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efavirenz 600 mg tablet generic sustiva

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Uses

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 adults, adolescents, and pediatric patients 3 months of age or older.

Efavirenz usually is used in HIV nonnucleoside reverse transcriptase inhibitor-based (NNRTI-based) regimens that include efavirenz and 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).

If an NNRTI-based regimen of efavirenz, emtricitabine, and tenofovir disoproxil fumarate (tenofovir DF) is used for treatment of HIV-1 infection, a fixed-combination preparation containing all 3 drugs (efavirenz/emtricitabine/tenofovir DF; Atripla) is commercially available and can be used in adults and pediatric patients 12 years of age or older weighing at least 40 kg to decrease pill burden and improve adherence. Efavirenz/emtricitabine/tenofovir DF can be used alone as a complete treatment regimen or in conjunction with other antiretrovirals.

Because of potential risks to the fetus, the manufacturer states that efavirenz (single entity or fixed combination) should not be used during the first trimester of pregnancy and pregnancy should be avoided during and for 12 weeks after therapy with the drug is discontinued.(See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)

The most appropriate antiretroviral regimen cannot be defined for each clinical scenario, and selection of specific antiretroviral agents for use in such regimens should be individualized based on current knowledge regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens,

Antiretroviral-naive Adults and Adolescents

For initial treatment in HIV-infected adults and adolescents who are antiretroviral-naive, the HHS Panel on Antiretroviral Guidelines for Adults and Adolescents states that efavirenz in conjunction with tenofovir alafenamide and emtricitabine or efavirenz in conjunction with tenofovir DF and emtricitabine (or lamivudine) are considered alternative NNRTI-based regimens. These experts also state that efavirenz in conjunction with abacavir and lamivudine (or emtricitabine) is another NNRTI-based regimen option for initial treatment in antiretroviral-naive adults and adolescents when recommended or alternative regimens cannot be used, but should be used only in patients with baseline plasma HIV RNA levels less than 100,000 copies/mL who are human leukocyte antigen (HLA)-B*5701 negative.

Study 006

Efavirenz has been evaluated for use in conjunction with 2 NRTIs or in conjunction with an HIV protease inhibitor (PI) in a phase 2 or 3 randomized, open-label study (study 006) in 1266 HIV-infected adults (mean age 36.5 years [range: 18-81 years], 83% male, 60% white, mean baseline CD4 T-cell count 320 cells/mm, mean baseline plasma HIV-1 RNA level 4.8 log10 copies/mL). Although a small number of patients included in study 006 had previously received NRTIs, most were antiretroviral-naive (had not previously received antiretroviral therapy) and none had previously received PIs, NNRTIs, or lamivudine. Patients were randomized to receive a 2-drug regimen of efavirenz (600 mg once daily) and indinavir (1 g every 8 hours); a 3-drug regimen of efavirenz (600 mg once daily), zidovudine (300 mg every 12 hours), and lamivudine (150 mg every 12 hours); or a 3-drug regimen of indinavir (800 mg every 8 hours), zidovudine (300 mg every 12 hours), and lamivudine (150 mg every 12 hours).

At 48 or 168 weeks, plasma HIV-1 levels were below 400 copies/mL in 57 or 40%, respectively, of those receiving efavirenz and indinavir; 69 or 48% of those receiving efavirenz, zidovudine, and lamivudine; and 50 or 29% of those receiving indinavir, zidovudine, and lamivudine. 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 below 50 copies/mL in 50 or 31%, respectively, of those receiving efavirenz and indinavir; 65 or 43% of those receiving efavirenz, zidovudine, and lamivudine; and 45 or 23% of those receiving indinavir, zidovudine, and lamivudine. Evaluation of CSF HIV-1 RNA levels in a limited number of individuals at week 17-35 indicated that all patients receiving an efavirenz regimen had CSF HIV-1 RNA levels below 400 copies/mL.

Study 934

Safety and efficacy of a regimen of efavirenz, emtricitabine, and tenofovir DF are based on results of a randomized, open-label study designed to demonstrate noninferiority of this regimen compared with a regimen of efavirenz, zidovudine, and lamivudine (study 934). In this study, 511 antiretroviral-naive HIV-infected patients (mean age 38 years, 86% male, 59% white, 23% black, median baseline plasma HIV-1 RNA level 5.01 log10 copies/mL [range: 3.56-6.54 log10 copies/mL], mean baseline CD4 T-cell count 245 cells/mm) were randomized to receive a once-daily regimen of efavirenz, emtricitabine, and tenofovir DF or a regimen of efavirenz once daily with the fixed combination of lamivudine and zidovudine (lamivudine/zidovudine; Combivir) twice daily. The primary measure used to assess noninferiority of the regimen of efavirenz, emtricitabine, and tenofovir DF to the regimen of efavirenz, zidovudine, and lamivudine was plasma HIV-1 RNA levels at week 48, specifically the number of patients with HIV-1 RNA levels less than 400 copies/mL. The 487 patients without baseline resistance to efavirenz who underwent randomization and received treatment were the predefined population used for the primary endpoint analysis.

Through week 48, the regimen of efavirenz, emtricitabine, and tenofovir DF met the criteria for noninferiority to the regimen of efavirenz, zidovudine, and lamivudine. At week 48, 84 or 80% of adults receiving the efavirenz, tenofovir DF, and emtricitabine regimen and 73 or 70% of adults receiving the efavirenz, zidovudine, and lamivudine regimen had plasma HIV-1 RNA levels less than 400 or 50 copies/mL, respectively. At week 48, increases in CD4 T-cell counts were greater in patients receiving the efavirenz, emtricitabine, and tenofovir DF regimen (mean increase of 190 cells/mm) than in those receiving the efavirenz, zidovudine, and lamivudine regimen (mean increase of 158 cells/mm). Virologic failure (i.e., individuals who failed to achieve virologic suppression or experienced rebound after achieving virologic suppression) was reported in 2% of those receiving efavirenz, emtricitabine, and tenofovir DF and in 4% of those receiving efavirenz, zidovudine, and lamivudine at week 48.

At 144 weeks, 64% of adults receiving the efavirenz, emtricitabine, and tenofovir DF regimen and 56% of those receiving the efavirenz, zidovudine, and lamivudine regimen had plasma HIV-1 RNA levels less than 50 copies/mL. The mean increase in CD4 T-cell count from baseline in these groups was 312 and 271 cells/mm, respectively, at 144 weeks.

Antiretroviral-experienced Adults

Study ACTG 364

Efavirenz has been evaluated for use in antiretroviral-experienced patients in a phase 2, randomized, double-blind, placebo-controlled study (study ACTG 364) in 196 HIV-infected adults (mean age 41 years [range: 18-76 years], 88% male, 74% white, mean baseline CD4 T-cell count 389 cells/mm, mean baseline plasma HIV-1 RNA level 8,130 copies/mL). In ACTG 364, patients with extensive prior therapy with NRTIs in ACTG trials (ACTG 175, ACTG 302/303) who had plasma HIV-1 RNA levels above 500 copies/mL (median baseline plasma HIV-1 levels of 5000-7000 copies/mL) were randomized to receive a 3-drug regimen of efavirenz (600 mg once daily) and 2 NRTIs; a 4-drug regimen of efavirenz (600 mg once daily), nelfinavir (750 mg 3 times daily), and 2 NRTIs; or a 3-drug regimen of nelfinavir (750 mg 3 times daily) and 2 NRTIs. At study entry, patients were assigned a new open-label NRTI regimen.

At 48 weeks, plasma HIV-1 levels were below 500 copies/mL (500 copies/mL is the lower limit of the assay used) in 63% of those receiving efavirenz and 2 NRTIs; 71% of those receiving efavirenz, nelfinavir, and 2 NRTIs; and 41% of those receiving nelfinavir and 2 NRTIs (without efavirenz).

