Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)

Efavirenz

Last Updated: April 16, 2019; Last Reviewed: April 16, 2019

Efavirenz (EFV, Sustiva)
Efavirenz (EFV, Sustiva)
For additional information see Drugs@FDA: https://www.accessdata.fda.gov/scripts/cder/daf/
Formulations
Capsules: 50 mg, 200 mg
Tablet: 600 mg

Generic Formulations:
  • 50 mg capsules
  • 200 mg capsules
  • 600 mg tablets
Fixed-Dose Combination Tablets:
  • [Atripla and Generic] Efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg
  • [Symfi] Efavirenz 600 mg/lamivudine 300 mg/TDF 300 mg
  • [Symfi Lo] Efavirenz 400 mg/lamivudine 300 mg/TDF 300 mg
Dosing Recommendations Selected Adverse Events
Neonatal Dose:
  • Efavirenz is not approved for use in neonates.
Pediatric Dose:
  • Efavirenz capsules can be opened and the contents used as a sprinkle preparation for infants and children who are unable to swallow capsules.
Infants and Children Aged 3 Months to <3 Years and Weighing ≥3.5 kg:
  • The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) does not recommend the use of efavirenz in children aged 3 months to <3 years due to highly variable pharmacokinetics in this age group.
  • Note: If the use of efavirenz is unavoidable due to a clinical situation, the Panel suggests using investigational doses of efavirenz in this age group (see investigational dosing Table A in the Pharmacokinetics and Dosing: Infants and Children Aged <3 Years section below). Evaluation of cytochrome P450 (CYP) 2B6 genotype is required prior to use in this age group. Therapeutic drug monitoring (TDM) should be used and efavirenz plasma concentration should be measured 2 weeks after initiation. If a child initiated efavirenz at an investigational dose while <3 years of age, some experts would also measure plasma concentration at age 3 years after the child transitions to the recommended dose for children aged ≥3 years (see the Therapeutic Drug Monitoring section in the text below). When making a dose adjustment based on efavirenz concentrations, consultation with an expert in pediatric HIV infection is recommended.
Children Aged ≥3 Years and Weighing ≥10 kg:
Once-Daily Doses of Efavirenz by Weight
Weight Efavirenz Dosea,b
10 kg to <15 kg 200 mg
15 kg to <20 kg 250 mg
20 kg to <25 kg 300 mg
25 kg to <32.5 kg 350 mg
32.5 kg to <40 kg 400 mg
≥40 kg 600 mg
a The dose in mg can be dispensed in any combination of capsule strengths. Capsules may be administered by sprinkling the contents onto an age-appropriate food (see Special Instructions).
b Some experts recommend a dose of efavirenz 367 mg/m2 body surface area (maximum dose 600 mg) due to concerns about underdosing at the upper end of each weight band (see Pediatric Use in text below for details). Weight bands approximate a dose of efavirenz 367 mg/m2, with a maximum dose of 600 mg.


Child and Adolescent (Weighing ≥40 kg) and Adult Dose:
  • Efavirenz 600 mg once daily
[Atripla] Efavirenz 600 mg/Emtricitabine/TDF
Child and Adolescent (Weighing ≥40 kg) and Adult Dose:
  • One tablet once daily
  • Take on an empty stomach
[Symfi] Efavirenz 600 mg/Lamivudine/TDF
Child and Adolescent (Weighing ≥40 kg) and Adult Dose:
  • One tablet once daily
  • Take on an empty stomach
[Symfi Lo] Efavirenz 400 mg/Lamivudine/TDF
Child and Adolescent (Weighing ≥35 kg) and Adult Dose:
  • One tablet once daily
  • Take on an empty stomach
Note: Symfi Lo has not been studied in children (sexual maturity rating [SMR] 1–3), and major inter-individual variability in efavirenz plasma concentrations has been found in pediatric patients in a multiethnic setting. The 400 mg dose of efavirenz may be too low in children or adolescents with SMRs 1 to 3 who weigh ≥40 kg. TDM is suggested by some Panel members when Symfi Lo is used in pediatric patients who weigh ≥40 kg.
  • Rash, which is generally mild and transient and appears to be more common in children than in adults
  • Central nervous system (CNS) symptoms such as fatigue, poor sleeping patterns, insomnia, vivid dreams, impaired concentration, agitation, seizures, depression, suicidal ideation
  • Use of efavirenz may produce false-positive results with some cannabinoid and benzodiazepine tests
  • Gynecomastia
  • Hepatotoxicity
  • Corrected QT prolongation
Special Instructions
  • Efavirenz can be swallowed as a whole capsule/tablet or administered by sprinkling the contents of an opened capsule on food as described below.
  • Bedtime dosing is recommended, particularly during the first 2 to 4 weeks of therapy, to improve tolerability of CNS side effects.
  • Administer efavirenz, Atripla, Symfi, or Symfi Lo on an empty stomach. Avoid administration with a high-fat meal, because this has the potential to increase absorption.
  • When using fixed-dose combination (FDC) tablets, see other drug sections in the Drug Appendix for special instructions and additional information about the individual drug components.
  • The Food and Drug Administration cautions that efavirenz should not be used during the first trimester of pregnancy because of potential teratogenicity. However, after a review of updated evidence regarding teratogenicity risks, the Perinatal Guidelines do not restrict use of efavirenz in female adolescents and adults who are pregnant or may become pregnant.
Instructions for Use of Efavirenz Capsule as a Sprinkle Preparation with Food or Formula:
  • Hold capsule horizontally over a small container and carefully twist to open to avoid spillage.
  • Gently mix capsule contents with 1 to 2 teaspoons of an age-appropriate soft food (e.g., applesauce, grape jelly, yogurt) or reconstituted infant formula at room temperature.
  • Administer within 30 minutes of mixing and do not consume additional food or formula for 2 hours after administration.
Metabolism/Elimination
  • CYP2B6 is the primary enzyme for efavirenz metabolism.
  • Cytochrome P450 (CYP) 3A and CYP2B6 inducer in vivo and CYP2C9, 2C19, and 3A4 isozyme inhibitor in vitro.
  • Efavirenz is not recommended for patients with moderate or severe hepatic impairment.
  • Interpatient variability in efavirenz exposure can be explained in part by polymorphisms in CYP450, with slower metabolizers at higher risk of toxicity (see Therapeutic Drug Monitoring in the text below for information about the management of mild or moderate toxicity).
Atripla, Symfi, and Symfi Lo Dosing in Adults with Renal Impairment:
  • Because these are FDC products and TDF, lamivudine, and emtricitabine require dose adjustments based on renal function, Atripla, Symfi, and Symfi Lo should not be used in patients with creatinine clearance <50 mL/min or in patients on dialysis.

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