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 14, 2020; Last Reviewed: April 14, 2020

Efavirenz (EFV, Sustiva)
Efavirenz (EFV, Sustiva)
Formulations
Capsules: 50 mg, 200 mg
Tablet: 600 mg

Generic Formulations:
  • 50 mg and 200 mg capsules
  • 600 mg tablets
Fixed-Dose Combination Tablets:
  • [Atripla and generic] Efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg
  • [Symfi] Efavirenz 600 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg
  • [Symfi Lo] Efavirenz 400 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg
When using fixed-dose combination (FDC) tablets, refer to other sections of the Drug Appendix for information about the individual components of the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets: Minimum Body Weights and Considerations for Use in Children and Adolescents

For additional information, see Drugs@FDA or DailyMed.
Dosing Recommendations Selected Adverse Events
Neonatal Dose:
  • Efavirenz (EFV) is not approved for use in neonates.
Pediatric Dose:
  • EFV 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 EFV in children aged 3 months to <3 years due to highly variable pharmacokinetics in this age group.
  • If the use of EFV is unavoidable due to a clinical situation, the Panel suggests using investigational doses of EFV in this age group (see 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 of EFV in this age group. Therapeutic drug monitoring (TDM) should be used and EFV plasma concentration should be measured 2 weeks after initiation. If a child initiated EFV at an investigational dose while aged <3 years, some experts would also measure EFV 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 below). When making a dose adjustment based on EFV 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 EFV 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 EFV 367 mg per m2 of body surface area (maximum dose 600 mg) due to concerns about underdosing at the upper end of each weight band (see the Pediatric Use section below for details). Weight bands approximate a dose of EFV 367 mg per m2 of body surface area, with a maximum dose of 600 mg.


Child and Adolescent (Weighing ≥40 kg) and Adult Dose:
  • EFV 600 mg once daily
[Atripla] Efavirenz 600 mg/Emtricitabine/Tenofovir Disoproxil Fumarate (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 ratings [SMRs] 1–3), and major interindividual variability in EFV plasma concentrations has been found in pediatric patients in a multiethnic setting. The 400 mg dose of EFV may be too low in children or adolescents with SMRs 1 to 3 who weigh ≥40 kg. The use of TDM is suggested by some Panel members when Symfi Lo is used in pediatric patients who weigh ≥40 kg (see the Therapeutic Drug Monitoring section below).
  • 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, late-onset ataxia, and encephalopathy
  • Use of EFV may produce false-positive results with some cannabinoid and benzodiazepine tests.
  • Gynecomastia
  • Hepatotoxicity
  • Corrected QT prolongation
Special Instructions
  • EFV capsules and tablets can be swallowed whole, or EFV capsules can be 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 EFV, Atripla, Symfi, or Symfi Lo on an empty stomach. Avoid administration with a high-fat meal, because this has the potential to increase absorption.
  • The Food and Drug Administration cautions that EFV 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 EFV in female adolescents and adults who are pregnant or who may become pregnant.
Instructions for Using Efavirenz Capsule as a Sprinkle Preparation with Food or Formula:
  • Hold capsule horizontally over a small container and carefully twist 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 EFV metabolism.
  • CYP3A and CYP2B6 inducer in vivo.
  • EFV is not recommended for patients with moderate or severe hepatic impairment.
  • Interpatient variability in EFV exposure can be explained in part by polymorphisms in CYP450, particularly CYP2B6 polymorphisms. Slower metabolizers are at higher risk of toxicity (see the Therapeutic Drug Monitoring section 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 because 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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