Study 073

Efficacy of the fixed combination efavirenz/emtricitabine/tenofovir DF was evaluated in a randomized, open-label study (study 073) in antiretroviral-experienced patients who had been receiving a suppressive regimen consisting of at least 2 NRTIs and a PI or NNRTI (mean age 43 years [range 22-73 years]), 88% male, 68% white, 29% black, median CD4 T-cell count 516 cells/mm). Patients had plasma HIV-1 RNA levels less than 200 copies/mL for at least 12 weeks on their existing regimen (96% had plasma HIV-1 levels less than 50 copies/mL), no known HIV-1 substitutions conferring resistance to the components of the fixed combination, and no history of virologic failure; patients were randomized to either switch to efavirenz/emtricitabine/tenofovir DF or continue their existing (baseline) regimen. At 48 weeks, 89 and 87% of those switched to efavirenz/emtricitabine/tenofovir DF had plasma HIV-1 RNA levels less than 200 and 50 copies/mL, respectively, compared with 88 and 85% of those who remained on their baseline regimen. This difference was not statistically significant. There was no change in CD4 T-cell count from baseline in either group.

Pediatric Patients

Efavirenz is used in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in children 3 months of age or older weighing at least 3.5 kg.

The fixed combination efavirenz/emtricitabine/tenofovir DF can be used alone as a complete regimen or in conjunction with other antiretrovirals for the treatment of HIV-1 infection in pediatric patients 12 years of age or older weighing at least 40 kg.

For initial treatment in HIV-infected pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a regimen that includes a ritonavir-boosted PI, NNRTI, or integrase strand transfer inhibitor (INSTI) in conjunction with 2 NRTIs (dual NRTIs). These experts state that efavirenz and 2 NRTIs is a preferred regimen for initial treatment in children 3 to less than 12 years of age and an alternative regimen for initial treatment in adolescents 12 years of age and older who are not sexually mature. Although efavirenz can be used in children as young as 3 months of age, these experts state the drug is not recommended for initial treatment regimens in those 3 months to less than 3 years of age.

For further information on treatment of HIV infection in pediatric patients,

Study AI266922

Safety and efficacy of efavirenz in conjunction with didanosine and emtricitabine were evaluated in an open-label trial (study AI266922) that included 37 antiretroviral-naive 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 log10 copies/mL, median baseline CD4 T-cell count 1144 cells/mm, median baseline CD4 T-cell percentage 25%). At 48 weeks, plasma HIV-1 RNA levels were less than 400 or 50 copies/mL in 57 or 46%, respectively, of patients (intent-to-treat analysis). The median increase in CD4 T-cell count was 196 cells/mm and the median increase in CD4 T-cell percentage was 6%.

Study PACTG 1021

Safety and efficacy of efavirenz in conjunction with didanosine and emtricitabine also were evaluated in an open-label trial (study PACTG 1021) that included 43 antiretroviral-naive 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/mm, median baseline CD4 T-cell percentage 18%). At 48 weeks, plasma HIV-1 RNA levels were less than 400 or 50 copies/mL in 77 or 70%, respectively, of patients (intent-to-treat analysis). The median increase in CD4 T-cell count was 238 cells/mm and the median increase in CD4 T-cell percentage was 13%.

Study PACTG 382

Safety and efficacy of efavirenz in pediatric patients were evaluated in an open-label study (study PACTG 382) that included 102 antiretroviral-naive 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/mm, median baseline CD4 T-cell percentage 30%). Patients received efavirenz in conjunction with nelfinavir and an NRTI. At 48 weeks, plasma HIV-1 RNA levels were less than 400 or 50 copies/mL in 57 or 43%, respectively, of patients (intent-to-treat analysis). The median increase in CD4 T-cell count was 128 cells/mm and the median increase in CD4 T-cell percentage was 5%.

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.

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). These experts state that efavirenz and 2 NRTIs can be considered an alternative regimen, but should be used for PEP only with expert consultation. 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.

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. However, initiation of PEP should not be delayed while waiting for expert consultation.

For information on types of occupational exposure to HIV and associated risk of infection, management of occupational exposure to HIV, efficacy and safety of postexposure prophylaxis, and recommendations regarding PEP,

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.

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 emtricitabine/tenofovir DF; Truvada); the recommended alternative nPEP regimen in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada).

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

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. However, initiation of nPEP should not be delayed while waiting for expert consultation.

For additional information on nonoccupational exposure to HIV and recommendations regarding postexposure prophylaxis,

Dosage and Administration

Administration

Efavirenz is administered orally once daily on an empty stomach, preferably at bedtime.

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

Single-entity efavirenz is commercially available as capsules or tablets. Efavirenz also is commercially available in fixed-combination tablets containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate (efavirenz/emtricitabine/tenofovir DF; Atripla).(See Fixed Combinations Containing Efavirenz under Dosage and Administration: Administration.)

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

Efavirenz Capsules

Efavirenz capsules should be swallowed whole.

For adults and pediatric patients 3 months of age or older 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). The use of infant formula for mixing should be considered only for infants who cannot consume solid foods. 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.

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. The appropriate number of efavirenz capsules (see Table 1) should be held horizontally over the small container, twisted open, and emptied. The contents of the capsules should be gently mixed into the soft food with a spoon and the entire mixture fed to the patient. 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.

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. The appropriate number of efavirenz capsules (see Table 1) should be held horizontally over the medicine cup, twisted open, and emptied. The contents of the capsules should be gently mixed into the infant formula using a small spoon. 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. 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.

Efavirenz Tablets

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

Fixed Combinations Containing Efavirenz

Efavirenz/emtricitabine/tenofovir DF (Atripla) tablets are administered orally once daily on an empty stomach, preferably at bedtime. Administration at bedtime may make efavirenz-associated adverse CNS effects more tolerable. A fixed-combination tablet containing 600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF is bioequivalent to a 600-mg tablet of efavirenz, 200-mg capsule of emtricitabine, and 300-mg tablet of tenofovir DF when taken in the fasting state. The fixed combination can be used alone as a complete treatment regimen or in conjunction with other antiretrovirals.

Efavirenz/emtricitabine/tenofovir DF should not be used concomitantly with single-entity efavirenz, unless needed for adjustment of the efavirenz dosage (e.g., when the fixed combination is used concomitantly with rifampin).

Because the antiretroviral agents contained in efavirenz/emtricitabine/tenofovir DF also are available in single-entity or other fixed-combination preparations, care should be taken to ensure that therapy is not duplicated if the fixed combination is used in conjunction with other antiretrovirals.(See Precautions Related to Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Dosage

Adult Dosage

Treatment of HIV Infection

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

When efavirenz/emtricitabine/tenofovir DF (Atripla) is used for treatment of HIV-1 infection, adults should receive 1 tablet (600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF) once daily.

Treatment of HIV Infection in Patients Receiving Rifampin

If efavirenz (Sustiva) is used for treatment of HIV-1 infection in patients receiving rifampin, those weighing 50 kg or more should receive an increased efavirenz dosage of 800 mg daily.(See Rifampin under Drug Interactions: Antimycobacterial Agents.)

If efavirenz/emtricitabine/tenofovir DF (Atripla) is used for treatment of HIV-1 infection in patients receiving rifampin, those weighing 50 kg or more should receive 1 tablet of the fixed combination (600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF) once daily and 200 mg of single-entity efavirenz (Sustiva) once daily to provide a total efavirenz dosage of 800 mg daily.

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).(See Uses: Postexposure Prophylaxis following Occupational Exposure to HIV.)

