Efavirenz (Monograph)

Brand name: Sustiva
Drug class: HIV Nonnucleoside Reverse Transcriptase Inhibitors
- Reverse Transcriptase Inhibitors
VA class: AM800
Chemical name: (±)-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one
Molecular formula: C₁₄H₉ClF₃NO₂
CAS number: 154635-17-3

Efavirenz is also contained as an ingredient in the following combinations:
Efavirenz, Emtricitabine, and Tenofovir Disoproxil Fumarate

Medically reviewed by Drugs.com on May 6, 2024. Written by ASHP.

Introduction

Antiretroviral; HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).^{1 2 3 12 14}

Uses for Efavirenz

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients ≥3 months of age weighing ≥3.5 kg;^{1 2 10 11 12 200 201} usually used in conjunction with 2 NRTIs.¹

For initial treatment in antiretroviral-naive adults and adolescents, experts state that efavirenz in conjunction with tenofovir alafenamide and emtricitabine or efavirenz in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) are alternative NNRTI-based regimens.²⁰⁰ Efavirenz in conjunction with abacavir and lamivudine (or emtricitabine) is another NNRTI-based regimen option for initial treatment in adults and adolescents when recommended or alternative regimens cannot be used, but use only in those with baseline plasma HIV RNA levels <100,000 copies/mL who are human leukocyte antigen (HLA)-B*5701 negative.²⁰⁰

For initial treatment in antiretroviral-naive pediatric patients, experts state that efavirenz and 2 NRTIs is a preferred regimen for initial treatment in children ≥3 to <12 years of age and an alternative regimen for initial treatment in adolescents ≥12 years of age who are not sexually mature.²⁰¹ Efavirenz is not recommended for initial treatment in those 3 months to <3 years of age.²⁰¹

Usually avoid efavirenz in pregnant women during first trimester;¹ avoid in women of childbearing age who may become pregnant.^{1 202} (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Efavirenz/emtricitabine/tenofovir DF fixed combination (Atripla) can be used in adults, adolescents, and children ≥12 years of age weighing ≥40 kg to decrease pill burden and improve adherence;²³² used alone as a complete treatment regimen or used in conjunction with other antiretrovirals.²³²

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)

Postexposure prophylaxis of HIV infection following occupational exposure^{† [off-label]} (PEP) in health-care personnel and others 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.¹⁹⁹

USPHS recommends 3-drug regimen of raltegravir in conjunction with emtricitabine and tenofovir DF as the preferred regimen for PEP following occupational exposures to HIV.¹⁹⁹ Efavirenz and 2 NRTIs can be considered an alternative regimen, but use for PEP only with expert consultation.¹⁹⁹ Preferred dual NRTI option for PEP regimens is emtricitabine and tenofovir DF (may be given as emtricitabine/tenofovir DF; Truvada); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be given as lamivudine/zidovudine; Combivir), or zidovudine and emtricitabine.¹⁹⁹

Management of occupational exposures to HIV is complex and evolving; consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible.¹⁹⁹ Do not delay initiation of PEP while waiting for expert consultation.¹⁹⁹

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)

Postexposure prophylaxis of HIV infection following nonoccupational exposure^{† [off-label]} (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.¹⁹⁸ Used in conjunction with other antiretrovirals.¹⁹⁸

When nPEP indicated in adults and adolescents ≥13 years of age with normal renal function, CDC states preferred regimen is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (given as emtricitabine/tenofovir DF; Truvada);¹⁹⁸ recommended alternative in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada).¹⁹⁸

CDC states efavirenz is an alternative antiretroviral that can be used in nPEP regimens, but use in such regimens only with expert consultation.¹⁹⁸

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

Related/similar drugs

Biktarvy, Descovy, Truvada, tenofovir, emtricitabine, abacavir, Atripla

Efavirenz Dosage and Administration

Administration

Oral Administration

Administer efavirenz (Sustiva) or efavirenz/emtricitabine/tenofovir DF (Atripla) orally once daily on an empty stomach, preferably at bedtime.^{1 232}

Administration at bedtime may make adverse CNS effects (dizziness, insomnia, impaired concentration, somnolence, abnormal dreams) more tolerable.^{1 232}

Efavirenz (Sustiva): Use in conjunction with other antiretrovirals.¹

Efavirenz/emtricitabine/tenofovir DF (Atripla): Use alone as a complete treatment regimen or use in conjunction with other antiretrovirals.²³² Because antiretrovirals in the fixed combination also are available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated if used in conjunction with other antiretrovirals.²³² (See Use of Fixed Combinations under Cautions.)

