AHFS Class:

• HIV Nonnucleoside Reverse Transcriptase Inhibitors 8:18.08.16

Generic Name(s):

• Efavirenz

• Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate

• Efavirenz, Lamivudine, and Tenofovir Disoproxil Fumarate

Efavirenz, an antiretroviral agent, is a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI).1,2,3,12,14

Treatment of HIV Infection

Efavirenz is used in conjunction with other antiretroviral agents for treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients ≥3 months of age weighing ≥3.5 kg.1,360

Efavirenz is commercially available as a single entity and in various fixed-combination preparations that contain additional antiretrovirals.1,232,351,357,360 These fixed-dose preparations include efavirenz, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF; e.g., Atripla^®) and efavirenz, lamivudine, and tenofovir DF (e.g., Symfi^®, Symfi Lo^®).232,351,357 See the full prescribing information for use of each of these combination products.232,351,357

Clinical Experience

Antiretroviral-naïve Adults and Adolescents

Efavirenz has been evaluated for use in conjunction with 2 NRTIs or in conjunction with an HIV protease inhibitor (PI) in a randomized, open-label study (Study 006) in 1266 HIV-infected adults (mean age 36.5 years [range: 18-81 years], 83% male, 60% white, median baseline CD4⁺ T-cell count 320 cells/mm³, median baseline plasma HIV-1 RNA level 4.8 log₁₀ copies/mL).1 Patients were randomized to receive either efavirenz 600 mg once daily, zidovudine 300 mg every 12 hours, and lamivudine 150 mg every 12 hours (n=422); efavirenz 600 mg once daily and indinavir 1000 mg every 8 hours (n=429); or indinavir 800 mg every 8 hours, zidovudine 300 mg every 12 hours, and lamivudine 150 mg every 12 hours (n=415).1 Response was defined as an HIV-1 RNA level <400 copies/mL maintained through week 48 or 168.1

At 48 or 168 weeks, plasma HIV-1 levels were <400 copies/mL in 57 or 40%, respectively, of those receiving efavirenz/indinavir; 69 or 48% of those receiving efavirenz/zidovudine/lamivudine; and 50 or 29% of those receiving indinavir/zidovudine/lamivudine.1 When an assay with lower limits of detection (<50 copies/mL) was used to measure plasma HIV-1 levels at 48 or 168 weeks, plasma HIV-1 levels were <50 copies/mL in 50 or 31%, respectively, of those receiving efavirenz/indinavir; 65 or 43% of those receiving efavirenz/zidovudine/ lamivudine; and 45 or 23% of those receiving indinavir/zidovudine/lamivudine.1

Safety and efficacy of a regimen of efavirenz, emtricitabine, and tenofovir DF have been evaluated in a randomized, open-label study designed to demonstrate noninferiority of this regimen compared with a regimen of efavirenz, zidovudine, and lamivudine in antiretroviral-naïve patients (Study 934).23,232 See full prescribing information for fixed-combination efavirenz, emtricitabine, and tenofovir DF (Atripla^®) for details of clinical experience with this regimen.232

Safety and efficacy of coformulated efavirenz 600 mg, lamivudine 300 mg, and tenofovir DF 300 mg (Symfi^®) have been evaluated in a randomized, double-blind trial comparing efavirenz 600 mg, lamivudine 300 mg, and tenofovir DF 300 mg with efavirenz 600 mg, lamivudine 300 mg, and stavudine 40 mg in antiretroviral-naïve patients (Trial 903).351,358 Safety and efficacy of coformulated efavirenz 400 mg, lamivudine 300 mg, and tenofovir DF 300 mg (Symfi Lo^®) were established based on results from Trial 903 and a randomized trial comparing efavirenz 400 mg with efavirenz 600 mg (both in combination with tenofovir DF and emtricitabine) in antiretroviral-naïve adults (ENCORE-1).357,359 See full prescribing information for these fixed-combination products for details of clinical experience with these regimens.351,357

Antiretroviral-experienced Adults

Efavirenz has been evaluated for use in antiretroviral-experienced patients in a phase 2, randomized, double-blind, placebo-controlled study (Study ACTG 364), which enrolled 196 adult patients (mean age 41 years, mean baseline CD4⁺ T-cell count 389 cells/mm³, mean baseline plasma HIV-1 RNA level 8130 copies/mL) who had completed 2 prior ACTG studies (ACTG 302 and 303).1,353 Patients were randomized to treatment with NRTIs with either efavirenz 600 mg once daily (n=65), nelfinavir 750 mg 3 times daily (n=66), or efavirenz plus nelfinavir (n=65).1 The primary outcome was the proportion of patients achieving an HIV-1 RNA level <500 copies/mL.353

At 48 weeks, an HIV-1 RNA level <500 copies/mL was attained in 63% of the efavirenz group, 41% of the nelfinavir group, and in 71% of the efavirenz/nelfinavir group.1

Efficacy of the fixed combination efavirenz/emtricitabine/tenofovir DF was evaluated in a randomized, open-label, noninferiority study (Study 073) in antiretroviral-experienced patients who had been receiving a suppressive regimen consisting of at least 2 NRTIs and a PI or nonnucleoside reverse transcriptase inhibitor (NNRTI).232,354 See full prescribing information for fixed-combination efavirenz, emtricitabine, and tenofovir DF (Atripla^®) for details of clinical experience with this regimen.232

Pediatric Patients

Safety and efficacy of efavirenz in conjunction with didanosine and emtricitabine were evaluated in a phase 2, open-label trial (Study AI266922) that included 37 antiretroviral-naïve or antiretroviral-experienced pediatric patients 3 months to 6 years of age (median age 0.7 years, median baseline plasma HIV-1 RNA level 5.88 log₁₀copies/mL, median baseline CD4⁺ T-cell count 1144 cells/mm³, median baseline CD4⁺ T-cell percentage 25%).1 All patients received a regimen of efavirenz, didanosine, and emtricitabine at a weight-adjusted dose.355 The efficacy outcome assessed was the proportion of patients with HIV-1 RNA levels <50 or 400 copies/mL at 48 weeks.1,355

At 48 weeks, plasma HIV-1 RNA levels were <400 or 50 copies/mL in 57 or 46%, respectively, of patients (intent-to-treat analysis).1 The median increase in CD4⁺ T-cell count was 196 cells/mm³ and the median increase in CD4⁺ T-cell percentage was 6%.1

Safety and efficacy of efavirenz in conjunction with didanosine and emtricitabine also were evaluated in an open-label trial (Study PACTG 1021) that included 37 antiretroviral-naïve pediatric patients 3 months to 21 years of age (median age 9.6 years, median baseline plasma HIV-1 RNA level 4.8 log₁₀ copies/mL, median baseline CD4⁺ T-cell count 367 cells/mm³, median baseline CD4⁺ T-cell percentage 18%).1 All patients received a regimen of efavirenz, didanosine, and emtricitabine given once daily at a weight-based dose.356 The primary virologic outcome was the proportion of patients achieving an HIV-1 RNA level <50 or 400 copies/mL, with a secondary outcome of virologic failure (HIV-1 RNA >400 or 50 copies/mL).356

At 48 weeks, plasma HIV-1 RNA levels were <400 or 50 copies/mL in 77 or 70%, respectively, of patients (intent-to-treat analysis).1 The median increase in CD4⁺ T-cell count was 238 cells/mm³ and the median increase in CD4⁺ T-cell percentage was 13%.1 Virologic suppression was maintained in 70% of patients through 96 weeks.356