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

Pediatric Dosage

Dosage of efavirenz (Sustiva) in children 3 months of age or older weighing 3.5 to less than 40 kg is based on weight.(See Table 1.) Adolescents and children who weigh 40 kg or more may receive the usual adult dosage of efavirenz.

Table 1. Efavirenz (Sustiva®) Dosage in Children 3 Months of Age or Older[1 ]
Weight in kg Efavirenz Dosage Number of Capsules or Tablets
3.5 to less than 5 100 mg once daily Two 50-mg capsules
5 to less than 7.5 150 mg once daily Three 50-mg capsules
7.5 to less than 15 200 mg once daily One 200-mg capsule
15 to less than 20 250 mg once daily One 200-mg and one 50-mg capsule
20 to less than 25 300 mg once daily One 200-mg and two 50-mg capsules
25 to less than 32.5 350 mg once daily One 200-mg and three 50-mg capsules
32.5 to less than 40 400 mg once daily Two 200-mg capsules
40 or more 600 mg once daily One 600-mg tablet or three 200-mg capsules

When efavirenz/emtricitabine/tenofovir DF (Atripla) is used for treatment of HIV-1 infection in pediatric patients 12 years of age or older weighing at least 40 kg, the recommended dosage is 1 tablet (600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF) once daily.

Dosage in Renal and Hepatic Impairment

Renal Impairment

While the pharmacokinetics of efavirenz have not been specifically studied in patients with renal failure, 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. Some experts state that the usual dosage of efavirenz (Sustiva) can be used in patients with impaired renal function.

When efavirenz/emtricitabine/tenofovir DF (Atripla) is used, usual dosage can be used in patients with creatinine clearances of 50 mL/minute or greater. The fixed combination should not be used in those with creatinine clearances less than 50 mL/minute.

Hepatic Impairment

Efavirenz dosage adjustments are not necessary in patients with mild hepatic impairment. 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.(See Precautions Related to Hepatic Impairment and Hepatic Effects under Cautions: Precautions and Contraindications.)

When efavirenz/emtricitabine/tenofovir DF (Atripla) is used, usual dosage can be used in patients with mild hepatic impairment; however, caution is advised.(See Precautions Related to Hepatic Impairment and Hepatic Effects under Cautions: Precautions and Contraindications.) The fixed combination should not be used in those with moderate or severe hepatic impairment.

Cautions

Information on the safety and efficacy of efavirenz has been obtained principally from phase 2 and 3 open-label studies in adults with asymptomatic or advanced human immunodeficiency virus (HIV) infection who received the recommended dosage of the drug in conjunction with HIV nucleoside reverse transcriptase inhibitors (NRTIs) and/or an HIV protease inhibitor (PI). Information also has been obtained from a phase 1 or 2 open-label study in HIV-infected children who received efavirenz in conjunction with nelfinavir and nucleoside antiretroviral agents.

The principal adverse effects of efavirenz in clinical studies include nervous system effects, psychiatric symptoms, and dermatologic effects. About 2.1% of adults receiving efavirenz in clinical trials discontinued the drug because of CNS effects and about 1.7 or 8.8% of adults or children 3-16 years of age, respectively, discontinued the drug because of rash.

Because many patients with HIV infection have serious underlying disease with multiple baseline symptomatology and clinical abnormalities and because many adverse effects that have been reported in patients receiving efavirenz also occur in HIV-infected patients not receiving the drug, a causal relationship between efavirenz and some adverse effects has not been established.

When the fixed combination containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate (efavirenz/emtricitabine/tenofovir DF; Atripla) is used, the adverse effects, precautions, and contraindications associated with each of the individual components should be considered.(See Precautions Related to Use of Fixed Combinations under Cautions: Precautions and Contraindications.)

Nervous System Effects and Psychiatric Symptoms

About 53% of adults receiving efavirenz (600 mg once daily) in controlled clinical studies reported adverse CNS effects such as abnormal dreams, abnormal thinking, agitation, amnesia, confusion, depersonalization, dizziness, euphoria, hallucinations, impaired concentration, insomnia, somnolence, and stupor; these adverse effects were reported in 25% of adults in the control groups not receiving efavirenz. These effects were described as mild (do not interfere with daily activities) in 33.3%, moderate (may interfere with daily activities) in 17.4%, or severe (interrupt usual daily activities) in 2% of patients receiving efavirenz and required discontinuance of the drug in 2.1%. Dizziness was reported in 28.1% and insomnia was reported in 16.3% of patients receiving the drug. Impaired concentration, somnolence, or abnormal dreams were reported in 6.2-8.3% and hallucinations were reported in 1.2% of patients. Treatment-emergent adverse CNS effects of moderate or severe intensity reported in adults receiving efavirenz in studies ACTG 364 and 006 include dizziness in 2-9%, insomnia in up to 7%, headache in 2-8%, impaired concentration in up to 5%, somnolence in up to 2%, and abnormal dreams in up to 3%. These adverse effects generally begin during the first 1-2 days of efavirenz therapy, improve with continued therapy, and usually resolve after the first 2-4 weeks of therapy. After 4 weeks of efavirenz therapy, the incidence of moderate or severe adverse CNS effects ranges from 5-9% in adults receiving efavirenz and 3-5% in those in the control groups not receiving the drug. Adverse CNS effects may be more tolerable if the daily dose of efavirenz is administered at bedtime.

Serious adverse psychiatric symptoms have been reported rarely in adults receiving efavirenz. 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. Analysis of data from clinical studies indicates that treatment with efavirenz is associated with an increased occurrence of these psychiatric symptoms. 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. Other psychiatric symptoms reported in controlled clinical studies in adults receiving efavirenz include depression (19%), anxiety (13%), and nervousness (7%); these symptoms were reported in 16, 9, or 2%, respectively, of those in the control groups not receiving the drug. 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. In addition, aggressive reactions, agitation, emotional lability, mania, neurosis, and paranoia have been reported during postmarketing surveillance.

Seizures have been reported in adults and pediatric patients receiving efavirenz; seizures generally have occurred in patients with a history of seizures. Fatigue has been reported in up to 8% of adults receiving efavirenz in clinical studies.

Adverse nervous system effects reported during postmarketing surveillance include abnormal coordination, ataxia, hypoesthesia, paresthesia, neuropathy, and tremor.

Adverse CNS effects occurred in 18% of children receiving efavirenz in clinical studies.

Dermatologic and Sensitivity Reactions

Rash has occurred in 26% of adults receiving efavirenz in clinical studies and in 17% of adults in control groups not receiving the drug. Although treatment-emergent rash generally manifests as mild to moderate maculopapular skin eruptions (NCI grade 1 and 2 reactions), rash associated with blistering, moist desquamation, or ulceration (NCI grade 3 reaction) has been reported in about 1% of adults receiving efavirenz in clinical studies. The incidence of grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in patients receiving efavirenz in clinical studies or in the expanded access program has been reported to be 0.1%.

Rash occurs more frequently in children than adults and has been reported in 32% of patients 3 months to 21 years of age receiving efavirenz in clinical studies. NCI grade 3 rash occurred in 1.1%, and grade 4 rash and erythema multiforme occurred in 2.2% of pediatric patients.

Treatment-emergent rash generally occurs within the first 2 weeks of efavirenz therapy; median time to onset of rash in clinical studies in adults or children was 11 or 28 days, respectively. In most patients who continued efavirenz treatment, the rash resolves within 1 month (median duration 16 days).

Pruritus has been reported in up to 9% of patients receiving efavirenz in clinical studies. Other adverse dermatologic and sensitivity reactions occurring in postmarketing reports include allergic reaction, erythema multiforme, photoallergic dermatitis, and Stevens-Johnson syndrome.

