted tipranavir is also not recommended. Consider therapy modification

Rolapitant: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Rolapitant. Management: Monitor for reduced rolapitant response. Recommended dexamethasone regimens should be used with rolapitant. Higher dexamethasone doses or more prolonged use may increase the potential for a significant interaction. Monitor therapy

Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Monitor therapy

Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Monitor therapy

Saxagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Saxagliptin. Monitor therapy

Sildenafil: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Sildenafil. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Simeprevir. Avoid combination

Simeprevir: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Simeprevir. Avoid combination

Sonidegib: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Sonidegib. Avoid combination

St John's Wort: May decrease the serum concentration of Reverse Transcriptase Inhibitors (Non-Nucleoside). Specifically, St. Johns Wort may increase the metabolism of Reverse Transcriptase Inhibitors (Non-Nucleoside). Avoid combination

Suvorexant: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Suvorexant. Consider therapy modification

Telaprevir: Etravirine may decrease the serum concentration of Telaprevir. Monitor therapy

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Tetrahydrocannabinol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Tipranavir: May decrease the serum concentration of Etravirine. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Trabectedin. Avoid combination

Ulipristal: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combination should be monitored for ulipristal toxicity. Avoid combination

Venetoclax: CYP3A4 Inducers (Moderate) may decrease the serum concentration of Venetoclax. Avoid combination

Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Monitor therapy

Vindesine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vindesine. Monitor therapy

Zopiclone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zopiclone. Management: The starting adult dose of zopiclone should not exceed 3.75 mg if combined with a moderate CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Zuclopenthixol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Zuclopenthixol. Monitor therapy

Adverse Reactions

Frequency not always defined.

>10%:

Dermatologic: Skin rash (≥grade 2: 10% to 15%)

Endocrine & metabolic: Hyperglycemia (≤250 mg/dL: 15%; 251 to 500 mg/dL: 4%), increased LDL cholesterol (≤190 mg/dL: 13%), increased serum cholesterol (total; ≤300 mg/dL: 20%; >300 mg/dL: 8%)

Gastrointestinal: Nausea

2% to 10%:

Central nervous system: Peripheral neuropathy (≥ grade 2: 4%)

Endocrine & metabolic: Increased serum triglycerides (≤750 mg/dL: 9%; >750 mg/dL: 4% to 6%)

Gastrointestinal: Diarrhea (children and adolescents ≥2%), increased amylase (>5 x ULN: 2%)

Hepatic: Increased serum ALT (≤5 x ULN: 6%; >5 x ULN: 3%), increased serum AST (≤5 x ULN: 6%; >5 x ULN: 3%)

Renal: Increased serum creatinine (≤1.8 x ULN: 6%; >1.8 x ULN: 2%)

<2% (Limited to important or life-threatening): Amnesia, anemia (including hemolytic), angina pectoris, angioedema, anorexia, atrial fibrillation, diabetes mellitus, DRESS syndrome (drug rash with eosinophilia and systemic symptoms), erythema multiforme, gastroesophageal reflux disease, gynecomastia, hemorrhagic stroke, hematemesis, hepatic failure, hepatitis, hepatomegaly, hypersensitivity reaction, hypersomnia, hypoesthesia, immune reconstitution syndrome, insomnia, lipodystrophy, lipohypertrophy, liver steatosis, myocardial infarction, pancreatitis, renal failure, rhabdomyolysis, seizure, Stevens-Johnson syndrome, syncope, toxic epidermal necrolysis

Warnings/Precautions

Concerns related to adverse effects:

• Fat redistribution: May cause redistribution of fat (eg, buffalo hump, peripheral wasting with increased abdominal girth, cushingoid appearance).

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

• Skin reactions/hypersensitivity: Severe and possibly life-threatening skin reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme) and hypersensitivity reactions ranging from rash (including drug rash with eosinophilia and systemic symptoms [DRESS]) and/or constitutional symptoms to occasional organ dysfunction (including hepatic failure) have been reported; discontinue immediately with signs or symptoms of severe skin reaction or hypersensitivity. Self-limiting (with continued therapy) mild-to-moderate rashes (higher incidence in females) were also observed in clinical trials (pediatric and adult), usually during second week of therapy initiation.

Concurrent drug therapy issues:

• High potential for interactions: Concomitant use of etravirine with some drugs may require cautious use, may not be recommended, or may require dosage adjustments.

Special populations:

• Appropriate use: Not for use in treatment-naive patients, or experienced patients without evidence of viral mutations conferring resistance to NNRTIs and PIs.

Monitoring Parameters

Cholesterol, triglycerides, serum glucose, hepatic transaminases (if signs or symptoms of hypersensitivity develop); signs of skin rash, signs and symptoms of infection

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been noted in animal reproduction studies. Etravirine crosses the placenta. Because available data in pregnant women are insufficient, the HHS Perinatal HIV Guidelines do not recommend use in antiretroviral-naive women. Hypersensitivity reactions (including hepatic toxicity and rash) are more common in women on NNRTI therapy; it is not known if pregnancy increases this risk. The pharmacokinetics of etravirine are not significantly altered in pregnancy and dosing adjustment is not needed.

Combination antiretroviral therapy (cART) therapy is recommended for all HIV-infected pregnant women. The goal of therapy is to keep the viral load below the limit of detection and prevent perinatal transmission. Therapy must be individualized. In general, women who become pregnant on a stable cART regimen may continue that regimen if viral suppression is effective, contraindications for use in pregnancy are not present, and the regimen is well tolerated. For HIV-infected couples planning a pregnancy, maximum viral suppression with cART is recommended prior to conception for the HIV-infected partner(s). When HIV is diagnosed during pregnancy in a woman who has never received antiretroviral therapy, cART should be considered as soon as possible after diagnosis to reduce the risk of perinatal transmission. If antiretroviral drug-resistance testing is done, treatment may be started prior to obtaining results, then adjusted accordingly. Monitoring during pregnancy is more frequent than in nonpregnant adults. If cART must be interrupted for <24 hours, stop then restart all medications simultaneously in order to decrease the chance of developing resistance. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children who develop significant organ system abnormalities (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction.

HIV-infected women not planning a pregnancy may use any available type of contraception, considering possible drug interactions and contraindications of the specific method. In addition, consistent use of condoms is also recommended (even during pregnancy) to prevent transmission of HIV or other sexually transmitted diseases.

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Health care providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2015).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), severe loss of strength and energy, burning or numbness feeling, vomiting blood, vision changes, urinary retention, change in amount of urine passed, angina, severe dizziness, passing out, arrhythmia, muscle pain, joint pain, confusion, memory impairment, seizures, shortness of breath, change in body fat, dysphagia, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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