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Table of Contents

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)

Efavirenz

(Last updated: March 5, 2015; last reviewed: March 5, 2015)

Efavirenz (EFV, Sustiva)

Efavirenz (EFV, Sustiva)

For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations

Capsules:
50 mg, 200 mg
Tablets: 600 mg

Fixed-Dose Combination Tablets: 

With Emtricitabine and Tenofovir Disoproxil Fumarate (Tenofovir):

  • Emtricitabine 200 mg + tenofovir 300 mg + efavirenz 600 mg (Atripla)
Dosing Recommendations

Neonatal Dose:
  • Efavirenz is not approved for use in neonates.
Pediatric Dose:
Infants and Children Aged 3 Months to <3 Years and Weight ≥3 kg:
  • The Panel recommends that efavirenz generally not be used in children aged 3 months to <3 years. If use of efavirenz is unavoidable due to the clinical situation, the Panel suggests the use of investigational doses of efavirenz in this age group. See text for investigational dosing tables; evaluation of CYP 2B6 genotype is required prior to use. Therapeutic drug monitoring is recommended with an efavirenz concentration measured 2 weeks after initiation; some experts would also measure at age 3 years when making the dose adjustment. For dose adjustment based on efavirenz concentrations, consultation with an expert is recommended.

Children Aged ≥3 Years and Weight ≥10 kg:
Administer Efavirenz Once Daily

Children Aged ≥3 Years and Weight ≥10 kg:
Weight (kg) Efavirenz Dose
(mg)a,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.

b Some experts recommend a dose of 367 mg/m2 body surface area (maximum dose 600 mg) because of concern for under-dosing, especially at the upper end of each weight band (see Pediatric Use for details).

Adolescent (Body Weight ≥40 kg)/Adult Dose:

  • 600 mg once daily

Atripla

  • Atripla should not be used in pediatric patients <40 kg where the efavirenz dose would be excessive.

Adult Dose:

  • One tablet once daily
Selected Adverse Events
  • Rash
  • Central nervous system (CNS) symptoms such as dizziness, somnolence, insomnia, abnormal dreams, impaired concentration, psychosis, seizures, suicidality
  • Increased transaminases
  • False-positive with some cannabinoid and benzodiazepine tests
  • Potentially teratogenic
  • Lipohypertrophy, although a causal relationship has not been established and this adverse event may be less likely than with the boosted protease inhibitors
Special Instructions
  • Efavirenz can be swallowed as a whole capsule or tablet or administered by sprinkling the contents of an opened capsule on food as described below.
  • Administer whole capsule or tablet of Atripla on an empty stomach. Avoid administration with a high-fat meal because of potential for increased absorption.
  • Bedtime dosing is recommended, particularly during the first 2 to 4 weeks of therapy, to improve tolerability of CNS side effects.
  • Efavirenz should be used with caution in female adolescents and adults with reproductive potential because of the potential risk of teratogenicity.
Instructions for Use of 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 1–2 teaspoons of an age-appropriate soft food (e.g., applesauce, grape jelly, yogurt), or reconstituted infant formula at room temperature.
  • Administer infant formula mixture using a 10-mL syringe.
  • After administration, an additional 2 teaspoons of food or infant formula must be added to the container, stirred, and dispensed to the patient.
  • Administer within 30 minutes of mixing and do not consume additional food or formula for 2 hours after administration.
Metabolism
  • Cytochrome P450 3A4 (CYP3A4) inducer/inhibitor (more inducer than inhibitor)
  • CYP2B6, CYP3A4, and CYP2A6 substrate
  • Dosing of efavirenz in patients with hepatic impairment: No recommendation is currently available; use with caution in patients with hepatic impairment.
  • Adult dose of Atripla in patients with renal impairment: Because Atripla is a fixed-dose combination product and tenofovir and emtricitabine require dose adjustment based on renal function, Atripla should not be used in patients with creatinine clearance <50 mL/minute or in patients on dialysis.
  • Interpatient variability in efavirenz exposure can be explained in part by polymorphisms in CYP450 with slower metabolizers at higher risk of toxicity (see text for information about therapeutic drug monitoring for management of mild or moderate toxicity).

Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://www.hiv-druginteractions.org/)

  • Metabolism: Mixed inducer/inhibitor of CYP3A4 enzymes; concentrations of concomitant drugs can be increased or decreased depending on the specific enzyme pathway involved. There are multiple drug interactions. Importantly, dosage adjustment or the addition of ritonavir may be necessary when efavirenz is used in combination with atazanavir, fosamprenavir, indinavir, ritonavir-boosted lopinavir, or maraviroc.
  • Before efavirenz is administered, a patient’s medication profile should be carefully reviewed for potential drug interactions with efavirenz.

Major Toxicities

  • More common: Skin rash, increased transaminase levels. Central nervous system (CNS) abnormalities, such as dizziness, somnolence, insomnia, abnormal dreams, confusion, abnormal thinking, impaired concentration, amnesia, agitation, depersonalization, hallucinations, euphoria, seizures, primarily reported in adults.
  • Rare: An association between efavirenz and suicidal ideation, suicide, and attempted suicide (especially among those with a history of mental illness or substance abuse) was found in one retrospective analysis of four comparative trials in adults.
  • Potential risk of teratogenicity. Classified as Food and Drug Administration (FDA) Pregnancy Class D, which means that there is positive evidence of human fetal risk based on studies in humans (see Pediatric Use section below; see also the Perinatal Guidelines).1

Resistance

The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see https://www.iasusa.org/sites/default/files/tam/22-3-642.pdf) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/DR/).

Pediatric Use

Approval
Efavirenz is FDA-approved for use as part of combination antiretroviral therapy in children aged ≥3 months who weigh at least 3.5 kg.

Pharmacokinetics: Pharmacogenomics
Efavirenz metabolism is controlled by enzymes that are polymorphically expressed and result in large interpatient variability in drug exposure. CYP2B6 is the primary enzyme for efavirenz metabolism, and pediatric patients with the CYP 2B6 516 T/T genotype (which has an allele frequency of 20% in African Americans) have reduced metabolism resulting in higher efavirenz levels compared with those with the G/G or G/T genotype.2-5 IMPAACT P1070 has shown that aggressive dosing with approximately 40 mg/kg using opened capsules resulted in therapeutic efavirenz concentrations in 68% of children aged <3 years with G/G or G/T genotype but excessive exposure in those with T/T genotype.4 Optimal dosing may require pretreatment CYP2B6 genotyping in children aged <3 years.4,6 Additional variant CYP2B6 alleles and variant CYP2A6 alleles have been found to influence efavirenz concentrations in adults and children.7-11

Pharmacokinetics and Dosing: Infants and Children Aged <3 Years
Limited pharmacokinetic (PK) data in children aged <3 years or who weigh <13 kg have shown that it is difficult to achieve target trough concentrations in this age group.4,12 Hepatic enzyme activity is known to change with age. Using a pharmacometric model, the increase in oral clearance of efavirenz as a function of age is predicted to reach 90% of mature value by the age of 9 months.5 This maturation of oral clearance is postulated to result from an increase in the expression of CYP 2B6 with age.5 CYP 2B6-516-G/G genotype is associated with the greatest expression of hepatic CYP 2B6 when compared with the CYP 2B6-516-G/T or -T/T genotype.2 In children with CYP 2B6-516-G/G genotype, oral clearance rate has been shown to be higher in children aged <5 years than in older children.2 Efficacy data for opened capsules with contents used as sprinkles suggest acceptable palatability and bioavailability for infants and children aged <3 years. IMPAACT study P1070, an ongoing study of HIV-infected and HIV/tuberculosis-coinfected children aged <3 years, using efavirenz dosed by weight band based on CYP2B6 GG/GT versus TT genotype (see Tables 1a and 1b below), showed HIV RNA <400 copies/mL in 61% by intent to treat analysis at 24 weeks.4 When used without regard to genotype, doses higher than the FDA-recommended doses resulted in therapeutic efavirenz concentrations in an increased proportion of study participants with GG/GT genotypes but excessive exposure in a high proportion of those with TT genotypes.4 Therefore, dosing tables have been modified so that infants and young children with TT genotype will receive a reduced dose. Additional subjects will be studied to confirm that this dose is appropriate for this subset of patients. The modified doses listed in Tables 1a and 1b are under investigation.