Efavirenz should be discontinued in patients with life-threatening cutaneous reactions (e.g., Stevens-Johnson syndrome) and alternative therapy considered. Although the drug should be discontinued in patients who experience serious rash (i.e., rash associated with blistering, desquamation, mucosal involvement, or fever), mild to moderate rash resolves in most patients within 1 month with continued efavirenz therapy. The median duration of rash in adults is 16 days.

Antihistamines and/or corticosteroids may improve tolerability and hasten resolution of rash. Therapy with efavirenz can be reinitiated in patients who temporarily interrupted therapy with the drug because of development of a rash. Although prophylaxis with antihistamines prior to initiating efavirenz in children can be considered, the efficacy of such a strategy for prevention of rash has not been determined.

Limited information is available on use of efavirenz in patients who discontinued nevirapine because of rash. When efavirenz was initiated in 19 patients who previously discontinued nevirapine because of rash, mild to moderate rash occurred in 9 of these patients while receiving efavirenz. In at least 2 adults who had experienced severe hypersensitivity reactions while receiving nevirapine, initiation of efavirenz with concomitant corticosteroid therapy (an 11-day prednisone regimen involving decreasing dosage) resulted in a mild rash in one patient but allowed use of efavirenz without any severe hypersensitivity reactions.

Hepatic Effects

Substantial increases in serum concentrations of AST (SGOT) or ALT (SGPT) (more than 5 times the upper limit of normal) occurred in 2-8% of evaluated adults receiving efavirenz in clinical studies; the frequency of increases in AST or ALT in patients receiving efavirenz was similar to that in patients receiving regimens that did not include efavirenz. In patients who were seropositive for hepatitis B virus (HBV) and/or hepatitis C virus (HCV), substantial increases in serum concentrations of AST or ALT (more than 5 times the upper limit of normal) occurred in 13 or 20%, respectively, of adults receiving efavirenz and in 7 or 7%, respectively, of adults receiving regimens that did not include efavirenz.

Increases in γ-glutamyltransferase (GGT, GGPT) (more than 5 times the upper limit of normal) occurred in 5-8% of patients receiving efavirenz in clinical studies; the frequency of increases in GGT in patients receiving efavirenz was similar to that in patients receiving regimens that did not include efavirenz.

There have been postmarketing reports of hepatic failure and hepatitis in patients receiving efavirenz. A few cases of hepatic failure, including some in patients with no preexisting hepatic disease or other identifiable risk factors, were characterized by a fulminant course and required transplantation or resulted in death.

GI Effects

Moderate or severe GI effects have been reported in up to 14% of adults receiving efavirenz in clinical studies. Nausea or diarrhea occurred in 2-14%, vomiting in up to 7%, dyspepsia in up to 3%, abdominal pain in 1-3%, and anorexia in up to 2% of patients receiving the drug. In addition, constipation and malabsorption have been reported during postmarketing surveillance.

Cardiovascular and Lipid Effects

Prolongation of the QT interval corrected for rate (QTc) has been reported in patients receiving efavirenz.

While the clinical importance remains to be determined, total serum cholesterol concentrations have been increased 10-20% in healthy individuals receiving efavirenz. In patients receiving a 3-drug regimen of efavirenz, zidovudine, and lamivudine, serum concentrations of nonfasting total cholesterol or high-density lipoprotein (HDL) cholesterol were increased approximately 20 or 25%, respectively; in patients receiving a 2-drug regimen of efavirenz and indinavir, these serum concentrations were increased approximately 40 or 35%, respectively. The effects of efavirenz on triglycerides and low-density lipoprotein (LDL) were not well characterized since serum samples were obtained under nonfasting conditions.

Flushing and palpitations have been reported during postmarketing surveillance.

Immune Reconstitution Syndrome

Patients receiving antiretroviral therapy may experience an immune reconstitution syndrome 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.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome) 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.

Adipogenic Effects

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. The mechanisms and long-term consequences of these adipogenic effects are unknown. A causal relationship has not been established.

Other Adverse Effects

Although a causal relationship has not been established, pancreatitis has been reported in a few patients receiving efavirenz. In addition, asymptomatic increases in serum amylase concentrations to greater than 1.5 times the upper limit of normal have been reported in 10% of patients receiving efavirenz compared with 6% of patients in control groups not receiving the drug.

In a clinical study (study 006), lipodystrophy occurred in 2.3% of patients receiving efavirenz and indinavir, 0.7% of patients receiving efavirenz, zidovudine, and lamivudine, and 1% of patients receiving indinavir, zidovudine, and lamivudine without efavirenz.

Moderate or severe pain has been reported in 1-13% of patients receiving efavirenz in clinical studies. Other adverse effects reported in patients receiving efavirenz during postmarketing surveillance include abnormal vision, arthralgia, asthenia, dyspnea, gynecomastia, myalgia, myopathy, and tinnitus.

Precautions and Contraindications

Efavirenz is contraindicated in patients who have had a clinically important hypersensitivity reaction (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic skin eruption) to efavirenz or any other ingredient in the formulation.

Fetal/Neonatal Morbidity and Mortality

Because efavirenz may cause fetal harm if administered during the first trimester of pregnancy, women of childbearing potential should undergo pregnancy testing before efavirenz or efavirenz/emtricitabine/tenofovir DF is initiated and measures should be taken to avoid pregnancy during and for 12 weeks after therapy with efavirenz is discontinued.(See Cautions: Pregnancy, Fertility, and Lactation.)

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.(See Drug Interactions.)

Efavirenz induces CYP3A and 2B6 and may alter plasma concentrations of drugs metabolized by these enzymes.(See Drug Interactions.)

Precautions Related to Nervous System Effects and Psychiatric Symptoms

Patients should be informed that adverse CNS effects (e.g., dizziness, insomnia, impaired concentration, somnolence, abnormal dreams) 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. 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.

Serious psychiatric symptoms (e.g., severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, delusions, paranoia, manic or psychosis-like reactions) have been reported rarely in patients receiving efavirenz. Patients should be asked about any history of mental illness or substance abuse prior to initiation of efavirenz and should be advised to immediately seek medical evaluation if they experience severe psychiatric symptoms while receiving the drug. 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.

Seizures have occurred in patients receiving efavirenz, generally in those with a history of seizures. Caution is advised if the drug is used in patients with a history of seizures. In patients receiving anticonvulsants that are metabolized principally by the liver (e.g., phenytoin, phenobarbital), anticonvulsant plasma concentrations should be monitored.(See Anticonvulsants under Drug Interactions: CNS Agents.)

Precautions Related to Hepatic Impairment and Hepatic Effects

Because efavirenz is extensively metabolized in the liver and because of limited clinical experience in patients with hepatic impairment, the manufacturer states that the drug should be used with caution in such patients. Efavirenz can be used with caution in patients with mild hepatic impairment without any dosage adjustments; however, the drugs are not recommended in patients with moderate or severe hepatic impairment since data are insufficient to determine whether dosage adjustments are necessary.

Serum liver enzyme concentrations should be assessed 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. Monitoring serum liver enzyme concentrations also should be considered in patients without preexisting hepatic dysfunction or other risk factors.

In patients with serum hepatic enzyme concentrations more than 5 times the upper limit of normal, the benefits of continued efavirenz therapy versus the risks of hepatotoxicity should be considered.

Precautions Related to Cardiovascular Effects

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.(See Drug Interactions.)

Precautions Related to Use of Fixed Combinations

When efavirenz/emtricitabine/tenofovir DF is used, the cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination must be considered. Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug. For cautionary information related to and , see Cautions in the individual drug monographs.

Efavirenz/emtricitabine/tenofovir DF should not be used concomitantly with single-entity efavirenz, unless needed for adjustment of efavirenz dosage (e.g., when the fixed combination is used concomitantly with rifampin).(See Rifampin under Drug Interactions: Antimycobacterial Agents.)

