Updated
Apr. 07, 2021
Reviewed
Apr. 07, 2021

Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)

Etravirine (ETR, Intelence)
Etravirine (ETR, Intelence)
Formulations

Tablets: 25 mg, 100 mg, 200 mg

For additional information, see Drugs@FDA or DailyMed

Dosing Recommendations Selected Adverse Events

Neonate and Infant Dose:

  • Etravirine (ETR) is not approved for use in neonates or infants.

Child Dose:

  • ETR is not approved for use in children aged <2 years. 
    Etravirine Dosing Table for Antiretroviral Therapy-Experienced Children and Adolescents Aged 2 to 18 Years and Weighing ≥10 kg
    Body Weight Twice-Daily Dose
    10 kg to <20 kg 100 mg
    20 kg to <25 kg 125 mg
    25 kg to <30 kg 150 mg
    ≥30 kg 200 mg
  • ETR is approved for use in children and adolescents who are treatment experienced. The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel)  recommends  that ETR is used as part of a regimen that includes a ritonavir (RTV)-boosted protease inhibitor (PI); see Efficacy in Clinical Trials and Drug Interactions below.


Adult Dose for Antiretroviral Therapy-Experienced Patients:

  • ETR 200 mg twice daily with food
  • Nausea
  • Diarrhea
  • Rash, including Stevens-Johnson syndrome
  • Hypersensitivity with rash, constitutional symptoms, and, sometimes, organ dysfunction, including hepatic failure
Special Instructions
  • ETR tablets are sensitive to moisture; store the tablets at room temperature in the original container with desiccant.
  • Always administer ETR with food. Area under the curve of ETR is decreased by about 50% when the drug is taken on an empty stomach. The type of food does not affect the exposure to ETR.
  • Swallowing ETR tablets whole is the preferred means of administration. Although the package insert contains instructions for dispersing ETR tablets in water or other liquids, using this administration method generally results in lower ETR exposures than swallowing tablets whole. Children who receive dispersed ETR tablets should switch to swallowing tablets whole as soon as developmentally able.
Metabolism/Elimination
  • ETR is an inducer of cytochrome P450 (CYP) 3A4 and an inhibitor of CYP2C9, CYP2C19, and P-glycoprotein. It is a substrate for CYP3A4, CYP2C9, and CYP2C19.
  • ETR is involved in multiple interactions with antiretroviral agents and other drugs (see Drug Interactions).

Etravirine Dosing in Patients with Hepatic Impairment:

  • No dose adjustment is required when using ETR in patients with mild or moderate hepatic insufficiency. No dosing information is available for patients with severe hepatic impairment.

Etravirine Dosing in Patients with Renal Impairment:

  • No dose adjustment is required when using ETR in patients with renal impairment.

Drug Interactions (see also the Adult and Adolescent Antiretroviral Guidelines and HIV Drug Interaction Checker)

  • Etravirine (ETR) is associated with multiple drug interactions. A patient’s medication profile should be carefully reviewed for potential drug interactions before ETR is administered.
  • ETR should not be administered with tipranavir/ritonavir, fosamprenavir/ritonavir, and unboosted protease inhibitors (PIs).
  • ETR should not be administered with other non-nucleoside reverse transcriptase inhibitors (NNRTIs) (i.e., nevirapine [NVP], efavirenz [EFV], rilpivirine, doravirine).
  • Limited data in adults suggest that ETR may reduce the trough concentration of raltegravir (RAL),1 but no dose adjustment is currently recommended when ETR and RAL are used together. ETR significantly reduces plasma concentrations of dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), and darunavir/cobicistat.2 DTG should be used with ETR only when these drugs are coadministered with atazanavir/ritonavir, darunavir/ritonavir (DRV/r), or lopinavir/ritonavir. ETR should not be coadministered with EVG/c. 