Safety and efficacy of efavirenz in pediatric patients were evaluated in an open-label study (Study PACTG 382) that included 102 antiretroviral-naïve or antiretroviral-experienced pediatric patients 3 months to 16 years of age (median age 5.7 years, 87% antiretroviral-experienced, median baseline plasma HIV-1 RNA level 4.57 log₁₀ copies/mL, median baseline CD4⁺ T-cell count 755 cells/mm³, median baseline CD4⁺ T-cell percentage 30%).1 Patients received efavirenz in conjunction with nelfinavir and an NRTI.1,47

At 48 weeks, plasma HIV-1 RNA levels were <400 or 50 copies/mL in 57 or 43%, respectively, of patients (intent-to-treat analysis).1 The median increase in CD4⁺ T-cell count was 128 cells/mm³ and the median increase in CD4⁺ T-cell percentage was 5%.1

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of antiretroviral therapy are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 NRTIs administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), an NNRTI, or a PI with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), antiretroviral regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

Efavirenz, an NNRTI, is commonly added to a dual-NRTI “backbone” to form a fully suppressive 3-drug antiretroviral regimen.200 In the 2024 HHS adult and adolescent HIV treatment guideline, efavirenz is included in various antiretroviral regimens.200 Some of these efavirenz-containing regimens are listed among recommended initial regimens in certain clinical situations, and include the following regimens: efavirenz plus either tenofovir DF or tenofovir alafenamide plus either lamivudine or emtricitabine.200

In the 2024 HHS pediatric HIV treatment guideline, efavirenz is included in various antiretroviral regimens.201 Efavirenz plus a 2-NRTI “backbone” is recommended as an alternative NNRTI-based regimen for initial treatment of children ≥3 years of age.201

In the 2024 HHS perinatal HIV treatment guideline, efavirenz is included in various antiretroviral regimens.202 Some of these efavirenz-containing regimens are listed among alternative regimens during pregnancy for antiretroviral-naïve patients and include the following regimens: efavirenz/tenofovir DF/emtricitabine, efavirenz/tenofovir DF/lamivudine, and efavirenz plus a preferred dual-NRTI “backbone.”202 Efavirenz (in conjunction with a dual-NRTI “backbone”) is also listed as a recommended alternative agent for pregnant patients who have received antiretroviral therapy in the past and are restarting an antiretroviral regimen or are currently on an antiretroviral regimen that is not well-tolerated or not fully suppressive.202

Postexposure Prophylaxis following Occupational Exposure to HIV

Efavirenz is used in conjunction with 2 NRTIs for postexposure prophylaxis of HIV infection following an occupational exposure† (PEP) in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV; it is considered an alternative agent that should be used only with expert consultation.199

The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).199 These experts recommend several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs).199 The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir^®), or zidovudine and emtricitabine.199

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Efavirenz is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission; it is considered an alternative agent that should be used only with expert consultation.198

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).198 The alternative nPEP regimen recommended in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada^®).198

Consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals.198 However, initiation of nPEP should not be delayed while waiting for expert consultation.198

General

Pretreatment Screening

• Assess cholesterol and triglyceride levels prior to initiation of efavirenz therapy.1,360
• Assess serum liver enzyme concentrations prior to initiation of efavirenz therapy.1,360
• Verify pregnancy status in females of reproductive potential prior to starting efavirenz.1,360

Patient Monitoring

• Monitor cholesterol and triglyceride levels at periodic intervals.1,360
• Monitor serum liver enzyme concentrations.1,360
• Monitor for adverse psychiatric and CNS effects.1,360
• Monitor for development of rash.1,360

Premedication and Prophylaxis

• Consider antihistamines for prevention of rash when initiating efavirenz in pediatric patients.1,360

Dispensing and Administration Precautions

• The Institute for Safe Medication Practices (ISMP) list of error-prone abbreviations, symbols, and dose designations states that the use of abbreviations for antiretroviral medications (e.g., DOR, TAF, TDF) during the medication use process should be avoided as their use has been associated with serious medication errors.362

Administration

Single-entity efavirenz is commercially available as capsules or tablets.1,360

Efavirenz capsules and tablets are administered orally once daily on an empty stomach, preferably at bedtime.1,360

Because administration with food increases plasma efavirenz concentrations and may increase the incidence of adverse effects, the drug should be taken on an empty stomach.1,360 Administration of efavirenz at bedtime may make adverse CNS effects (e.g., dizziness, insomnia, impaired concentration, somnolence, abnormal dreams) more tolerable.1,360

Efavirenz is used in conjunction with other antiretrovirals.1,360 Single-entity efavirenz should not be used concomitantly with efavirenz/emtricitabine/tenofovir disoproxil fumarate (tenofovir DF; e.g., Atripla^®), unless needed for adjustment of efavirenz dosage (e.g., when the fixed combination is used concomitantly with rifampin).1,360

Capsules

Efavirenz capsules should be swallowed whole.1

For adults and pediatric patients ≥3 months of age not able to swallow capsules or tablets, efavirenz capsules may be opened and the contents administered by mixing with a small amount (1-2 teaspoonfuls) of soft food (capsule sprinkle method).1 The use of infant formula for mixing should be considered only for infants who cannot consume solid foods.1 The efavirenz mixture should be administered within 30 minutes after preparation, and the patient should not consume any additional food or infant formula for 2 hours after the mixture.1

To mix the contents of efavirenz capsules with food, 1-2 teaspoonfuls of age-appropriate soft food (e.g., applesauce, grape jelly, yogurt) should be added to a small container.1 The appropriate number of efavirenz capsules (see Table 1) should be held horizontally over the small container, twisted open, and emptied.1 The contents of the capsules should be gently mixed into the soft food with a spoon and the entire mixture fed to the patient.1 Then, an additional 2 teaspoonfuls of soft food should be added to the small container, stirred to disperse any remaining efavirenz residue, and fed to the patient.1

To mix the contents of efavirenz capsules with infant formula for infants not able to consume solid food, 10 mL (2 teaspoonfuls) of reconstituted room temperature infant formula should be added to a 30-mL medicine cup.1 The appropriate number of efavirenz capsules (see Table 1) should be held horizontally over the medicine cup, twisted open, and emptied.1 The contents of the capsules should be gently mixed into the infant formula using a small spoon.1 The infant formula mixture should be drawn up into a 10-mL oral dosing syringe and administered into the infant's right or left inner cheek.1 Then, an additional 10 mL of infant formula should be added to the medicine cup, stirred to disperse any remaining efavirenz residue, drawn up into the oral dosing syringe, and administered to the infant.1

Store capsules at 20-25°C (excursions permitted between 15-30°C).1

Tablets

Efavirenz tablets should be swallowed whole with liquid; the tablets should not be broken or crushed.360

Store tablets at 20-25°C (excursions permitted between 15-30°C).360

Fixed Combinations Containing Efavirenz

Efavirenz is commercially available in fixed-combination tablets containing efavirenz, emtricitabine, and tenofovir DF (e.g., Atripla^®) and efavirenz, lamivudine, and tenofovir DF (e.g., Symfi^® and Symfi Lo^®).232,351,357 See the full prescribing information for administration of each of these combination products.232,351,357