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

Efavirenz/emtricitabine/tenofovir DF should not be used concomitantly with any preparation containing emtricitabine or tenofovir DF. In addition, because of similarities between emtricitabine and lamivudine, the fixed combination should not be used concomitantly with any preparation containing lamivudine or with adefovir dipivoxil.

If efavirenz/emtricitabine/tenofovir DF is used, clinicians should consider that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving NRTIs in conjunction with other antiretrovirals.

If efavirenz/emtricitabine/tenofovir DF is used, clinicians should consider that severe, acute HBV infection has been reported following discontinuance of emtricitabine or tenofovir DF in HIV-infected patients coinfected with HBV. The fixed combination is not labeled by the US Food and Drug Administration for treatment of chronic HBV infection, and safety and efficacy have not been established in HIV-infected patients coinfected with HBV. Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after the fixed combination is discontinued in coinfected patients. If appropriate, initiation of HBV treatment may be warranted.

Other Precautions

Because increased serum concentrations of total cholesterol and triglycerides have been reported in patients receiving efavirenz, cholesterol and triglyceride testing should be performed prior to and at periodic intervals during efavirenz therapy.

Patients should be advised that rash is a common side effect of efavirenz and, although rash usually goes away without any treatment change, it may be serious. Therefore, patients should promptly contact a clinician is rash occurs.

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance, have been reported in patients receiving antiretroviral therapy. The mechanisms responsible for these adipogenic effects and the long-term consequences of these effects are unknown. A causal relationship has not been established. Patients receiving efavirenz should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term consequences of these adipogenic effects are not known.

Patients should be informed that efavirenz in conjunction with other antiretroviral agents is not a cure for HIV infection and that opportunistic infections and other complications associated with HIV disease may still occur. Patients receiving efavirenz should be under close clinical observation by clinicians experienced in treatment of diseases associated with HIV infection, and patients should be advised to seek medical care if any clinically important change in their health status occurs. Patients receiving antiretroviral therapy must be continuously evaluated and therapeutic modifications made as appropriate.

Patients should be advised 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. Patients should continue to practice safer sex (e.g., use latex or polyurethane condoms to minimize sexual contact with body fluids), never share personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reuse or share needles.

Pediatric Precautions

Safety and efficacy of single-entity efavirenz (Sustiva) have not been established in neonates and infants younger than 3 months of age or in those weighing less than 3.5 kg, and the drug should not be used in these pediatric patients. Some experts state that efavirenz is not recommended for initial treatment in antiretroviral-naive pediatric patients 3 months to less than 3 years of age.

Efavirenz/emtricitabine/tenofovir DF (Atripla) should not be used in pediatric patients younger than 12 years of age or in those weighing less than 40 kg.

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 and include rash and adverse CNS and GI effects. Rash has been reported more frequently in children than adults (32 versus 26%) and the incidence of moderate to severe rash (NCI grade 3 or 4) has been greater in children than adults. Because of the high incidence of dermatologic reactions in children, antihistamines may be considered for the prevention of rash when initiating efavirenz in children; however, the efficacy of such a strategy has not been determined.

Efavirenz is not recommended in sexually active adolescent females of childbearing potential who desire to become pregnant or when reliable contraception cannot be ensured.(See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)

Geriatric Precautions

Safety and efficacy of efavirenz have not been evaluated systematically in geriatric patients. Dosage for geriatric patients should be selected carefully because of limited experience in this age group and because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Mutagenicity and Carcinogenicity

Efavirenz was not mutagenic or genotoxic in several in vitro and in vivo genotoxicity assays, including Salmonella typhimurium and Escherichia coli bacterial mutation assays, mammalian mutation assays in Chinese hamster ovary cells, chromosomal aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and a mouse bone marrow micronucleus assay.

The carcinogenic potential of efavirenz has been evaluated in long-term studies in mice and rats. The incidence of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas was increased above background rates in female mice but not in male mice. In rats, no increase in tumor incidence above background was observed at efavirenz exposure that were 0.1 (males) or 0.2 (females) times the human exposure at recommended dosages of the drug.

Pregnancy, Fertility, and Lactation

Pregnancy

Efavirenz may cause fetal harm if administered during the first trimester of pregnancy; however, some experts state that the relative risk with first-trimester exposure is unclear. 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, but prospective pregnancy data are not sufficient to adequately assess this risk.

Reproduction studies in cynomolgus monkeys using efavirenz dosages of 60 mg/kg daily throughout pregnancy (gestation days 20-150) resulted in maternal efavirenz systemic exposure levels 1.3 times those reported with the recommended human dosage and fetal umbilical venous concentrations approximately 0.7 times maternal concentrations and malformations (i.e., anencephaly and unilateral anophthalmia, microphthalmia, cleft palate) in 3 of 20 fetuses/offspring. In rats, an efavirenz dosage of 200 mg/kg daily was associated with an increased incidence of early resorptions and 100 mg/kg daily was associated with early neonatal mortality. Reproduction studies in rabbits have not revealed evidence of harm to the fetus. Efavirenz crosses the placenta in cynomolgus monkeys, rats, and rabbits, and produces fetal blood concentrations in these species that are similar to maternal blood concentrations.

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including efavirenz, the Antiretroviral Pregnancy Registry was established. Clinicians are encouraged to contact the registry at 800-258-4263 or http://www.APRegistry.com to report cases of prenatal exposure to antiretroviral agents.

Based on prospective reports from the Antiretroviral Pregnancy Registry 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). 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. Defects reported prospectively in first-trimester exposures included a case of myelomeningocele and a case of anophthalmia that included severe oblique facial clefts and amniotic banding. There also have been at least 6 retrospective reports of CNS defects, including myelomeningocele, and all involved exposures during the first trimester. Although a causal relationship between efavirenz and these defects has not been established, similar defects were observed in preclinical studies of the drug.

A meta-analysis of data from 23 studies that included 2026 reports of live births following first-trimester exposures to efavirenz found no increased risk of overall birth defects in infants born to women receiving efavirenz during the first trimester compared with those receiving other antiretrovirals. However, the number of reported first trimester exposures remains insufficient to rule out a significant increase in low-incidence birth defects (incidence of neural tube defects in the general US population is 0.02-0.2%).

Women of childbearing potential should be advised about the teratogenic potential of efavirenz and should not receive single-entity efavirenz or efavirenz/emtricitabine/tenofovir DF until pregnancy is excluded. Such women should undergo pregnancy testing before initiation of therapy and should be instructed to avoid pregnancy during and for 12 weeks after discontinuance of therapy with efavirenz or efavirenz/emtricitabine/tenofovir DF and to notify a clinician if they desire to become pregnant or become pregnant while receiving a regimen containing efavirenz. 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) while receiving efavirenz and for 12 weeks after the drug is discontinued. Hormonal contraceptives containing progesterone may have decreased effectiveness when used concomitantly with efavirenz.(See Drug Interactions: Estrogens and Progestins.)

The manufacturer states that efavirenz should not be used during the first trimester of pregnancy.

The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that efavirenz in conjunction with 2 NRTIs is an alternative NNRTI-based regimen for initial treatment in antiretroviral-naive pregnant women, but may be a preferred NNRTI-based regimen for initial treatment in pregnant women 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. However, these experts state that efavirenz should be avoided during the first 8 weeks of pregnancy. These 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.

If a pregnant woman already receiving an efavirenz-based regimen presents for antenatal care during the first trimester of pregnancy, the HHS panel suggests that the regimen can be continued if it is well tolerated and providing adequate virologic suppression. This strategy recognizes that the risk of neural tube defects is restricted to the first 5-6 weeks of pregnancy and pregnancy is 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 an increased risk of perinatal HIV transmission.