Do not use single-entity efavirenz (Sustiva) and efavirenz/emtricitabine/tenofovir DF (Atripla) concomitantly, unless needed for adjustment of efavirenz dosage (e.g., when fixed combination used concomitantly with rifampin).^{1 232}

Capsules (Sustiva)

Swallow capsules whole on an empty stomach.¹

For adults and pediatric patients ≥3 months of age not able to swallow capsules or tablets, administer capsule contents by mixing with small amount (1–2 teaspoonfuls) of soft food (capsule sprinkle method).¹ Consider mixing with infant formula only if infant cannot consume solid foods.¹ Administer efavirenz mixture within 30 minutes after preparation; do not consume any additional food or infant formula for 2 hours after the mixture.¹

Mixing capsule contents into food: Add 1–2 teaspoonfuls of age-appropriate soft food (e.g., applesauce, grape jelly, yogurt) to a small container.¹ Hold appropriate number of capsules (see Table 1) horizontally over the small container, twist open, and empty onto the food.¹ Gently mix with a spoon; feed entire mixture to patient.¹ Then, add additional 2 teaspoonfuls of soft food to the small container, stir to disperse remaining efavirenz residue, and feed to patient.¹

Mixing capsule contents into infant formula: Add 10 mL (2 teaspoonfuls) of reconstituted room temperature infant formula to a 30-mL medicine cup.¹ Hold appropriate number of capsules (see Table 1) horizontally over the medicine cup, twist open, and empty onto the formula.¹ Gently mix with small spoon.¹ Draw up infant formula mixture into 10-mL oral dosing syringe; administer into infant's right or left inner cheek.¹ Then, add additional 2 teaspoonfuls of infant formula to the medicine cup, stir to disperse remaining efavirenz residue, draw up into oral dosing syringe, and administer to infant.¹

Tablets (Sustiva, Atripla)

Swallow tablets whole on an empty stomach; do not break or crush.¹

Dosage

Pediatric Patients

Treatment of HIV Infection

Oral

Efavirenz (Sustiva): Dosage in children ≥3 months of age weighing 3.5 to <40 kg is based on weight.¹ (See Table 1.) Adolescents and children weighing ≥40 kg may receive usual adult dosage.¹

Efavirenz/emtricitabine/tenofovir DF (Atripla) in children ≥12 years of age weighing ≥40 kg: 1 tablet (600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF) once daily.²³²

Adults

Treatment of HIV Infection

Oral

Efavirenz (Sustiva): 600 mg once daily.¹

Efavirenz/emtricitabine/tenofovir DF (Atripla): 1 tablet (efavirenz 600 mg, emtricitabine 200 mg, and tenofovir DF 300 mg) once daily.²³²

Treatment of HIV Infection in Patients Weighing ≥50 kg Receiving Rifampin

Oral

Efavirenz (Sustiva): 800 mg once daily.¹ (See Specific Drugs and Laboratory Tests under Interactions.)

Efavirenz/emtricitabine/tenofovir DF (Atripla): 1 tablet (efavirenz 600 mg, emtricitabine 200 mg, and tenofovir DF 300 mg) once daily and 200 mg of single-entity efavirenz (Sustiva) once daily to provide total efavirenz dosage of 800 mg daily.²³²

Postexposure Prophylaxis of HIV following Occupational Exposure† [off-label]

Oral

Efavirenz (Sustiva): 600 mg once daily.¹⁹⁹ Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).¹⁹⁹

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.¹⁹⁹

Special Populations

Hepatic Impairment

Treatment of HIV Infection

Efavirenz (Sustiva): Dosage adjustments not needed in patients with mild hepatic impairment;¹ do not use in those with moderate or severe hepatic impairment.¹ (See Hepatic Impairment under Cautions.)