Pharmacogenetic Testing

Poor CYP2B6 metabolizers may be at an increased risk for increased efavirenz levels and adverse effects with efavirenz, including CNS toxicity, hepatic injury, and QT prolongation.1,360,361 Genetic variants associated with poor CYP2B6 metabolic function (particularly CYP2B6 c.516G>T and c.983T>C) have been linked to decreased efavirenz clearance and increased risk for efavirenz toxicity and/or treatment discontinuation.361 The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides recommendations for efavirenz dosing guided by CYP2B6 phenotype.361 For adults and pediatric patients weighing ≥40 kg who are intermediate CYP2B6 metabolizers, consider initiating efavirenz at a reduced dosage of 400 mg/day (moderate recommendation).361 For adults and pediatric patients weighing ≥40 kg who are poor CYP2B6 metabolizers, consider initiating efavirenz at a reduced dosage of 200-400 mg/day (moderate recommendation).361 Consult the CPIC guideline for more details and definitions of CYP2B6 phenotypes based on genotype.361

Dosage

Adults

Treatment of HIV infection

The usual dosage of efavirenz for treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and adolescents is 600 mg once daily.1,360

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel or other individuals, efavirenz is administered in a dosage of 600 mg once daily in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).199

PEP should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.199

Pediatric Patients

Treatment of HIV Infection

Dosage of efavirenz in children ≥3 months of age weighing 3.5 to <40 kg is based on weight.1,360 (see Table 1.) Adolescents and children who weigh ≥40 kg may receive the usual adult dosage of efavirenz.1,360

Dosage Adjustment for Concomitant Use with Voriconazole

If efavirenz is used for treatment of HIV-1 infection in patients receiving voriconazole, the voriconazole dosage should be increased to 400 mg every 12 hours and the efavirenz dosage should be reduced to 300 mg daily using the capsule formulation.1,360

Dosage Adjustment for Concomitant Use with Rifampin

If efavirenz is used for treatment of HIV-1 infection in patients receiving rifampin, those weighing ≥50 kg should receive an increased efavirenz dosage of 800 mg daily.1,360

Special Populations

Hepatic Impairment

Efavirenz dosage adjustments are not necessary in patients with mild hepatic impairment (Child-Pugh Class A).1,360 Because efavirenz is extensively metabolized in the liver and because of limited clinical experience, the drug is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C).1,360

Renal Impairment

The manufacturer makes no specific dosage recommendations for patients with renal impairment.1,360

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients, but recommends cautious dosage selection because of possible age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1,360

Contraindications

• Clinically important hypersensitivity reaction (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic skin eruption) to efavirenz or any other ingredient in the formulation.1,360
• Concomitant use with elbasvir and grazoprevir.1,360

Warnings/Precautions

Drug Interactions

Plasma concentrations of efavirenz may be altered if used concomitantly with drugs that are substrates, inhibitors, or inducers of cytochrome P-450 (CYP) 3A.1,360

Efavirenz induces CYP3A and 2B6 and may alter plasma concentrations of drugs metabolized by these enzymes.1,360

QT Prolongation

Prolongation of the QT interval corrected for rate (QTc) has been reported in patients receiving efavirenz, including in patients with the poor metabolizer genotype.1,360,361

Because QTc interval prolongation has been reported with efavirenz, an alternative antiretroviral should be considered in patients at higher risk of torsades de pointes and in patients receiving a drug known to increase the risk of torsades de pointes.1,360

Resistance

Efavirenz must be used in conjunction with other antiretrovirals, and should not be added as a single agent to a failing antiretroviral regimen.1,360 When efavirenz is used as monotherapy, viral resistance evolves rapidly.1,360 When choosing antiretroviral agents to be used in conjunction with efavirenz, the potential for viral cross-resistance should be considered.1,360

Psychiatric Symptoms

Serious adverse psychiatric symptoms have been reported rarely in patients receiving efavirenz.1,360 Severe depression (2.4%), suicidal ideation (0.7%), nonfatal suicide attempts (0.5%), aggressive behavior (0.4%), paranoid reactions (0.4%), or manic reactions (0.2%) have been reported in patients receiving efavirenz in controlled clinical studies; these psychiatric symptoms were reported in up to 0.9% of those in the control groups not receiving the drug.1,360 Analysis of data from clinical studies indicates that treatment with efavirenz is associated with an increased occurrence of these psychiatric symptoms.1,360 Other factors associated with an increased occurrence of these psychiatric symptoms were a history of drug use (injection), history of psychiatric disorders, and treatment with an antipsychotic drug at study entry.1,360 Although a causal relationship with efavirenz has not been established, there have been occasional postmarketing reports of delusions, psychosis-like behavior, catatonia, and death by suicide in patients receiving efavirenz.1,360

Patients should be advised to immediately seek medical evaluation if they experience severe psychiatric symptoms while receiving the drug.1,360 If it appears that the psychiatric symptoms may possibly be related to use of efavirenz, a determination should be made whether the drug should be discontinued after weighing the risks and benefits of continued therapy.1,360

Nervous System Symptoms

About 53% of adults receiving efavirenz in controlled clinical studies reported adverse CNS effects such as dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, and hallucinations; these adverse effects were reported in 25% of adults in the control groups not receiving efavirenz.1,360 These effects were described as severe (interrupt usual daily activities) in 2% of patients receiving efavirenz and required discontinuance of the drug in 2.1%.1,360 Dizziness was reported in 28.1% and insomnia was reported in 16.3% of patients receiving the drug.1,360 Impaired concentration, somnolence, or abnormal dreams were reported in 6.2-8.3% and hallucinations were reported in 1.2% of patients.1,360 These adverse effects generally begin during the first 1-2 days of efavirenz therapy and usually resolve after the first 2-4 weeks of therapy.1,360 After 4 weeks of efavirenz therapy, the incidence of moderate or severe adverse CNS effects ranged from 5-9% in adults receiving efavirenz and 3-5% in those in the control groups not receiving the drug.1,360 Adverse CNS effects may be more tolerable if the daily dose of efavirenz is administered at bedtime.1,360

Late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium) may occur months to years after beginning efavirenz therapy.1,360 Some late-onset neurotoxicity events have occurred in patients with CYP2B6 genetic polymorphisms, which are associated with increased efavirenz levels.1,360

Patients should be informed that adverse CNS effects may occur during the first few weeks of efavirenz therapy and that the drug may impair their ability to perform hazardous activities requiring mental alertness or physical coordination such as operating machinery or driving a motor vehicle.1,360 In addition, patients receiving efavirenz should be informed that there is a potential for additive CNS effects if they use efavirenz concomitantly with psychoactive drugs or alcohol.1,360 Prompt evaluation of patients who present with serious neurologic adverse experiences is recommended to assess whether the events are related to efavirenz and whether the drug should be discontinued.1,360

Fetal/Neonatal Morbidity and Mortality

Efavirenz may cause fetal harm if administered during pregnancy.1,360 Retrospective case reports have described neural tube defects in infants whose mothers were exposed to efavirenz during the first trimester of pregnancy.1,360 Although prospective data in humans are inadequate to assess risks and a causal relationship between efavirenz exposure in the first trimester and neural tube defects has not been established, similar malformations have been observed in animal studies.1,360

Because efavirenz may cause fetal harm if administered during the first trimester of pregnancy, females of childbearing potential should undergo pregnancy testing before efavirenz is initiated; effective contraception should be used during therapy and for 12 weeks after therapy is discontinued.1,360 If a patient becomes pregnant during efavirenz therapy, the patient should be apprised of the potential risk to a fetus.1,360

Rash

Rash has been reported in 26% of adults receiving efavirenz in clinical studies and in 17% of adults in control groups not receiving the drug.1,360 Most reported cases were mild to moderate in severity and occurred within the first 2 weeks of treatment (median time to onset, 11 days); in most patients who continued efavirenz therapy, rash resolved within 1 month (median duration, 16 days).360 The incidence of grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in adult patients receiving efavirenz in clinical studies or in the expanded access program has been reported to be 0.1%.1,360