If efavirenz or a fixed combination containing efavirenz is used during the first trimester, or if the patient becomes pregnant while taking the drug, she should be apprised of the potential harm to the fetus.

Fertility

Reproductive studies in rats have not revealed evidence of impaired fertility or reproductive performance in males or females receiving efavirenz and the drug did not affect male sperm. The reproductive performance of offspring of female rats given efavirenz was not affected.

Lactation

Efavirenz is distributed into human milk

Because of the risk of transmission of HIV to an uninfected infant through breast milk, the US Centers for Disease Control and Prevention (CDC) and other experts recommend that HIV-infected women not breast-feed infants, regardless of antiretroviral therapy. Therefore, because of the potential for HIV transmission and the potential for serious adverse effects from efavirenz in infants if the drug were distributed into milk, women should be instructed not to breast-feed while they are receiving efavirenz.

Drug Interactions

The following drug interactions are based on studies using efavirenz. Drug interaction studies have not been performed using the fixed combination containing efavirenz, emtricitabine, and tenofovir disoproxil fumarate (efavirenz/emtricitabine/tenofovir DF; Atripla). When efavirenz/emtricitabine/tenofovir DF is used, interactions associated with each drug in the fixed combination should be considered.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Metabolism of efavirenz is mediated principally by cytochrome P-450 (CYP) isoenzymes 3A and 2B6, and drugs that induce these isoenzymes are expected to reduce efavirenz plasma concentrations. Efavirenz has been shown to induce CYP enzymes resulting in induction of its own metabolism. Efavirenz induces CYP3A and 2B6, and may alter plasma concentrations of drugs metabolized by these enzymes.

In vitro, efavirenz inhibits CYP isoenzymes 2C9 and 2C19 (KI values 8.5-17 mcM) at clinically important concentrations, and the possibility exists that efavirenz may alter the pharmacokinetics of drugs metabolized by these isoenzymes. In vitro studies indicate that efavirenz does not inhibit the CYP isoenzyme 2E1 and is a weak inhibitor of 2D6 and 1A2 (KI values of 82-160 mcM).

Anticoagulants

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

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.

Isavuconazonium

Concomitant use of isavuconazonium sulfate (prodrug of isavuconazole) and efavirenz may result in decreased isavuconazole concentrations.

If isavuconazonium sulfate and efavirenz are used concomitantly, isavuconazole concentration monitoring should be considered and the patient should be monitored for antifungal efficacy. Adjustment of isavuconazonium sulfate dosage may be necessary.

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. Failure to achieve therapeutic itraconazole concentrations has been reported in patients receiving efavirenz.

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. Some experts state that concomitant use of itraconazole and efavirenz should be avoided; if the drugs are used concomitantly, plasma concentrations of itraconazole should be monitored closely and dosage of the antifungal adjusted accordingly.

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.

Posaconazole

Concomitant use of posaconazole (400 mg twice daily) and efavirenz (400 mg once daily) reduces peak plasma concentrations and AUC of posaconazole by 45 and 50%, respectively, but does not affect efavirenz concentrations.

Concomitant use of posaconazole and efavirenz should be avoided unless potential benefits outweigh risks. If the drugs are used concomitantly, plasma concentrations of posaconazole should be monitored and dosage of the antifungal adjusted accordingly.

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.

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. 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. Usual dosage of voriconazole and usual dosage of efavirenz should not be used concomitantly.

Concomitant use of voriconazole and the fixed combination efavirenz/emtricitabine/tenofovir DF is contraindicated.

Antihistamine Drugs

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 area under the plasma concentration time curve (AUC) of efavirenz. The manufacturer of efavirenz states that dosage adjustments are not necessary in patients receiving concomitant cetirizine.

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.

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. Some experts state that if artemether/lumefantrine and efavirenz are used concomitantly, the patient should be closely monitored for antimalarial efficacy and malaria recurrence.

Atovaquone and Proguanil

Concomitant use of efavirenz and the fixed combination of atovaquone and proguanil (atovaquone/proguanil) decreases the AUC of atovaquone and proguanil.

Concomitant use of atovaquone/proguanil and efavirenz is not recommended. Some experts state that dosage recommendations are not available for concomitant use of atovaquone/proguanil and that alternatives to that fixed combination should be considered for malaria prophylaxis, if possible.

Antimycobacterial Agents

Bedaquiline

Concomitant use of bedaquiline and efavirenz may result in decreased bedaquiline concentrations.

Concomitant use of bedaquiline and efavirenz is not recommended.

Rifabutin

Concomitant use of efavirenz and rifabutin has resulted in decreased plasma concentration of rifabutin and 25-O-desacetylrifabutin (an active metabolite). In a limited number of healthy individuals, concomitant use of rifabutin (300 mg once daily) and efavirenz (600 mg once daily) for 10-14 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.

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. Some clinicians suggest that rifabutin dosage be increased to 450-600 mg once daily or 600 mg 3 times weekly in patients receiving efavirenz, provided an HIV protease inhibitor (PI) is not included in the regimen.

Rifampin

Concomitant use of efavirenz and rifampin has resulted in decreased plasma efavirenz concentrations and AUC. 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%; there was no change in the peak plasma concentration or AUC of rifampin. The clinical importance of these reduced plasma efavirenz concentrations remains to be determined.

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. Some experts suggest that an efavirenz dosage of 600 mg once daily can be used in patients weighing less than 60 kg if virologic response is monitored and therapeutic drug monitoring considered; these experts state that efavirenz dosage should be increased to 800 mg once daily in those weighing more than 60 kg.

If the fixed combination efavirenz/emtricitabine/tenofovir DF is used in patients receiving rifampin, the manufacturer recommends that those weighing at least 50 kg receive 1 tablet of the fixed combination (600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir DF) once daily and 200 mg of single-entity efavirenz once daily to provide a total efavirenz dosage of 800 mg daily.

Rifapentine

Efavirenz and rifapentine should not be used concomitantly. HIV-infected tuberculosis patients treated with rifapentine have a higher rate of tuberculosis relapse than those treated with other rifamycin-based tuberculosis regimens; an alternative antimycobacterial agent is recommended in HIV patients.

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Enfuvirtide

There is in vitro evidence of additive to synergistic antiretroviral effects between enfuvirtide and efavirenz.

Maraviroc

Concomitant use of maraviroc and efavirenz results in clinically important decreases in plasma maraviroc concentrations and AUC. If maraviroc is used concomitantly with efavirenz, the recommended dosage of maraviroc is 600 mg twice daily, provided the regimen does not include a potent CYP3A inhibitor.

There is no in vitro evidence of antagonistic antiretroviral effects between maraviroc and efavirenz.

HIV Integrase Inhibitors (INSTIs)

Dolutegravir

Concomitant use of dolutegravir and efavirenz decreases plasma concentrations and AUC of dolutegravir, but does not appear to affect the pharmacokinetics of efavirenz.

If efavirenz is used concurrently with dolutegravir in adults or pediatric patients weighing 40 kg or more who are antiretroviral-naive or antiretroviral-experienced but INSTI-naive, dolutegravir should be given in a dosage of 50 mg twice daily. If efavirenz is used concurrently with dolutegravir in pediatric patients weighing 30 kg to less than 40 kg who are antiretroviral-naive or antiretroviral-experienced but INSTI-naive, dolutegravir should be given in a dosage of 35 mg twice daily. Whenever possible, an alternative to efavirenz that is not a metabolic inducer should be considered when dolutegravir is used in INSTI-experienced patients who have HIV-1 with documented or suspected INSTI resistance.

There is no in vitro evidence of antagonistic antiretroviral effects between dolutegravir and efavirenz.