Major Toxicities

  • More common: Nausea, diarrhea, and mild rash. Rash occurs most commonly during the first 6 weeks of therapy. Rash generally resolves after 1 to 2 weeks on continued therapy. A history of NNRTI-related rash does not appear to increase the risk of developing rash with ETR. However, patients who have a history of severe rash with prior NNRTI use should not receive ETR.
  • Less common (more severe): Peripheral neuropathy, severe rash, hypersensitivity reactions (HSRs), and erythema multiforme all have been reported. Instances of severe rash have included Stevens-Johnson syndrome, and HSRs have included constitutional symptoms and organ dysfunction, including hepatic failure. Discontinue ETR immediately if signs or symptoms of severe skin reactions or HSRs develop (including severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, and eosinophilia). Clinicians should monitor a patient’s clinical status, including levels of liver transaminases, and initiate appropriate therapy when necessary. Continuing to use ETR after the onset of severe rash may result in a life-threatening reaction. People who have a history of severe rash while using NVP or EFV should not receive ETR.

Resistance

The International AIDS Society-USA (IAS-USA) maintains a list of updated resistance mutations and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use

Approval

ETR is approved by the Food and Drug Administration for use in antiretroviral therapy (ART)-experienced children and adolescents aged 2 to 18 years.

Efficacy in Clinical Trials

In the Paediatric study of Intelence As an NNRTI Option (PIANO) study,3 ART-experienced children aged 6 years to <18 years received ETR with a ritonavir (RTV)-boosted PI as part of an optimized background regimen. At Week 24, 67% of these participants had plasma HIV RNA concentrations <400 copies/mL, and 52% had HIV RNA <50 copies/mL. At Week 48, 56% of the participants had HIV RNA <50 copies/mL and a mean increase in their CD4 T lymphocyte (CD4) cell counts of 156 cells/mm3 from baseline. At Week 48, 68% of children aged 6 years to <12 years had plasma HIV RNA <50 copies/mL, whereas only 48% of adolescents aged 12 years to <18 years achieved a plasma viral load of <50 copies/mL.

In a retrospective study of 23 adolescents and young adults in Spain receiving ETR-based therapy, 78% of participants achieved HIV RNA <50 copies/mL at a median of 48.4 weeks of follow-up.4

In the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1090,5 ART-experienced children aged ≥2 years to <6 years received ETR with a ritonavir-boosted PI as part of an optimized background regimen. Participants received ETR at a dose of 100 mg twice daily (10 kg to <20 kg) or 125 mg twice daily (20 kg to <25 kg). At Week 48, 75% had an HIV-1 RNA <400 copies/mL or a >2-log reduction in HIV-1 RNA from baseline. The mean increase in CD4 count and CD4 percentage over 48 weeks was 298.5 cells/mm3 and 5.2%, respectively. Due to the PIANO and IMPAACT 1090 study findings, if ETR is utilized to treat an ART-experienced child or adolescent, The Panel recommends that ETR is part of a regimen that includes a ritonavir (RTV)-boosted protease inhibitor (PI) plus an optimized background regimen.

Pharmacokinetics

In a Phase 1 dose-finding study that involved children aged 6 to 17 years, 17 children were given ETR 4 mg/kg twice daily. The study reported that two pharmacokinetic (PK) parameters—area under the curve for 12 hours post-dose (AUC0–12h) and minimum plasma concentration (Cmin)—were lower than the corresponding parameters observed in adults during previous studies.6 However, a higher dose (ETR 5.2 mg/kg twice daily; maximum 200 mg per dose) yielded acceptable parameters and was chosen for evaluation in the Phase 2 PIANO study. Exposures (mean AUC0–12h) remained lower in older adolescents than in adults and younger children, and exposures were lower in Asian participants than in either White or Black participants. In the PIANO study, children and adolescents with ETR concentrations in the lowest quartile (<2,704 ng·h/mL or C0h <145 ng/mL) were less likely to achieve sustained virologic responses (defined as plasma viral loads <50 copies/mL) after 48 weeks of treatment than those with ETR concentrations in the upper three quartiles.7