Rash occurs more frequently in pediatric patients than adults, with a reported incidence of 32% in pediatric clinical studies in 182 HIV-infected pediatric patients.1,360 Grade 3 rash occurred in 2 patients, and grade 4 rash (erythema multiforme) occurred in 4 patients.1,360 Median time to onset of rash was 28 days in this patient population (range, 3-1642 days).360

Therapy with efavirenz can generally be reinitiated in patients who temporarily interrupted therapy with the drug because of development of a rash.1,360 Efavirenz should be discontinued in patients who experience serious rash (i.e., rash associated with blistering, desquamation, mucosal involvement, or fever).360 Antihistamines and/or corticosteroids may improve tolerability and hasten resolution of rash.1,360 The manufacturer states that prophylaxis with antihistamines prior to initiation of efavirenz in children should be considered.1,360 Efavirenz should be discontinued in patients with life-threatening cutaneous reactions (e.g., Stevens-Johnson syndrome) and alternative therapy considered.1,360

Hepatotoxicity

There have been postmarketing reports of hepatic failure and hepatitis in patients receiving efavirenz.1,360 A few cases of hepatic failure were characterized by a fulminant course and required transplantation or resulted in death.1,360 Hepatotoxicity has been reported in patients with or without pre-existing hepatic disease or identifiable risk factors.360

Efavirenz can be used with caution and careful monitoring in patients with mild hepatic impairment without any dosage adjustments; however, the drug is not recommended in patients with moderate or severe hepatic impairment since data are insufficient to determine whether dosage adjustments are necessary.1,360

Serum liver enzyme concentrations should be assessed prior to and during efavirenz treatment in all patients.1,360 In patients with persistent serum hepatic enzyme concentrations >5 times the ULN, consider discontinuing efavirenz.1,360 Efavirenz therapy should be discontinued if elevations in serum hepatic enzyme concentrations develop with clinical signs or symptoms of hepatitis or hepatic decompensation.1,360

Convulsions

Convulsions have occurred in patients receiving efavirenz, generally in those with a history of seizures.1,360 Caution is advised if the drug is used in patients with a history of seizures.1,360 In patients receiving anticonvulsants that are metabolized principally by the liver (e.g., phenytoin, phenobarbital), anticonvulsant plasma concentrations should be monitored periodically.1,360

Lipid Elevations

Treatment with efavirenz has resulted in increased serum concentrations of total cholesterol and triglycerides.1,360 Assess serum cholesterol and triglyceride levels prior to initiating efavirenz therapy and monitor periodically during treatment.1,360

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients receiving multiple-drug antiretroviral therapy, including efavirenz.1,360 During the initial phase of therapy, patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]); this may necessitate further evaluation and treatment.1,360

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome, autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1,360

Fat Redistribution

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been reported in patients receiving antiretroviral therapy.1,360 The mechanisms and long-term consequences of these adipogenic effects are unknown.1,360 A causal relationship has not been established.1,360

Pharmacogenomics

Efavirenz is primarily metabolized by CYP2B6.361 Poor CYP2B6 metabolizers may be at an increased risk for adverse effects with efavirenz, including CNS toxicity, hepatic injury, and QTc intervalprolongation.1,360,361 Genetic variants associated with poor CYP2B6 metabolic function (particularly CYP2B6 c.516G>T and c.983T>C) have been linked to decreased efavirenz clearance and increased risk for efavirenz toxicity and/or treatment discontinuation.361 The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides recommendations for efavirenz dosing guided by CYP2B6 phenotype.361 Dosage adjustments are recommended for adults and pediatric patients weighing ≥40 kg who are poor or intermediate CYP2B6 metabolizers.361 (See Pharmacogenetic Testing under Dosage and Administration: Administration.) Consult the CPIC guideline for more details and definitions of CYP2B6 phenotypes based on genotype.361

Use of Fixed Combinations

When preparations containing efavirenz in fixed combination with other drugs (e.g., efavirenz, emtricitabine, and tenofovir disoproxil fumarate [tenofovir DF; e.g., Atripla^®]; efavirenz, lamivudine, and tenofovir DF [e.g., Symfi^® and Symfi Lo^®]) are used, the cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination must be considered; consult the full prescribing information of each fixed combination preparation for specific information.232,351,357

Specific Populations

Pregnancy

Efavirenz may cause fetal harm if administered during the first trimester of pregnancy.1,360 There are retrospective case reports of neural tube defects in infants born to mothers who were exposed to efavirenz during the first trimester of pregnancy.1,360 Although prospective data in humans are inadequate to assess risks and a causal relationship between efavirenz exposure in the first trimester and neural tube defects has not been established, similar malformations have been observed in animal studies.1,360 The manufacturer states that efavirenz should not be used during the first trimester of pregnancy.1,360

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to antiretroviral agents, including efavirenz, during pregnancy.1,202,360 Clinicians are encouraged to contact the registry at 800-258-4263 or [Web] to report cases of prenatal exposure to antiretroviral agents.1,360

Based on prospective reports from the APR of approximately 1000 live births following exposure to efavirenz (including more than 800 live births following first-trimester exposures), there was no difference between overall birth defects with efavirenz compared with the background birth defect rate (2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program).1,360 An interim report issued in December 2014 that used data from the registry indicated that the prevalence of birth defects was 2.3% following first-trimester exposures to efavirenz.1,360 Defects reported prospectively in first-trimester exposures included 1 case of neural tube defect and 1 case of anophthalmia with severe oblique facial clefts and amniotic banding.1,360

Females of reproductive potential should be advised about the teratogenic potential of efavirenz.1,360 Such patients should undergo pregnancy testing before initiation of therapy.1,360 If efavirenz is used during the first trimester, or if pregnancy occurs during therapy, the patient should be apprised of the potential risk to the fetus.1,360

Lactation

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding.202 The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding.202 During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant.202 Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk.202 Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.202

Females and Males of Reproductive Potential

Females of reproductive potential should undergo pregnancy testing prior to initiation of efavirenz and use effective contraception while receiving efavirenz and for 12 weeks after the drug is discontinued.1,360 Hormonal contraceptives containing progesterone may have decreased effectiveness when used concomitantly with efavirenz; barrier contraception should always be used in combination with other methods.1,360

Pediatric Use

Safety and efficacy of single-entity efavirenz have not been established in neonates and infants <3 months of age or in those weighing <3.5 kg, and the drug should not be used in these pediatric patients.1,360

Adverse effects reported in pediatric patients 3 months to 21 years of age receiving efavirenz are similar to those reported in adults receiving the drug.1,360 Rash has been reported more frequently in children than adults, and the incidence of grade 3 or 4 rash has been greater in children than adults.1,360 Because of the high incidence of dermatologic reactions in children, antihistamines should be considered for the prevention of rash when initiating efavirenz in children.1,360

Geriatric Use

Clinical studies of efavirenz have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric individuals respond differently to the drug than younger adults.1,360 Dosage selection in elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, and/or cardiac function and the potential for concomitant disease and drug therapy.1,360

Hepatic Impairment

Pharmacokinetics of efavirenz are not affected by mild hepatic impairment (Child-Pugh class A); data are insufficient to determine whether moderate or severe hepatic impairment (Child-Pugh class B or C) affects pharmacokinetics of the drug.1,360