Elvitegravir

Concomitant use of cobicistat-boosted elvitegravir and efavirenz may result in altered concentrations of elvitegravir, cobicistat, and efavirenz.

Cobicistat-boosted elvitegravir and efavirenz should not be used concomitantly.

Raltegravir

Concomitant use of raltegravir and efavirenz results in decreased plasma concentrations and AUC of raltegravir; these effects are not considered clinically important. Dosage adjustments are not necessary if raltegravir is used concomitantly with efavirenz.

There is in vitro evidence of additive to synergistic antiretroviral effects between raltegravir and efavirenz.

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Concomitant use of efavirenz and other NNRTIs (delavirdine, etravirine, nevirapine, rilpivirine) is not recommended.

Concomitant use of efavirenz and etravirine may result in decreased etravirine concentrations and loss of therapeutic effect.

Concomitant use of efavirenz and nevirapine results in decreased efavirenz concentrations and AUC; nevirapine concentrations are not affected. An increased incidence of adverse effects and no improvement in efficacy has been reported when these NNRTIs were used concomitantly.

Concomitant use of efavirenz and rilpivirine may result in decreased plasma rilpivirine concentrations.

HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Results of in vitro studies using some NRTIs (e.g., abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine) indicate that the antiretroviral effects of efavirenz and these drugs are additive to synergistic against HIV-1.

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. Concomitant use of tenofovir DF and efavirenz does not affect plasma concentrations or AUCs of either drug. Clinically important pharmacokinetic interactions between efavirenz and other NRTIs (abacavir, emtricitabine, stavudine, tenofovir DF) are not expected.

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

Concomitant use of didanosine and efavirenz/emtricitabine/tenofovir DF should be undertaken with caution and patients should be monitored closely for didanosine-associated adverse effects (e.g., pancreatitis, lactic acidosis, neuropathy).

HIV Protease Inhibitors (PIs)

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

Results of in vitro studies indicate that the antiretroviral effects of efavirenz and some PIs (amprenavir [active metabolite of fosamprenavir], indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) are additive to synergistic against HIV-1. There is no in vitro evidence of antagonistic antiretroviral effects between efavirenz and atazanavir or darunavir.

Atazanavir

Concomitant use of unboosted atazanavir (without low-dose ritonavir or cobicistat) and efavirenz results in substantially decreased plasma concentration and AUC of atazanavir, but no clinically important effect on efavirenz concentrations. Depending on the specific regimen used, concomitant use of ritonavir-boosted atazanavir and efavirenz may increase atazanavir plasma concentrations and AUC. Concomitant use of cobicistat-boosted atazanavir with efavirenz results in decreased plasma concentrations of atazanavir and cobicistat, but no change in efavirenz concentrations.

Unboosted atazanavir (without low-dose ritonavir or cobicistat) should not be used concomitantly with efavirenz in antiretroviral-naive or antiretroviral-experienced patients.

If ritonavir-boosted atazanavir is used concomitantly with efavirenz in antiretroviral-naive 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.Ritonavir-boosted atazanavir should not be used concomitantly with efavirenz in antiretroviral-experienced patients.

If cobicistat-boosted atazanavir is used concomitantly with efavirenz in antiretroviral-naive adults, a regimen of single-entity atazanavir 400 mg and single-entity cobicistat 150 mg once daily (with food) and efavirenz 600 mg once daily (without food, preferably at bedtime) is recommended.Cobicistat-boosted atazanavir should not be used concomitantly with efavirenz in antiretroviral-experienced patients.

Concomitant use of atazanavir (with or without low-dose ritonavir) and the fixed combination efavirenz/emtricitabine/tenofovir DF is not recommended; data are insufficient to make dosage recommendations.

Darunavir

Concomitant use of ritonavir-boosted darunavir (darunavir 300 mg and ritonavir 100 mg twice daily) and efavirenz (600 mg once daily) increased the AUC of efavirenz by 21% and decreased the AUC of darunavir by 13%. The clinical importance of this interaction remains to be established. Concomitant use of cobicistat-boosted darunavir and efavirenz may result in decreased darunavir and cobicistat concentrations and may result in loss of therapeutic effect and development of darunavir resistance.

If ritonavir-boosted darunavir is used concomitantly with efavirenz, dosage adjustments are not necessary. However, some experts state that the patient should be monitored closely and consideration given to monitoring plasma concentrations of darunavir and efavirenz.

Cobicistat-boosted darunavir should not be used concomitantly with efavirenz because of possible loss of therapeutic effect and development of resistance to darunavir.

Fosamprenavir

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

Depending on the specific regimen of ritonavir-boosted fosamprenavir used, concomitant use with efavirenz may affect amprenavir concentrations. Concomitant use of efavirenz (600 mg once daily) with fosamprenavir 1.4 g once daily and ritonavir 200 mg once daily does not affect peak plasma amprenavir concentrations, but decreases the AUC and trough plasma concentrations of amprenavir. When additional ritonavir is added this regimen and efavirenz (600 mg once daily) is used concomitantly with fosamprenavir 1.4 g once daily and ritonavir 300 mg once daily, the AUC and peak plasma concentrations of amprenavir are increased slightly and trough plasma amprenavir concentrations are not affected. When a twice-daily regimen of ritonavir-boosted fosamprenavir is used, concomitant use of efavirenz (600 mg once daily) with fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily does not affect amprenavir AUC or peak plasma concentrations, but decreases trough plasma amprenavir concentrations.

If ritonavir-boosted fosamprenavir is used in patients receiving efavirenz, the usual efavirenz dosage should be used with fosamprenavir 1.4 g once daily and ritonavir 300 mg once daily or, alternatively, fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily.

If a once-daily regimen of ritonavir-boosted fosamprenavir is used in patients receiving efavirenz/emtricitabine/tenofovir DF, 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/emtricitabine/tenofovir DF, ritonavir dosage should not be adjusted.

Indinavir

Concomitant use of indinavir and efavirenz decreases the AUC of indinavir, but does not have a clinically important effect on plasma concentrations or AUC of efavirenz.

The optimum dosage of indinavir for use in conjunction with efavirenz has not been established; increasing indinavir dosage to 1 g every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.

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 results in decreased trough plasma concentrations and AUCs of both lopinavir and efavirenz. 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.

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

If a twice-daily regimen of lopinavir/ritonavir is used in adult or pediatric patients receiving efavirenz, an increased lopinavir/ritonavir dosage is recommended. Dosage depends on the lopinavir/ritonavir preparation used (tablets, oral solution) and clinical characteristics of the patient.

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%.

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

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%. If ritonavir is used concomitantly with efavirenz or efavirenz/emtricitabine/tenofovir DF, serum hepatic enzymes should be monitored and the patient should be monitored for adverse effects (e.g., dizziness, nausea, paresthesia).

Saquinavir

Concomitant use of saquinavir and efavirenz can substantially decrease the peak plasma concentration and AUC of saquinavir. In one study, administration of saquinavir (1.2 g every 8 hours as Fortovase [no longer commercially available in US]) and efavirenz (600 mg once daily) for 10 days decreased the peak plasma concentration and AUC of saquinavir by 50 and 62%, respectively, and decreased the peak plasma concentration and AUC of efavirenz by 12-13%.

The manufacturer of saquinavir states that concomitant use of ritonavir-boosted saquinavir and efavirenz is not recommended. Appropriate dosages for concomitant use of ritonavir-boosted saquinavir and efavirenz with respect to safety and efficacy have not been established.

Some experts state that the usual dosage of ritonavir-boosted saquinavir (1 g of saquinavir and 100 mg of ritonavir twice daily) may be used in patients receiving efavirenz.