Efavirenz/emtricitabine/tenofovir DF (Atripla): Use usual dosage in patients with mild hepatic impairment; however, caution advised.²³² Do not use in those with moderate or severe hepatic impairment.²³²

Renal Impairment

Treatment of HIV Infection

Efavirenz (Sustiva): Dosage adjustments not needed.²⁰⁰

Efavirenz/emtricitabine/tenofovir DF (Atripla): Use usual dosage in patients with Cl_cr ≥50 mL/minute;²³² do not use in those with Cl_cr <50 mL/minute.²³²

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.^{1 232}

Cautions for Efavirenz

Contraindications

• Efavirenz and efavirenz/emtricitabine/tenofovir DF: History of clinically important hypersensitivity reaction (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic skin eruption) to efavirenz or any ingredient in the formulation.^{1 232}

• Efavirenz/emtricitabine/tenofovir DF: Consider contraindications associated with each drug in the fixed combination.²³²

Warnings/Precautions

Interactions

Efavirenz plasma concentrations may be altered if CYP3A substrates, inhibitors, or inducers used concomitantly.¹ In addition, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A or 2B6.¹ (See Interactions.)

Psychiatric Symptoms

Serious adverse psychiatric symptoms (severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, paranoid reactions) reported rarely in efavirenz clinical studies.^{1 232}

Depression, anxiety, and nervousness also reported in clinical studies.¹ Although causal relationship not established, there have been occasional postmarketing reports of delusions, psychosis-like behavior, catatonia, and death by suicide in patients receiving efavirenz.¹ Aggressive reactions,¹ agitation,¹ emotional lability,¹ mania,¹ neurosis,¹ and paranoia¹ also reported during postmarketing surveillance.

Factors associated with increased occurrence of psychiatric symptoms include history of injection drug use, history of psychiatric disorders, and treatment with antipsychotic drugs at study entry.^{1 232}

If serious psychiatric adverse events occur, evaluate to determine if symptoms are related to efavirenz; if so, determine whether risks of continued efavirenz outweigh benefits.^{1 232}

Nervous System Effects

Dizziness or insomnia reported frequently; abnormal dreams, hallucinations, or impaired concentration also reported.¹ These adverse effects generally begin during first 1–2 days of therapy, improve with continued therapy, and usually resolve after first 2–4 weeks.¹

Seizures reported,¹ generally in those with a history of seizures.¹ Use with caution in patients with history of seizures.¹ Monitor anticonvulsant plasma concentrations if used in patients receiving anticonvulsants that are metabolized principally by the liver (e.g., phenytoin, phenobarbital).¹ (See Specific Drugs and Laboratory Tests under Interactions.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm if administered during first trimester of pregnancy.^{1 232} Teratogenicity demonstrated in animals.¹ Birth defects (including neural tube defects) reported in humans, usually with first-trimester exposure.¹ (See Pregnancy under Cautions.)

Advise women of childbearing potential about the teratogenic potential of efavirenz;^{1 232} perform test to rule out pregnancy before initiating efavirenz or fixed combination containing efavirenz.^{1 232}

Avoid pregnancy during therapy and for 12 weeks after discontinuance of efavirenz or fixed combination containing efavirenz.^{1 232} Women of childbearing potential should use a reliable method of barrier contraception in addition to or instead of a hormonal contraceptive (oral or other hormonal contraceptive).^{1 200 202 232} (See Specific Drugs and Laboratory Tests under Interactions.)

Dermatologic and Sensitivity Reactions

Rash (maculopapular skin eruptions) reported frequently.^{1 2} Pruritus; rash associated with blistering, moist desquamation, or ulceration; allergic reaction; photoallergic dermatitis; erythema multiforme; and Stevens-Johnson syndrome also reported.^{1 2}

Median time to rash onset 11 days in adults and 28 days in pediatric patients; median duration 16 days.¹ Mild to moderate rash generally resolves within 1 month with continued efavirenz.¹ May be reinitiated after temporary interruption for rash.¹ Antihistamines and/or corticosteroids may improve tolerability and hasten resolution of rash.¹

Discontinue in patients with life-threatening cutaneous reactions (e.g., Stevens-Johnson syndrome) and consider alternative therapy.^{1 232}

Discontinue in patients with serious rash (e.g., rash associated with blistering, desquamation, mucosal involvement, or fever).¹

Hepatotoxicity

Substantial increases in serum AST or ALT concentrations (>5 times ULN) reported in clinical studies in HIV-infected patients coinfected with HBV and/or HCV.¹

Hepatic failure and hepatitis reported, some with a fulminant course requiring transplantation or resulting in death.¹ Hepatic failure has occurred in some patients with no preexisting hepatic disease or other identifiable risk factors.¹

Use with caution in patients with hepatic impairment.^{1 232} (See Hepatic Impairment under Cautions.)