Table A. Pharmacokinetic Parameters in Children, Adolescents, and Adults Receiving Etravirine Twice Daily with an Optimized Background Regimen, Including a Ritonavir-Boosted Protease Inhibitor7
Population Mean ETR AUC0-12h (ng·h/mL) Mean ETR C0h (ng/mL)
Children Aged 6–11 Years
(n = 41)
5,684 377
Adolescents Aged 12–17 Years
(n = 60)
4,895 325
Adults
(n = 575)
5,506 393
Key: AUC0–12h = area under the curve for 12 hours post-dose; C0h = pre-dose concentration during chronic administration; ETR = etravirine

IMPAACT P1090 examined the PK and safety of ETR in treatment-experienced children with HIV aged ≥2 years to <6 years.5 All participants received ETR as part of an optimized background regimen, which included a ritonavir-boosted PI. The tablets were swallowed whole or dispersed in liquid. ETR was initially given at a dose of 5.2 mg/kg twice daily to a cohort of six children; however, at this dose, the geometric mean ETR AUC0–12h values fell below the target range of 60% of the values seen in adults. Subsequent participants were given twice-daily doses of ETR that were determined by weight band: children weighing 10 kg to <20 kg were given 100 mg per dose, and children weighing 20 kg to <25 kg were given 125 mg per dose. 

The protocol-specified PK targets for ETR were achieved at these doses; the geometric mean AUC0–12h was 3,823 ng·hr/mL, which was within the target range of 2,713 ng·hr/mL to 6,783 ng·hr/mL (60% to 150% of the AUC0–12h value seen in adults). However, considerable intersubject variability was observed, with five (33.3%) of 15 participants having AUC0–12h values that were below the 10th percentile for the adult AUC0–12h range (<2,350 ng·hr/mL). The ETR AUC0–12h values were significantly lower in children who received dispersed tablets than in children who swallowed intact tablets: 2,919 ng·hr/mL (n =11) versus 10,982 ng·hr/mL (n = 3), respectively (P = 0.0008). The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) recommends that children swallow tablets whole (rather than dispersed in liquid) as soon as developmentally able. 

Six children with HIV aged 1 year to <2 years also were enrolled in P1090. Although the ETR exposures satisfied protocol-defined PK targets (AUC0–12h between 2,713 ng·hr/mL to 6,783 ng·hr/mL), they were lower in these children compared with historical data in adults and adolescents (geometric mean ETR AUC0–12h of 3,328 ng*hr/mL). Virologic failure, which was defined as a confirmed viral load of ≥400 copies/mL or less than a 2-log reduction in HIV-1 RNA from baseline, occurred in four of six children by Week 48. Thus, the Panel does not recommend the use of ETR in those younger than 2 years of age.  

Given that both the PIANO and P1090 trials were conducted in children receiving RTV-boosted PIs as part of their optimized background regimens, the Panel recommends using ETR as part of a regimen that includes an RTV-boosted PI.

Toxicity

In the PIANO study, rash and diarrhea were the most common adverse drug reactions that were deemed to be possibly related to the use of ETR. Rash (Grade 2 or higher) occurred in 13% of pediatric subjects and emerged at a median of 10 days, lasting a median of 7 days. Rash was observed more frequently in female patients (13 of 64 patients; 20.3%) than in male patients (two of 37 patients; 5.4%). In P1090, adverse drug reactions that were reported for children aged ≥2 years to <6 years were comparable in frequency, type, and severity to those reported for adults. Twelve participants (46.2%) developed rashes within the first 48 weeks of ETR, but these rashes were not attributed to the use of ETR, and no subject discontinued the study prematurely due to rash. Diarrhea occurred in eight (30.8%) of 26 patients.