Because efavirenz is extensively metabolized in the liver and because of limited clinical experience, the drug is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C).1,360 Efavirenz can be used with caution and careful monitoring in patients with mild hepatic impairment.1,360

Renal Impairment

While the pharmacokinetics of efavirenz have not been specifically studied in patients with renal impairment, renal clearance of the drug is negligible and clinically important decreases in efavirenz clearance are not anticipated if efavirenz is administered to patients with renal impairment.1,360

Common Adverse Effects

Moderate to severe adverse effects occurring in >5% of patients receiving efavirenz include impaired concentration, abnormal dreams, rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting.1,360

Efavirenz is a substrate of cytochrome P-450 (CYP) 3A and CYP2B6.1 Efavirenz has been shown to induce CYP3A and 2B6 in vivo; in vitro studies have shown that efavirenz is also an inhibitor of CYP2C9 and 2C19.1 Efavirenz did not inhibit CYP2E1 in vitro, and did not inhibit CYP2D6 or 1A2 at clinically relevant concentrations.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Metabolism of efavirenz is mediated principally by CYP isoenzymes 3A and 2B6, and drugs that induce these isoenzymes are expected to reduce efavirenz plasma concentrations.1,360 Efavirenz has been shown to induce CYP enzymes resulting in induction of its own metabolism.1,360 Efavirenz induces CYP3A and 2B6, and may alter plasma concentrations of drugs metabolized by these enzymes.1,360

In vitro, efavirenz inhibits CYP isoenzymes 2C9 and 2C19 at clinically important concentrations, and the possibility exists that efavirenz may alter the pharmacokinetics of drugs metabolized by these isoenzymes.1,360

Drugs Associated with QT Prolongation

Although limited information is available on the potential for a pharmacodynamic interaction between efavirenz and drugs that prolong the QT interval, QTc prolongation has been observed with the use of efavirenz.1,360 Consider alternatives to efavirenz in patients who require therapy with another drug that has a known risk of torsades de pointes.1,360

Alcohol

Concomitant administration of efavirenz with alcohol may result in increased CNS effects.1,360

Anticonvulsants

Concomitant use of efavirenz and carbamazepine results in decreased plasma concentrations and AUCs of efavirenz and carbamazepine.1,360 Concomitant use of efavirenz and phenobarbital or phenytoin may result in decreased plasma concentrations of the anticonvulsant and/or efavirenz.1,360

The manufacturer of efavirenz states that data are insufficient to make dosage recommendations for concomitant use of efavirenz and carbamazepine.1,360 If possible, use of another anticonvulsant should be considered.1,360 If phenobarbital or phenytoin is used concomitantly with efavirenz, plasma concentrations of the anticonvulsant should be monitored.1,360

Antifungal Agents

Fluconazole

Concomitant use of fluconazole (200 mg daily) and efavirenz (400 mg daily) for 7 days in healthy individuals did not result in clinically important changes in the pharmacokinetics of either drug, and dosage adjustments are not necessary in patients receiving the drugs concomitantly.1,360

Itraconazole

Concomitant use of itraconazole (200 mg every 12 hours for 28 days) and efavirenz (600 mg once daily for 14 days) reduced peak plasma concentrations of itraconazole by 37% and the area under the plasma concentration-time curve (AUC) by 39%; there was no change in the peak plasma concentration or AUC of efavirenz.1,360

The manufacturer of efavirenz states that dosage recommendations for concomitant use of efavirenz and itraconazole are not available, and an alternative antifungal should be considered.1,360

Ketoconazole

Although specific drug interaction studies with efavirenz and ketoconazole have not been performed to date, the possibility exists that efavirenz may decrease plasma concentrations of this antifungal.1,360 Consider alternative antifungal treatment, as no dosage recommendations for concomitant use of efavirenz and ketoconazole are available.360

Posaconazole

Concomitant use of posaconazole (400 mg twice daily) and efavirenz (400 mg once daily) for 10 and 20 days reduces peak plasma concentrations and AUC of posaconazole by 45 and 50%, respectively.1,360

Concomitant use of posaconazole and efavirenz should be avoided unless potential benefits outweigh risks.1,360

Voriconazole

Concomitant use of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) and efavirenz (400 mg once daily for 9 days) reduced peak plasma concentrations and AUC of voriconazole by 61 and 77%, respectively, and increased peak plasma concentrations and AUC of efavirenz by 38 and 44%, respectively.1,360

If efavirenz and voriconazole are used concomitantly, the maintenance dosage of voriconazole should be increased to 400 mg every 12 hours and the efavirenz dosage should be reduced to 300 mg once daily.1,360 The 300-mg dose of efavirenz should be administered using the capsule preparations; the 600-mg tablet should not be broken in half in order to provide a 300-mg dose.1,360 Usual dosage of voriconazole and usual dosage of efavirenz should not be used concomitantly.1,360

Antimalarial Agents

Artemether and Lumefantrine

Concomitant use of the fixed combination of artemether and lumefantrine (artemether/lumefantrine) and efavirenz decreases plasma concentrations and AUC of artemether and the active metabolite of artemether (dihydroartemisinin) and decreases the AUC of lumefantrine.1,360

Because of the risk of QT interval prolongation, the manufacturer of efavirenz states that alternatives to artemether/lumefantrine should be considered in patients receiving efavirenz.1,360

Atovaquone and Proguanil

Concomitant use of efavirenz and the fixed combination of atovaquone and proguanil (atovaquone/proguanil) is predicted to decrease the AUC of atovaquone and proguanil.1,360

Concomitant use of atovaquone/proguanil and efavirenz is not recommended.1,360

Antimycobacterial Agents

Rifabutin

Concomitant use of efavirenz and rifabutin has resulted in decreased plasma concentration of rifabutin and 25- O -desacetylrifabutin (an active metabolite).1,360 In a limited number of healthy individuals, concomitant use of rifabutin (300 mg once daily) and efavirenz (600 mg once daily) for 14 days reduced the peak plasma rifabutin concentration by 32% and the AUC of the drug by 38%; there was no change in the peak plasma concentration or AUC of efavirenz.1,360

Because of this pharmacokinetic interaction, the manufacturer of efavirenz recommends that rifabutin dosage be increased by 50% and that doubling of rifabutin daily dosage be considered when the antimycobacterial agent is given 2 or 3 times weekly.1,360

Rifampin

Concomitant use of efavirenz and rifampin has resulted in decreased plasma efavirenz concentrations and AUC.1,360 In a limited number of healthy individuals, concomitant use of rifampin (600 mg daily) and efavirenz (600 mg daily) for 7 days reduced peak plasma efavirenz concentrations by 20% and the AUC of the drug by 26%.1,360

If efavirenz is used in conjunction with rifampin in patients weighing 50 kg or more, the manufacturer of efavirenz recommends that efavirenz dosage be increased to 800 mg once daily.1,360

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Maraviroc

Concomitant use of maraviroc (100 mg twice daily) and efavirenz (600 mg daily) reduced peak plasma concentrations of maraviroc by 51% and AUC by 45%.1,360

Refer to the maraviroc prescribing information for recommendations on concomitant use with efavirenz.1,360

HIV Integrase Inhibitors (INSTIs)

Raltegravir

Concomitant use of raltegravir and efavirenz results in decreased plasma concentrations and AUC of raltegravir.1,360 Dosage adjustments are not necessary if raltegravir is used concomitantly with efavirenz.1,360

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Concomitant use of efavirenz and other NNRTIs is not recommended.1,360

Results of in vitro studies indicate that the antiretroviral effects of efavirenz and some NNRTIs (nevirapine) are additive against HIV-1.1,360