Assess serum liver enzyme concentrations prior to and during efavirenz treatment in patients with underlying hepatic disease (including those with HBV and/or HCV infection), patients with markedly increased serum transaminase concentrations, and patients receiving other drugs associated with liver toxicity.^{1 232}

Also consider monitoring serum liver enzymes in patients without preexisting hepatic dysfunction or other risk factors.^{1 232}

In patients with serum hepatic enzyme concentrations >5 times ULN, consider whether benefits of continued efavirenz therapy outweigh risks of hepatotoxicity.^{1 232}

Use of Fixed Combinations

Efavirenz/emtricitabine/tenofovir DF: Consider cautions, precautions, contraindications, and interactions associated with each drug in the fixed combination.²³² Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.²³²

Do not use efavirenz/emtricitabine/tenofovir DF concomitantly with single-entity efavirenz, unless needed for adjustment of efavirenz dosage (e.g., when fixed combination used concomitantly with rifampin).^{1 232} (See Specific Drugs and Laboratory Tests under Interactions.)

Because the antiretrovirals contained in efavirenz/emtricitabine/tenofovir DF also are available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated if the fixed combination is used in conjunction with other antiretrovirals.²³²

Do not use efavirenz/emtricitabine/tenofovir DF concomitantly with any preparation containing emtricitabine or tenofovir DF.²³² In addition, do not use concomitantly with any preparation containing lamivudine or with adefovir.²³²

Cardiovascular and Lipid Effects

Prolongation of QT interval corrected for rate (QT_c) reported.¹ Consider alternative antiretroviral in patients at increased risk of torsades de pointes and in those receiving a drug known to increase risk of torsades de pointes.¹ (See Interactions.)

Increased serum concentrations of total cholesterol and triglycerides reported.¹ Assess serum cholesterol and triglycerides prior to and periodically during therapy.¹

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance, reported in patients receiving antiretroviral therapy.¹

Mechanism and long-term consequences of fat redistribution unknown;¹ causal relationship not established.¹

Immune Reconstitution Syndrome

During initial treatment, HIV-infected patients who respond 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]);¹ this may necessitate further evaluation and treatment.¹

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

Specific Populations

Pregnancy

Efavirenz may cause fetal harm if administered during first trimester of pregnancy.^{1 232} There are retrospective case reports of neural tube defects in infants born to mothers with first trimester exposure to efavirenz,¹ but prospective pregnancy data not sufficient to adequately assess this risk.^{1 202}

Efavirenz/emtricitabine/tenofovir DF (Atripla): Category D.²³²

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].^{1 202}

Data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall birth defects for efavirenz compared with background rate for birth defects.¹

Women of childbearing potential should use effective contraceptive measures during therapy and for 12 weeks after discontinuance of efavirenz or efavirenz/emtricitabine/tenofovir DF.^{1 232} (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Manufacturer states avoid use during first trimester of pregnancy.¹

Experts state efavirenz in conjunction with 2 NRTIs is an alternative NNRTI-based regimen for initial treatment in antiretroviral-naive pregnant women,²⁰² but may be a preferred NNRTI-based regimen for initial treatment when drug interactions with PI-based regimens are a concern or when the convenience of a fixed-combination, single-tablet, once-daily regimen is advantageous.²⁰² However, these experts state efavirenz should be avoided during first 8 weeks of pregnancy.²⁰²

Experts also state that antiretroviral regimens that do not include efavirenz should be strongly considered in women who are planning to become pregnant or are sexually active and not using effective contraception, provided such regimens are acceptable to the provider and not expected to compromise the health of the woman.²⁰²

If a pregnant woman already receiving an efavirenz-containing regimen presents for antenatal care during first trimester, some experts suggest the regimen can be continued if well tolerated and providing adequate virologic suppression.²⁰² This strategy recognizes that risk of neural tube defects is limited to first 5–6 weeks of pregnancy and pregnancy rarely recognized until after 4–6 weeks and that unnecessary changes in antiretroviral regimens during pregnancy may be associated with loss of virologic control and increased risk of perinatal HIV transmission.²⁰²