References

  1. Do VT, Higginson RT, Fulco PP. Raltegravir dosage adjustment in HIV-infected patients receiving etravirine. Am J Health Syst Pharm. 2011;68(21):2049-2054. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22011983.
  2. Molto J, Curran A, Miranda C, et al. Pharmacokinetics of darunavir/cobicistat and etravirine alone and co-administered in HIV-infected patients. J Antimicrob Chemother. 2017;73(3):732-737. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29237008.
  3. Tudor-Williams G, Cahn P, Chokephaibulkit K, et al. Etravirine in treatment-experienced, HIV-1-infected children and adolescents: 48-week safety, efficacy and resistance analysis of the phase II PIANO study. HIV Med. 2014;15(9):513-524. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24589294.
  4. Briz V, Palladino C, Navarro M, et al. Etravirine-based highly active antiretroviral therapy in HIV-1-infected paediatric patients. HIV Med. 2011;12(7):442-446. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21395964.
  5. MacBrayne CE, Rutstein R, Yogev R, et al. Etravirine pharmacokinetics in treatment-experienced children ages 1-<6 years. Abstract 465. Presented at: Conference on Retroviruses and Opportunistic Infections. 2018. Boston, MA. Available at: https://www.croiconference.org/sessions/etravirine-pharmacokinetics-treatment-experienced-children-ages-1.
  6. Konigs C, Feiterna-Sperling C, Esposito S, et al. Pharmacokinetics and short-term safety and tolerability of etravirine in treatment-experienced HIV-1-infected children and adolescents. AIDS. 2012;26(4):447-455. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22156961.
  7. Kakuda TN, Brochot A, Green B, et al. Pharmacokinetics and pharmacokinetic/pharmacodynamic relationships of etravirine in HIV-1-infected, treatment-experienced children and adolescents in PIANO. J Clin Pharmacol. 2016;56(11):1395-1405. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27060341.
Etravirine (ETR, Intelence)
Etravirine (ETR, Intelence)
Formulations

Tablets: 25 mg, 100 mg, 200 mg

For additional information, see Drugs@FDA or DailyMed

Dosing Recommendations Selected Adverse Events

Neonate and Infant Dose:

  • Etravirine (ETR) is not approved for use in neonates or infants.

Child Dose:

  • ETR is not approved for use in children aged <2 years. 
    Etravirine Dosing Table for Antiretroviral Therapy-Experienced Children and Adolescents Aged 2 to 18 Years and Weighing ≥10 kg
    Body Weight Twice-Daily Dose
    10 kg to <20 kg 100 mg
    20 kg to <25 kg 125 mg
    25 kg to <30 kg 150 mg
    ≥30 kg 200 mg
  • ETR is approved for use in children and adolescents who are treatment experienced. The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel)  recommends  that ETR is used as part of a regimen that includes a ritonavir (RTV)-boosted protease inhibitor (PI); see Efficacy in Clinical Trials and Drug Interactions below.


Adult Dose for Antiretroviral Therapy-Experienced Patients:

  • ETR 200 mg twice daily with food
  • Nausea
  • Diarrhea
  • Rash, including Stevens-Johnson syndrome
  • Hypersensitivity with rash, constitutional symptoms, and, sometimes, organ dysfunction, including hepatic failure
Special Instructions
  • ETR tablets are sensitive to moisture; store the tablets at room temperature in the original container with desiccant.
  • Always administer ETR with food. Area under the curve of ETR is decreased by about 50% when the drug is taken on an empty stomach. The type of food does not affect the exposure to ETR.
  • Swallowing ETR tablets whole is the preferred means of administration. Although the package insert contains instructions for dispersing ETR tablets in water or other liquids, using this administration method generally results in lower ETR exposures than swallowing tablets whole. Children who receive dispersed ETR tablets should switch to swallowing tablets whole as soon as developmentally able.
Metabolism/Elimination
  • ETR is an inducer of cytochrome P450 (CYP) 3A4 and an inhibitor of CYP2C9, CYP2C19, and P-glycoprotein. It is a substrate for CYP3A4, CYP2C9, and CYP2C19.
  • ETR is involved in multiple interactions with antiretroviral agents and other drugs (see Drug Interactions).

Etravirine Dosing in Patients with Hepatic Impairment:

  • No dose adjustment is required when using ETR in patients with mild or moderate hepatic insufficiency. No dosing information is available for patients with severe hepatic impairment.

Etravirine Dosing in Patients with Renal Impairment:

  • No dose adjustment is required when using ETR in patients with renal impairment.

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