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Results of in vitro studies using some NRTIs (e.g., abacavir, emtricitabine, lamivudine, tenofovir, zidovudine) indicate that the antiretroviral effects of efavirenz and these drugs are additive against HIV-1.1,360

Concomitant use of efavirenz (600 mg once daily for 14 days) and zidovudine (300 mg every 12 hours for 14 days) or lamivudine (150 mg every 12 hours for 14 days) does not affect plasma concentrations or AUCs of the NRTIs.1,360 Concomitant use of tenofovir DF and efavirenz does not affect plasma concentrations or AUCs of either drug.1,360 Clinically important pharmacokinetic interactions between efavirenz and other NRTIs (abacavir, emtricitabine, tenofovir DF) are not expected.1,360

Dosage adjustments are not necessary if efavirenz is used concomitantly with abacavir, emtricitabine, lamivudine, tenofovir DF, or zidovudine.1,360

HIV Protease Inhibitors (PIs)

Clinically important pharmacokinetic interactions may occur when efavirenz is used with some PIs.1,360

Results of in vitro studies indicate that the antiretroviral effects of efavirenz and some PIs (lopinavir, nelfinavir, ritonavir) are additive against HIV-1.1,360 In vitro studies indicate that efavirenz exhibits additive to antagonistic antiretroviral activity with atazanavir.1,360

Atazanavir

Concomitant use of unboosted atazanavir and efavirenz reduced peak plasma concentrations of atazanavir by 59% and the AUC of the drug by 74%.1,360 Depending on the specific regimen used, concomitant use of ritonavir-boosted atazanavir and efavirenz may increase atazanavir plasma concentrations and AUC.1,360

If ritonavir-boosted atazanavir is used concomitantly with efavirenz in antiretroviral-naïve adults, a regimen of atazanavir 400 mg and ritonavir 100 mg once daily (with food) and efavirenz 600 mg once daily (without food, preferably at bedtime) is recommended.1,360 Ritonavir-boosted atazanavir should not be used concomitantly with efavirenz in antiretroviral-experienced patients.1,360

Fosamprenavir

Concomitant use of efavirenz and fosamprenavir (without low-dose ritonavir) results in substantially decreased concentrations of amprenavir (the active metabolite of fosamprenavir).1,360 Appropriate dosages for concomitant use of fosamprenavir (without low-dose ritonavir) and efavirenz with respect to safety and efficacy have not been established.1,360

If a once-daily regimen of ritonavir-boosted fosamprenavir is used in patients receiving efavirenz, ritonavir dosage should be increased to 300 mg once daily; if a twice-daily regimen of ritonavir-boosted fosamprenavir is used in patients receiving efavirenz, ritonavir dosage should not be adjusted.1,360

Lopinavir

Concomitant use of efavirenz (600 mg once daily) and the fixed combination containing lopinavir and ritonavir (lopinavir/ritonavir; 400 mg of lopinavir and 100 mg of ritonavir administered as capsules [no longer commercially available in the US] twice daily) for 9 days resulted in decreased trough plasma concentrations and AUCs of both lopinavir and efavirenz.1,360 Concomitant use of efavirenz (600 mg once daily) and lopinavir/ritonavir (600 mg of lopinavir and 150 mg of ritonavir administered as tablets twice daily) for 9 days results in an increased lopinavir peak plasma concentrations and AUC.1,360

A once-daily regimen of lopinavir/ritonavir should not be used in patients receiving efavirenz.1,360

If a twice-daily regimen of lopinavir/ritonavir is used in adult or pediatric patients receiving efavirenz, an increased lopinavir/ritonavir dosage is recommended.1,360 Refer to the lopinavir/ritonavir prescribing information for dosage recommendations when efavirenz is used concomitantly in pediatric and adult patients.1,360

Nelfinavir

Concomitant use of nelfinavir (750 mg every 8 hours) and efavirenz (600 mg daily) for 7 days increased the peak plasma concentration and AUC of nelfinavir by 21 and 20%, respectively, and decreased the peak plasma concentration and AUC of efavirenz by 12%.1,360

Dosage adjustments are not necessary if nelfinavir is used concomitantly with efavirenz.1,360

Ritonavir

Concomitant use of ritonavir (500 mg every 12 hours for 8 days) and efavirenz (600 mg daily for 10 days) increased the AUC of each drug by about 20%.1,360 If ritonavir is used concomitantly with efavirenz, serum hepatic enzymes should be monitored and the patient should be monitored for adverse effects (e.g., dizziness, nausea, paresthesia).1,360

Bupropion

Concomitant use of bupropion and efavirenz decreases peak plasma concentrations and AUC of bupropion and increases peak plasma concentrations of hydroxybupropion (an active metabolite).1,360

In patients receiving efavirenz, bupropion dosage should be titrated based on clinical response, but should not exceed the maximum recommended bupropion dosage.1,360

Cardiovascular Agents

Antilipemic Agents

Concomitant use of efavirenz and certain hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins), including atorvastatin, pravastatin, and simvastatin, results in decreased plasma concentrations of the antilipemic agent, but does not have a clinically important effect on efavirenz concentrations.1,360

Consult the prescribing information for the HMG-CoA reductase inhibitor for dosage recommendations when used with efavirenz.1,360

Calcium-channel Blocking Agents

Concomitant use of diltiazem and efavirenz results in decreased concentrations of diltiazem and slightly increased concentrations of efavirenz.1,360 If diltiazem is used concomitantly with efavirenz, dosage of the calcium-channel blocking agent should be titrated based on clinical response; dosage of efavirenz or efavirenz/emtricitabine/tenofovir DF does not need to be adjusted.1,360

Concomitant use of other calcium-channel blocking agents (e.g., felodipine, nicardipine, nifedipine, verapamil) is predicted to result in decreased concentrations of the calcium-channel blocking agent.1,360 If efavirenz is used concomitantly with any of these drugs, dosage of the calcium-channel blocking agent should be titrated based on clinical response.1,360

Cetirizine

Administration of cetirizine (10 mg as a single dose) and efavirenz (600 mg daily for 10 days) decreased the peak plasma concentration of cetirizine by 24% but had no substantial effect on the AUC of efavirenz.1,360 The manufacturer of efavirenz states that dosage adjustments are not necessary in patients receiving concomitant cetirizine.1,360

Drugs Affecting Gastric Acidity

Systemic availability of efavirenz is not affected by concomitant use with an aluminum/magnesium hydroxide antacid or a histamine H₂-receptor antagonist (e.g., famotidine).1,360 Concomitant use of efavirenz and an antacid preparation containing aluminum hydroxide 400 mg, magnesium hydroxide 400 mg, and simethicone 40 mg/30 mL dose in healthy individuals did not alter the absorption of efavirenz.1,360 Dosage adjustments are not needed if efavirenz is used concomitantly with famotidine or aluminum/magnesium hydroxide antacids.1,360

Estrogens and Progestins

Concomitant use of efavirenz (600 mg once daily for 14 days) and an oral contraceptive containing 0.035 mg of ethinyl estradiol and 0.25 mg of norgestimate did not affect peak plasma concentrations or AUC of ethinyl estradiol, but resulted in substantially decreased peak plasma concentrations and AUC of norelgestromin and levonorgestrel (metabolites of norgestimate).1,360

Concomitant use of efavirenz and etonogestrel subcutaneous implant has not been studied, but decreased etonogestrel concentrations are expected.1,360 There have been postmarketing reports of subcutaneous implant contraceptive failure in women receiving efavirenz.1,360