If efavirenz or a fixed combination containing efavirenz is used during first trimester or if pregnancy occurs, apprise patient of potential harm to the fetus.^{1 232}

Lactation

Efavirenz distributed into human milk.²⁰²

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.^{1 202 232}

Pediatric Use

Efavirenz (Sustiva): Safety and efficacy not evaluated in neonates and infants <3 months of age or who weigh <3.5 kg;¹ not recommended in these pediatric patients.^{1 201} Some experts state efavirenz not recommended for initial treatment in antiretroviral-naive pediatric patients 3 months to <3 years of age.²⁰¹

Efavirenz/emtricitabine/tenofovir DF (Atripla): Safety and efficacy not established in pediatric patients <12 years of age or weighing <40 kg.²³²

Adverse effects reported with efavirenz in pediatric patients 3 months to 21 years of age are similar to those reported in adults with the exception of rash.¹ Rash reported more frequently in children than adults and the incidence of moderate to severe rash has been greater in children than adults.¹

Not recommended in sexually active adolescent females of childbearing potential who desire to become pregnant or when reliable contraception cannot be ensured.²⁰¹ (See Pregnancy under Cautions.)

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.^{1 232}

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.^{1 232}

Hepatic Impairment

Efavirenz (Sustiva): Use with caution in mild hepatic impairment;¹ do not use in moderate or severe hepatic impairment.¹

Efavirenz/emtricitabine/tenofovir DF (Atripla): Use with caution in mild hepatic impairment;²³² do not use in moderate or severe hepatic impairment.²³²

Monitor hepatic enzyme concentrations in patients with known or suspected HBV or HCV infection, patients with substantially increased transaminase concentrations, and in patients receiving other drugs associated with hepatotoxicity.¹ (See Hepatotoxicity under Cautions.)

Renal Impairment

Efavirenz (Sustiva): Pharmacokinetics not specifically studied; clinically important decreases in clearance not anticipated.¹ (See Renal Impairment under Dosage and Administration.)

Efavirenz/emtricitabine/tenofovir DF (Atripla): Do not use in those with Cl_cr <50 mL/minute.²³²

Common Adverse Effects

Rash, dizziness, nausea, headache, fatigue, insomnia, vomiting.¹

Drug Interactions

Metabolized by CYP3A and CYP2B6.¹

Inhibits CYP2C9 and CYP2C19 and, to a lesser extent, CYP2D6 and CYP1A2.¹ Does not inhibit CYP2E1.¹

Induces CYP3A and CYP2B6.¹

The following drug interactions are based on studies using efavirenz.¹ Drug interaction studies not performed using efavirenz/emtricitabine/tenofovir DF.²³² When fixed combinations are used, consider interactions associated with each drug in the fixed combination.²³²

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP isoenzymes 3A, 2B6, 2C9, or 2C19 with possible alteration in metabolism of efavirenz and/or other drug.¹

Specific Drugs and Laboratory Tests

Efavirenz Pharmacokinetics

Absorption

Bioavailability

Peak plasma efavirenz concentrations attained within 3–5 hours.¹

Fixed-combination tablet containing efavirenz 600 mg, emtricitabine 200 mg, and tenofovir DF 300 mg (efavirenz/emtricitabine/tenofovir DF; Atripla) is bioequivalent to a 600-mg efavirenz tablet, 200-mg emtricitabine capsule, and 300-mg tenofovir DF tablet taken simultaneously in fasting state.²³²

Food

Administration with food increases efavirenz bioavailability.¹

Compared with administration in the fasting state, AUC increased 22 or 17% when a single 600-mg efavirenz dose as capsules was administered with a high-fat, high-calorie meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat normal calorie meal (440 kcal, 2 g fat, 4% calories from fat), respectively.¹

Compared with administration in the fasting state, AUC increased 28% when a single 600-mg efavirenz dose as tablets was administered with a high-fat, high-calorie meal (1000 kcal, 500–600 kcal from fat).¹

In healthy adults, 600-mg efavirenz dose administered by opening 200-mg capsules and mixing contents of 3 capsules with 2 teaspoonfuls of soft food (e.g., applesauce, grape jelly, yogurt) or infant formula resulted in efavirenz AUC that met bioequivalency criteria compared with intact capsules administered in fasting state.¹