Investigational Dosing for Children Aged 3 Months to <3 Years Based on CYP 2B6 Genotype

Table 1a. Protocol P1070 Dosing for Patients with CYP 2B6 516 GG and GT Genotypes (Extensive Metabolizers [EM])
Weight (kg) Efavirenz Dose (mg)
3 kg–4.99 kg 200 mg
5 kg–6.99 kg 300 mg
7 kg–13.99 kg 400 mg
14 kg–16.99 kg 500 mg
≥17 kg 600 mg

Table 1b. Protocol P1070 Dosing for patients with CYP 2B6 516 TT genotype (Slow Metabolizers [SM])
Weight (kg) Efavirenz Dose (mg)
3 kg–6.99 kg 50 mg
7 kg–13.99 kg 100 mg
14 kg–16.99 kg 150 mg
≥17 kg 150 mg

a Investigational doses are based on IMPAACT study P1070.4 Evaluation of CYP 2B6 genotype is required. Therapeutic drug level monitoring is recommended with a trough measured 2 weeks after initiation and at age 3 years for possible dose adjustment.

The FDA has approved efavirenz for use in infants and children aged 3 months to <3 years at doses derived from a population PK model based on data from adult subjects in PACTG 1021 and PACTG 382, and AI266-922, which is an ongoing study assessing the PK, safety, and efficacy of capsule sprinkles in children aged 3 months to 6 years (see Table 2).

Table 2: FDA-Approved Dosing for Children Aged 3 Months to <3 Years (Without Regard to CYP 2B6 Genotype)
Weight (kg) Efavirenz Dose (mg)
3.5 kg to <5 kg 100 mg
5 kg to <7.5 kg 150 mg
7.5 kg to <15 kg 200 mg
15 kg to <20 kg 250 mg

The FDA-approved doses are lower than the CYP 2B6 extensive metabolizer doses and higher than the CYP 2B6 slow metabolizer doses currently under study in P1070. Further studies are needed to determine if the FDA dosing can achieve therapeutic levels for the group aged 3 months to 3 years. There is concern that FDA-approved doses may result in frequent under-dosing in CYP 2B6 extensive metabolizers. Estimates of efavirenz area under the curve (AUC) for FDA dosing using P1070 data are given in Table 3.6 Estimates were calculated as follows: P1070 observed AUC X (FDA dose/P1070 CYP 2B6 genotype-directed study dose). A high initial dose of efavirenz in the first version of the P1070 protocol was used to produce a target AUC of 35 to 180 mcg*h/mL, a systemic exposure similar to that shown to be safe and effective in older children and adults.6 Estimates indicate that FDA-recommended doses of efavirenz will produce excessive efavirenz AUCs in 67% of slow metabolizer (SM) and sub-therapeutic AUCs in 38% of extensive metabolizer (EM) children aged <3 years, whereas CYP 2B6 genotype-directed dosing resulted in achievement of target AUCs in 83% of EM children and 89% of SM children.

Table 3: Estimated Efavirenz AUC for FDA Dosing Compared with AUC for P1070 Dosingb
Metabolizer Phenotype Median AUC
(mcg*h/mL)
Number with Estimated Plasma AUC <35 mcg*h/mL Number with Estimated Plasma AUC 35-180 mcg*h/mL
Number with Estimated Plasma AUC >180 mcg*h/mL
EM (CYP2B6 516 GG/GT) n = 29
P1070 dosing 106.3 4 (14%) 24 (83%) 1 (3%)
FDA dosing 51.3 11 (38%) 17 (59%) 1 (3%)
SM (CYP2B6 516 TT) n = 9
P1070 dosing 113.2 0 (0%) 8 (89%) 1 (11%)
FDA dosing 245.1 0 (0%) 3 (33%) 6 (67%)

b Moore CB, et al. Abstrct 903. Presented at: 20th Conference on Retroviruses and Opportunistic Infections (CROI). 2014. Boston, MA

Key to Acronyms: AUC = area under the curve; CYP = cytochrome P450; EM = extensive metabolizer; FDA = Food and Drug Administration; SM = slow metabolizer

The Panel recommends that efavirenz generally not be used in children aged 3 months to <3 years. If the clinical situation demands use of efavirenz, Panel members recommend determining CYP2B6 genotype (search for laboratory performing this testing at http://www.ncbi.nlm.nih.gov/gtr/labs). Patients should be classified as extensive CYP 2B6 516 GG and GT genotypes versus slow CYP 2B6 516 TT genotype metabolizers to guide dosing as indicated by the investigational doses from IMPAACT study P1070 (see Tables 1a and 1b). Whether the doses used are investigational or FDA-approved, efavirenz plasma concentrations should be measured 2 weeks post-initiation (see Role of Therapeutic Drug Monitoring). For dose adjustment, consultation with an expert is recommended. In addition, when dosing following the P1070 investigational dose recommendations, some experts would measure efavirenz concentrations at age 3 years to guide dose adjustment.