Females of reproductive potential should use a reliable method of barrier contraception in addition to a hormonal contraceptive (e.g., oral or other hormonal contraceptive) during and for 12 weeks after efavirenz is discontinued.1,360

HCV Antivirals

HCV Polymerase Inhibitors

Sofosbuvir and Velpatasvir

Concomitant use of the fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) and efavirenz results in decreased velpatasvir plasma concentrations and may result in loss of sofosbuvir/velpatasvir therapeutic effects.1,360

Concomitant use of sofosbuvir/velpatasvir and efavirenz is not recommended.1,360

Sofosbuvir, Velpatasvir, and Voxilaprevir

Concomitant use of the fixed combination of sofosbuvir, velpatasvir and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir) and efavirenz results in decreased velpatasvir and voxilaprevir plasma concentrations and may result in loss of sofosbuvir/velpatasvir/voxilaprevir therapeutic effects.1,360

Concomitant use of sofosbuvir/velpatasvir/voxilaprevir and efavirenz is not recommended.1,360

HCV Replication Complex Inhibitors

Elbasvir and Grazoprevir

Concomitant use of efavirenz and the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir) results in substantially decreased elbasvir and grazoprevir concentrations, which may lead to loss of virologic response to the HCV antiviral.1,360

Concomitant use of elbasvir/grazoprevir and efavirenz is contraindicated.1,360

Glecaprevir and Pibrentasvir

Concomitant use of efavirenz and the fixed combination of glecaprevir and pibrentasvir (glecaprevir/pibrentsavir) results in substantially decreased glecaprevir and pibrentasvir concentrations, which may lead to loss of virologic response to the HCV antiviral.1,360

Concomitant use of glecaprevir/pibrentasvir and efavirenz is not recommended.1,360

Immunosuppressive Agents

Concomitant use of efavirenz and immunosuppressive agents metabolized by CYP3A (e.g., cyclosporine, sirolimus, tacrolimus) may result in decreased concentrations of the immunosuppressive agent, but is not expected to affect efavirenz concentrations.1,360

If efavirenz is used concomitantly with an immunosuppressive agent metabolized by CYP3A , dosage of the immunosuppressive agent may need to be adjusted.1,360 When efavirenz is initiated or discontinued, plasma concentrations of the immunosuppressive agent should be monitored for at least 2 weeks until stable concentrations are reached.1,360

Lorazepam

Administration of lorazepam (2 mg as a single dose) and efavirenz (600 mg daily for 10 days) increased the peak plasma concentration of lorazepam by 16%, but did not affect the AUC of the drug.1,360 Dosage adjustments are not necessary in patients receiving lorazepam and efavirenz concomitantly.1,360

Macrolide Antibiotics

Because of the risk of QT interval prolongation, the manufacturer of efavirenz states that alternatives to macrolide antibiotics should be considered in patients receiving efavirenz.1,360

Administration of azithromycin (600 mg as a single dose) and efavirenz (400 mg daily for 7 days) in healthy individuals did not result in clinically important changes in the pharmacokinetics of either drug, and the manufacturer of efavirenz states that dosage adjustments are not necessary in patients receiving the drugs concurrently.1,360

Administration of clarithromycin (500 mg every 12 hours) and efavirenz (400 mg daily) for 7 days in healthy individuals decreased the peak plasma concentration and AUC of clarithromycin by 26 and 39%, respectively, and increased the peak plasma concentration and AUC of 14-hydroxyclarithromycin by 49 and 34%, respectively.1,360

Methadone

Administration of methadone at stable maintenance doses of 35-100 mg daily and efavirenz (600 mg daily for 14-21 days) decreased the peak plasma concentration and AUC of methadone by 45 and 52%, respectively.1,360

Individuals receiving concurrent efavirenz and methadone therapy should be closely monitored for signs of opiate withdrawal; an increase in the maintenance dosage of methadone may be necessary in such individuals.1,360

Praziquantel

Coadministration of praziquantel with efavirenz is not recommended because efavirenz increases the metabolism of praziquantel, resulting in a significant decrease in plasma praziquantel concentrations with a risk of treatment failure.1,360

Psychotherapeutic Agents

Administration of efavirenz in patients receiving psychoactive drugs may result in increased CNS effects.1,360

Selective Serotonin Reuptake Inhibitors

Concomitant use of paroxetine and efavirenz does not result in clinically important drug interactions; dosage adjustments are not needed.1,360

Concomitant use of sertraline and efavirenz results in decreased plasma concentrations and AUC of sertraline.1,360 Sertraline dosage adjustments should be guided by clinical response.1,360

Tests for Cannabinoids

False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected subjects receiving efavirenz.1,360 The manufacturer recommends confirming positive screening tests for cannabinoids by a more specific method.1,360

Warfarin

Concomitant use of efavirenz and warfarin is predicted to alter plasma warfarin concentrations resulting in increased or decreased effects of the anticoagulant.1,360 The international normalized ratio (INR) should be monitored in patients receiving efavirenz and warfarin concomitantly and warfarin dosage adjusted accordingly.1,360

Description

Although the complete mechanism(s) of antiviral activity of efavirenz has not been fully elucidated, the drug inhibits human immunodeficiency virus type 1 (HIV-1) by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.1,3,360 Efavirenz binds directly to HIV-1 reverse transcriptase and exerts a virustatic effect by acting as a specific, noncompetitive HIV-1 reverse transcriptase inhibitor.1,3,11,12

Efavirenz is a highly specific inhibitor of HIV-1 reverse transcriptase and does not appear to interfere with the activity of cellular DNA polymerases, including human α-, β-, γ-, or δ-polymerases.1,3

The pharmacokinetics of efavirenz have been studied in healthy individuals, adults with human immunodeficiency virus (HIV) infection, and HIV-infected children 3-16 years of age.1,2,24,25 The pharmacokinetics of efavirenz capsules (or capsule contents mixed with soft food or infant formula) in pediatric patients were predicted using a population pharmacokinetic model.1,360

Following oral administration of efavirenz 200, 400, or 600 mg once daily in HIV-infected adults, mean peak plasma concentration, mean trough plasma concentration, and AUC of the drug at steady-state were dose proportional.1,360 In HIV-infected adults receiving efavirenz 200, 400, or 600 mg once daily, peak plasma concentrations of the drug generally occur in 3-5 hours and steady-state plasma concentrations are achieved in 6-10 days.1,360 Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism.1,360 Following continued administration of efavirenz, plasma concentrations are lower than expected from single-dose studies, presumably because of increased clearance of the drug.1,360 In one study in individuals receiving efavirenz 200-400 mg once daily for 10 days, plasma concentrations of the drug were 22-42% lower than those predicted from single-dose studies.1,360 Oral bioavailability of efavirenz may be affected by administration with food.1,360 Administration of a single 600-mg dose of efavirenz as capsules with a high-fat, high-calorie meal (894 kcal, 54 g fat, 54% of calories from fat) or a reduced-fat, normal-calorie meal (440 kcal, 2 g fat, 4% of calories from fat) increases peak plasma concentrations of the drug by 39 or 51%, respectively, and AUC by 22 or 17%, respectively, compared with administration in the fasting state.1,360 Administration of a single 600-mg dose of efavirenz as tablets with a high-fat, high-calorie meal (approximately 1000 kcal, 500-600 kcal from fat) increases peak plasma concentrations and AUC of the drug by 79 and 28%, respectively, compared with administration in the fasting state.360 Therefore, the manufacturer states that efavirenz should be administered on an empty stomach.1,360 In healthy adults who received a 600-mg efavirenz dose administered by opening 200-mg capsules and mixing the contents of 3 capsules with 2 teaspoonfuls of soft food (e.g., applesauce, grape jelly, yogurt) or infant formula, the AUC of efavirenz met bioequivalency criteria compared with intact capsules administered in the fasted state.1,360