Distribution

Extent

Not fully characterized.¹

Low efavirenz concentrations distributed into CSF.¹

Animal studies indicate efavirenz crosses placenta in rats, rabbits, and primates.²⁰² Distributed into human milk.²⁰²

Plasma Protein Binding

99.5–99.75%.¹

Elimination

Metabolism

Metabolized by CYP3A and CYP2B6; undergoes subsequent glucuronidation.¹

Elimination Route

16–61% excreted in feces (principally as unchanged drug) and 14–34% eliminated in urine as unchanged drug (<1%) or metabolites.¹

Not removed by hemodialysis; probably not removed by peritoneal dialysis.^{1 67}

Half-life

52–76 hours after a single dose and 50–55 hours after multiple doses.¹

Special Populations

Hepatic impairment: Pharmacokinetics not affected by mild impairment (Child-Pugh class A);¹ data insufficient to determine whether affected by moderate or severe impairment (Child-Pugh class B or C).¹

Stability

Storage

Oral

Capsules

Efavirenz (Sustiva): 25°C (may be exposed to 15–30°C).¹

Tablets

Efavirenz (Sustiva): 25°C (may be exposed to 15–30°C).¹

Efavirenz/emtricitabine/tenofovir DF (Atripla): 25°C (may be exposed to 15–30°C).²³²

Actions and Spectrum

• Pharmacologically related to other NNRTIs (e.g., delavirdine, etravirine, nevirapine, rilpivirine); differs structurally from these drugs; also differs pharmacologically and structurally from other currently available antiretrovirals.^{1 2 3 6 12 14 52 53 212 215}

• Active against HIV-1; inactive against HIV-2.^{1 3}

• Inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.^{1 3}

• HIV-1 with reduced susceptibility to efavirenz have been selected in vitro and have emerged during therapy with the drug.^{1 3 9 14 18 18}

• Strains of HIV-1 resistant to efavirenz may be cross-resistant to some other NNRTIs (e.g., delavirdine, nevirapine).^{3 9 10 18 32 50 200 201 1 215}

• Cross-resistance between efavirenz and NRTIs unlikely since the drugs bind at difference sites on reverse transcriptase and have difference mechanisms of action.^{1 3 9 10 32} Cross-resistance between efavirenz and PIs unlikely since the drugs have different target enzymes and mechanisms of action.^{1 32}

Advice to Patients

• Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.^{1 232} Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.^{1 232}

• Importance of using efavirenz in conjunction with other antiretrovirals—not for monotherapy.¹ Efavirenz/emtricitabine/tenofovir DF (Atripla) can be used alone as a complete treatment regimen or can be used in conjunction with other antiretrovirals.²³²

• Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.^{1 232}

• Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.²⁰⁰ Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.^{1 200}

• Importance of reading patient information provided by the manufacturer.^{1 232}

• Importance of taking efavirenz on an empty stomach, preferably at bedtime.^{1 232}

• In patients not able to swallow capsules or tablets, 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 If a dose is missed, do not take a double dose to make up for missed dose.¹

• Advise patients that adverse CNS effects (e.g., dizziness, insomnia, impaired concentration, drowsiness, abnormal dreams) are common during first weeks of efavirenz therapy.^{1 232} Taking the drug at bedtime may improve tolerability.¹ Additive effects may occur if used with alcohol or psychoactive drugs.^{1 232} If CNS effects occur, avoid potentially hazardous tasks such as driving or operating machinery.^{1 232}

• Advise patients that serious psychiatric symptoms (e.g., severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms) have occurred.^{1 232} Importance of informing clinician of any history of mental illness or substance abuse.^{1 232} Importance of seeking immediate medical evaluation if severe psychiatric symptoms occur.^{1 232}

• Risk of rash.^{1 232} Since rash may be serious, importance of promptly contacting clinician if rash occurs.^{1 232}

• Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.^{1 232}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, and any concomitant illnesses.^{1 232}

• Importance of women using a reliable barrier method of contraception instead of or in addition to a hormonal contraceptive (oral or other hormonal contraceptive) during and for 12 weeks after efavirenz therapy.^{1 232}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 232} Advise HIV-infected women not to breast-feed.^{1 232}

• Importance of advising patients of other important precautionary information.^{1 232} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Frequently asked questions

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