Pharmacokinetics: Children Aged ≥3 Years and Adolescents
Long-term HIV RNA suppression has been associated with maintenance of trough efavirenz concentrations > 1 mcg/mL in adults.13 Early HIV RNA suppression in children has also been seen with higher drug concentrations. Higher efavirenz troughs of 1.9 mcg/mL were seen in subjects with HIV RNA levels ≤400 copies/mL versus efavirenz troughs of 1.3 mcg/mL in subjects with detectible virus (>400 copies/mL).14 In a West African pediatric study, ANRS 12103, early reduction in viral load (by 12 weeks) was greater in children with efavirenz minimum plasma concentration (Cmin) levels >1.1 mcg/mL or area under the curve (AUC) >51 mcg h/mL.15

Even with the use of FDA-approved pediatric dosing in children aged ≥3 years, efavirenz concentrations can be suboptimal.2,15-19 Therefore, some experts recommend therapeutic drug monitoring (TDM) with efavirenz and possibly use of higher doses in young children, especially in select clinical situations such as virologic rebound or lack of response in an adherent patient. In one study in which the efavirenz dose was adjusted in response to measurement of the AUC, the median administered efavirenz dose was 13 mg/kg (367 mg/m2) and the range was from 3 to 23 mg/kg (69–559 mg/m2).14 A PK study in 20 children aged 10 to 16 years treated with lopinavir/ritonavir 300 mg/m2 twice daily plus efavirenz 350 mg/m2 once daily showed adequacy of the lopinavir trough values but suggested that the efavirenz trough was lower than PK targets. The authors therefore recommended that higher doses of efavirenz might be needed when these drugs are used together.20 TDM can be considered when using efavirenz in combinations with potentially complex drug interactions.

Toxicity: Children versus Adults
The toxicity profile for efavirenz differs for adults and children. A side effect commonly seen in children is rash, which was reported in up to 40% of children compared with 27% of adults. The rash is usually maculopapular, pruritic, and mild to moderate in severity and rarely requires drug discontinuation. Onset is typically during the first 2 weeks of treatment. Although severe rash and Stevens-Johnson syndrome have been reported, they are rare. In adults, CNS symptoms have been reported in more than 50% of patients. These symptoms usually occur early in treatment and rarely require drug discontinuation, but they can sometimes occur or persist for months. Bedtime efavirenz dosing appears to decrease the occurrence and severity of these neuropsychiatric side effects. For patients who can swallow capsules or tablets, ensuring that efavirenz is taken on an empty stomach also reduces the occurrence of neuropsychiatric adverse effects. An association between efavirenz and suicidal ideation, suicide, and attempted suicide (especially among those with a history of mental illness or substance abuse) was found in one retrospective analysis of four comparative trials in adults.21 In several studies, the incidence of neuropsychiatric adverse effects was correlated with efavirenz plasma concentrations and the symptoms occurred more frequently in patients receiving higher concentrations.13,22-25 In patients with pre-existing psychiatric conditions, efavirenz should be used cautiously for initial therapy. Adverse CNS effects occurred in 14% of children receiving efavirenz in clinical studies26 and in 30% of children with efavirenz concentrations greater than 4 mcg/mL.3 CNS adverse effects may be harder to detect in children because of the difficulty in assessing neurologic symptoms such as impaired concentration, sleep disturbances, or behavior disorders in these patients.