Efavirenz is about 99.5-99.75% bound to plasma proteins, principally albumin.1,360 Efavirenz appears to induce its own metabolism.1,360 The terminal elimination half-life of efavirenz reported in single-dose studies is longer than that reported in multiple-dose studies and has averaged 52-76 hours after a single oral dose and 40-55 hours following administration of 200-400 mg daily for 10 days.1,360 In addition, following continued administration of efavirenz, plasma concentrations are lower than expected from single-dose studies, presumably because of increased clearance.1,360 The metabolic fate of efavirenz has not been fully determined, but the drug is metabolized in the liver.1,360 Efavirenz is principally metabolized by the cytochrome P-450 (CYP) isoenzymes 3A and 2B6 to several hydroxylated metabolites, which undergo subsequent glucuronidation.1,360 Efavirenz is excreted principally in the feces.1,360 Following oral administration of 400 mg of radiolabeled efavirenz on day 8, 14-34% of the dose was excreted in urine (nearly all in the form of metabolites), and 16-61% was excreted in feces (predominantly as unchanged drug).1,360 Because efavirenz is highly protein bound, it is unlikely that substantial amounts of the drug would be removed from the body by dialysis.1,360 Pharmacokinetic studies have not revealed gender- or race-related differences in the pharmacokinetics of efavirenz.1,360 Pharmacokinetics of efavirenz are not affected by mild hepatic impairment (Child-Pugh class A); data are insufficient to determine whether moderate or severe hepatic impairment (Child-Pugh class B or C) affects pharmacokinetics of the drug.1,360 The pharmacokinetics of efavirenz have not been specifically studied in patients with renal impairment.1,360

Spectrum

Efavirenz has a very limited spectrum of activity.1,3 The drug has in vitro virustatic activity against human immunodeficiency virus type 1 (HIV-1), but is inactive against HIV type 2 (HIV-2).1,3

The antiretroviral activity of efavirenz has been evaluated in vitro in various cell culture systems including lymphoblastoid cell lines, peripheral blood mononuclear cells, and macrophage/monocyte cultures.1,3 The precise relationship between in vitro susceptibility of HIV-1 to efavirenz and inhibition of in vivo replication of the virus or clinical response to therapy with the drug has not been determined.1,32,200

Resistance

Strains of HIV-1 with reduced susceptibility to efavirenz (i.e., greater than 380-fold increase in IC90 from baseline) have been produced in vitro by serial passage of the retrovirus in the presence of increasing concentrations of the drug.1,3,9,10 In addition, strains of HIV-1 resistant to efavirenz emerge rapidly if the drug is administered alone1,3,14,19 and also have been reported in patients receiving the drug in conjunction with other antiretroviral agents.1,3,9,14,18,19

Although the complete mechanism(s) of resistance or reduced susceptibility to efavirenz has not been fully determined to date, mutation of HIV reverse transcriptase appears to be the principal mechanism of resistance.1,3,9,10 Acquisition of a single mutation can result in resistance to efavirenz.1,3,9,10,18,19,32

Efavirenz-resistant variants isolated from patients receiving efavirenz in conjunction with other antiretrovirals (i.e., indinavir or zidovudine and lamivudine) in clinical trials have included K103N, V108I, Y188L, G190S, K103N/V108I, L100I/K103N, or K103N/G190S.1,9,18,19,32

Mutations at amino acid positions 98, 101, 106, and 225 also have been reported in patients who received efavirenz.1 The mutation at amino acid position 103 (i.e., K103N) is the most frequently observed change.1,3,9,14,18,19

Genotypic and/or phenotypic changes in HIV isolates have been monitored in patients receiving efavirenz in conjunction with other antiretrovirals (i.e., indinavir or zidovudine and lamivudine) in clinical studies.1,9,18,19 Nucleic acid sequencing of plasma virus from patients whose viral load rebounded while receiving efavirenz-containing regimens revealed the emergence of K103N reverse transcriptase-mutant viruses around the time of viral load rebound.9,18,19 Most patients subsequently developed variants that contained K103N in combination with additional linked mutations (i.e., L100I, V108I, P225H).1,9,18,19 Viral isolates with K103N, V108I, and/or Y188L mutations have a 20-fold or greater increase in efavirenz IC₅₀ compared with baseline.9

Strains of HIV-1 resistant to efavirenz may be cross-resistant to some other NNRTIs.1,3,9,10,18,32,50,200 The resistance profile of efavirenz overlaps that of some other NNRTIs (e.g., delavirdine, nevirapine).14,18 The K103N mutation has been observed with delavirdine, efavirenz, and nevirapine12,18 and can cause broad cross-resistance among the agents; high-level cross-resistance is seen when K103N is present in combination with certain other mutations.18,32

The potential for cross-resistance between efavirenz and nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zidovudine) is considered low because the drugs bind at different sites on reverse transcriptase and have different mechanisms of action.1,3,9,10,32 Because efavirenz and HIV protease inhibitors (e.g., amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir) have different enzyme targets, cross-resistance between efavirenz and these drugs is unlikely.1,32

Advice to Patients

• Detail critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1,360 Stress importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1,360
• Stress importance of using efavirenz in conjunction with other antiretrovirals—not for monotherapy.1,360
• Stress importance of taking efavirenz on an empty stomach, preferably at bedtime.1,360
• If patient is not able to swallow capsules or tablets, stress importance of patient or caregiver reading and carefully following instructions for mixing and administering capsule contents in small amount of soft food or infant formula.1
• If a dose is missed, patient should take the missed dose as soon as it is remembered, unless it is almost time for next dose.1,360 If a dose is missed, do not take a double dose to make up for missed dose.1,360
• Advise patients that adverse CNS effects (e.g., dizziness, insomnia, impaired concentration, drowsiness, abnormal dreams) are common during first weeks of efavirenz therapy.1,360 Taking the drug at bedtime may improve tolerability.1,360 Additive effects may occur if used with alcohol or psychoactive drugs.1,360 If CNS effects occur, avoid potentially hazardous tasks such as driving or operating machinery.1,360 Advise patients of risk of late-onset neurotoxicity, including ataxia and encephalopathy, which may occur months to years after beginning efavirenz therapy.1,360
• Advise patients that serious psychiatric symptoms (e.g., severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms) have occurred.1,360 Stress importance of informing clinician of any history of mental illness or substance abuse and seeking immediate medical evaluation if severe psychiatric symptoms occur.1,360
• Risk of rash.1,360 Since rash may be serious, stress importance of promptly contacting clinician if rash occurs.1,360
• Advise patients to watch for early warning signs of liver inflammation or failure (e.g., fatigue, weakness, lack of appetite, nausea and vomiting), as well as later signs (e.g., jaundice, confusion, abdominal swelling, discolored feces), and to consult their health care professional without delay if such symptoms occur.1,360
• Advise patients that redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1,360
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.1,360
• Stress importance of females using a reliable barrier method of contraception in addition to a hormonal contraceptive (oral or other hormonal contraceptive) during and for 12 weeks after efavirenz therapy.1,360
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1,360
• Advise patients of other important precautionary information.1,360

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Aurobindo Pharma USA, Inc. Efavirenz capsules prescribing information. East Windsor, NJ; 2023 Dec.

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