Toxicity: Potential Risk of Teratogenicity
Prenatal efavirenz exposure has been associated with CNS congenital abnormalities in the offspring of cynomolgus monkeys. As of July 2010, the Antiretroviral Pregnancy Registry has received prospective reports of 792 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (718 pregnancies). Birth defects occurred in 17 of 604 live births (first-trimester exposure) and 2 of 69 live births (second/third-trimester exposure). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first trimester exposure to efavirenz has also been prospectively reported; however, this case included severe oblique facial clefts and amniotic banding, a known associate with anophthalmia. There have been six retrospective reports of findings consistent with neural tube defects, including meningomyelocele. All mothers were exposed to efavirenz-containing regimens in the first trimester. Although a causal relationship has not been established between these events and use of efavirenz, similar defects have been observed in preclinical studies of efavirenz.27 Based on these types of reports, efavirenz has been classified as FDA Pregnancy Class D, which means that there is positive evidence of human fetal risk based on studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

A recent updated meta-analysis found no association with the potential for teratogenicity following first-trimester efavirenz exposure. However, because of the low incidence of CNS anomalies in the overall population and relatively small number of exposures in the current literature, continued birth outcomes prospective surveillance is warranted.28 Although the data on the use of efavirenz in pregnancy are reassuring, many experts remain reluctant to consider use of efavirenz in adolescents who are trying to conceive or who are not using effective birth control, so as to avoid the use of efavirenz during the first trimester of pregnancy (the primary period of fetal organogenesis).29 Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz and should be counseled about the potential risk to the fetus and desirability of avoiding pregnancy. Alternate antiretroviral regimens that do not include efavirenz should be strongly considered in women who are planning to become pregnant or who are sexually active and not using effective contraception (if such alternative regimens are acceptable to provider and patient and will not compromise a woman’s health). See Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.1

Therapeutic Drug Monitoring
Note: See Role of Therapeutic Drug Monitoring.
In the setting of potential toxicity, it is reasonable for a clinician to use TDM to determine whether the toxicity is due to an efavirenz concentration in excess of the normal therapeutic range.30,31 This is the only setting in which dose reduction would be considered appropriate management of drug toxicity, and even then, it should be used with caution. Also, the Panel recommends TDM when dosing efavirenz in children aged 3 months to <3 years due to variable PK properties in this young age group. An efavirenz concentration, preferably a trough, measured 2 weeks after initiation, and consultation with an expert, is recommended for dose adjustment. Long-term HIV RNA suppression has been associated with maintenance of trough efavirenz concentrations greater than 1000 ng/mL in adults.13 In addition, some experts would measure efavirenz concentrations at age 3 years for potential dose adjustment if dosing was initiated at age <3 years using investigational dose recommendations.

References

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  6. Moore CB, Capparelli E, Samson P, Bwakura-Dangarembizi M, al e. CYP2B6 polymorphisms challenge generalized FDA efavirenz dosing guidelines in children <3 years. Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections. 2014. Boston, MA.
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  23. Zugar A. Studies disagree on frequency of late cns side effects from efavirenz. AIDS Clin Care. 2006;4(1). 
  24. Treisman GJ, Kaplin AI. Neurologic and psychiatric complications of antiretroviral agents. AIDS. 2002;16(9):1201-1215. Available at http://www.ncbi.nlm.nih.gov/pubmed/12045485.
  25. Wintergerst U, Hoffmann F, Jansson A, et al. Antiviral efficacy, tolerability and pharmacokinetics of efavirenz in an unselected cohort of HIV-infected children. J Antimicrob Chemother. 2008;61(6):1336-1339. Available at http://www.ncbi.nlm.nih.gov/pubmed/18343800.
  26. Shubber Z, Calmy A, Andrieux-Meyer I, et al. Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis. AIDS. 2013;27(9):1403-1412. Available at http://www.ncbi.nlm.nih.gov/pubmed/23343913.
  27. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 January 1989 through 31 January 2014. 2014. Available at http://www.apregistry.com/forms/interim_report.pdf. Accessed January 9, 2015.
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  29. Saitoh A, Hull AD, Franklin P, Spector SA. Myelomeningocele in an infant with intrauterine exposure to efavirenz. J Perinatol. 2005;25(8):555-556. Available at http://www.ncbi.nlm.nih.gov/pubmed/16047034.
  30. van Luin M, Gras L, Richter C, et al. Efavirenz dose reduction is safe in patients with high plasma concentrations and may prevent efavirenz discontinuations. J Acquir Immune Defic Syndr. 2009;52(2):240-245. Available at http://www.ncbi.nlm.nih.gov/pubmed/19593159.
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