Tipranavir

Concomitant use of efavirenz (600 mg once daily) and ritonavir-boosted tipranavir (tipranavir 500 mg twice daily with ritonavir 100 mg twice daily) results in decreased plasma concentrations and AUC of tipranavir but does not affect the pharmacokinetics of efavirenz. Pharmacokinetics of the PI are not affected if efavirenz (600 mg once daily) is used concomitantly with a higher dosage of ritonavir-boosted tipranavir (tipranavir 750 mg twice daily with ritonavir 200 mg twice daily).

Some experts state that dosage adjustments are not necessary if efavirenz and ritonavir-boosted tipranavir are used concomitantly.

Atovaquone

Concomitant use of efavirenz and atovaquone decreases atovaquone AUC. To avoid concomitant use, some experts state that an alternative to atovaquone should be considered for the treatment of Pneumocystis jirovecii pneumonia (PCP) or toxoplasmosis or an alternative to efavirenz should be considered. If efavirenz and atovaquone are used concomitantly, the patient should be monitored for therapeutic efficacy of atovaquone.

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.

Atorvastatin

If atorvastatin is used concomitantly with efavirenz, atorvastatin dosage should be titrated based on lipid response and should not exceed the maximum recommended dosage.

Lovastatin

If lovastatin is used concomitantly with efavirenz, lovastatin dosage should be titrated based on lipid response and should not exceed the maximum recommended dosage. Lovastatin should be avoided if efavirenz is used concomitantly with a ritonavir-boosted PI.

Pitavastatin

Concomitant use of pitavastatin and efavirenz results in decreased AUC and increased peak plasma concentrations of pitavastatin; dosage adjustments are not necessary.

Pravastatin

If pravastatin is used concomitantly with efavirenz, pravastatin dosage should be titrated based on lipid response and should not exceed the maximum recommended dosage.

Rosuvastatin

Data are not available regarding concomitant use of rosuvastatin and efavirenz; if the drugs are used concomitantly, rosuvastatin dosage should be titrated based on lipid response and should not exceed the maximum recommended dosage.

Simvastatin

If simvastatin is used concomitantly with efavirenz, simvastatin dosage should be titrated based on lipid response and should not exceed the maximum recommended dosage. Simvastatin should be avoided if efavirenz is used in a regimen that includes a ritonavir-boosted PI.

Calcium-channel Blocking Agents

Concomitant use of diltiazem and efavirenz results in decreased concentrations of diltiazem and slightly increased concentrations of efavirenz. If diltiazem is used concomitantly with efavirenz or efavirenz/emtricitabine/tenofovir DF, 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.

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. If efavirenz is used concomitantly with any of these drugs, dosage of the calcium-channel blocking agent should be titrated based on clinical response.

CNS Agents

Opiates and Opiate Partial Agonists

Buprenorphine

Concomitant use of buprenorphine (sublingual or buccal) and efavirenz may decrease the AUC of buprenorphine and norbuprenorphine. Some experts state that dosage adjustments are not recommended, but patients should be monitored for withdrawal symptoms.

Data are not available regarding concomitant use of buprenorphine (subdermal implant) and efavirenz. If efavirenz is initiated after insertion of the buprenorphine implant, clinical monitoring is recommended.

Methadone

Administration of methadone (35-100 mg daily) and efavirenz (600 mg daily for 14-21 days) in HIV-infected individuals with a history of drug dependence decreased the peak plasma concentration and AUC of methadone by 45 and 52%, respectively, and resulted in manifestations of opiate withdrawal. The maintenance dosage of methadone was increased by an average of 22% to alleviate withdrawal symptoms.

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

Anticonvulsants

Concomitant use of efavirenz and carbamazepine results in decreased plasma concentrations and AUCs of efavirenz and carbamazepine. Concomitant use of efavirenz and phenobarbital or phenytoin may result in decreased plasma concentrations of the anticonvulsant and/or efavirenz. The manufacturer of efavirenz states that data are insufficient to make dosage recommendations for concomitant use of efavirenz and carbamazepine. If carbamazepine, phenobarbital, or phenytoin is used concomitantly with efavirenz, plasma concentrations of the anticonvulsant and efavirenz should be monitored. If possible, use of another anticonvulsant should be considered.

Concomitant use of efavirenz and valproic acid in HIV-infected adults does not affect the pharmacokinetics of either drug.

The manufacturer of efavirenz/emtricitabine/tenofovir DF states that data are insufficient to make dosage recommendations for concomitant use of the fixed combination and carbamazepine; an alternative anticonvulsant should be used.

Psychotherapeutic Agents

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

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).

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

Selective Serotonin-reuptake Inhibitors

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

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

Pimozide

Efavirenz and pimozide should not be used concomitantly.

Sedatives and Hypnotics

Concomitant use of efavirenz and midazolam or triazolam is expected to substantially increase concentrations of the benzodiazepine. Efavirenz and oral midazolam or triazolam should not be used concomitantly. Some experts state that parenteral midazolam can be given in a single dose with caution in a monitored situation for procedural sedation in patients receiving efavirenz.

Data are not available regarding concomitant use of alprazolam and efavirenz; if the drugs are used concomitantly, some clinicians suggest that patients be monitored for therapeutic effectiveness of the benzodiazepine.

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. Dosage adjustments are not necessary in patients receiving lorazepam and efavirenz concomitantly.

Corticosteroids

Concomitant use of dexamethasone and efavirenz may result in decreased efavirenz concentrations. If dexamethasone and efavirenz are used concomitantly, virologic response should be monitored; alternative corticosteroids should be considered for long-term use.

Ergot Alkaloids

Efavirenz and ergot alkaloids (e.g., dihydroergotamine, ergotamine, methylergonovine) should not be used concomitantly.

If methylergonovine maleate (Methergine) is used to treat postpartum hemorrhage in a woman receiving efavirenz, additional uterotonic agents may be needed since efavirenz potentially could decrease methylergonovine concentrations resulting in an inadequate treatment effect.

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). Efavirenz concentrations were not affected by the oral contraceptive.

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

Concomitant use of levonorgestrel subcutaneous implant and efavirenz has resulted in a 47% decrease in plasma concentrations of levonorgestrel. In addition, unintended pregnancies have been reported in women with a levonorgestrel implant who were receiving efavirenz.

Studies evaluating concomitant use of efavirenz and orally administered levonorgestrel demonstrate a 64-83% decrease in levonorgestrel AUC. Efficacy of levonorgestrel as an emergency contraceptive is expected to be decreased in women receiving efavirenz. In a study in healthy women, concomitant use of efavirenz (600 mg once daily) and oral levonorgestrel (two 0.75-mg doses 12 hours apart) resulted in an estimated 56% decrease in the AUC of the progestin compared with use of levonorgestrel alone. It is not known whether efavirenz has a similar effect when oral levonorgestrel is given as a single 1.5-mg dose.

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

GI Drugs

Efavirenz and cisapride should not be used concomitantly.

Concomitant use of drugs that alter gastric pH is not expected to affect absorption of efavirenz. Systemic availability of efavirenz is not affected by concomitant use with an antacid or a histamine H2-receptor antagonist (e.g., famotidine). 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. Dosage adjustments are not needed if efavirenz is used concomitantly with famotidine or antacids.

HCV Antivirals

HCV Polymerase Inhibitors

Sofosbuvir

Concomitant use of sofosbuvir (single 400-mg dose) and efavirenz (600 mg once daily as the fixed combination efavirenz/emtricitabine/tenofovir DF) does not have a clinically important effect on the pharmacokinetics of sofosbuvir.

Dosage adjustments are not needed if sofosbuvir and efavirenz are used concomitantly.

Sofosbuvir and Velpatasvir

Concomitant use of the fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir) and the fixed combination efavirenz/emtricitabine/tenofovir DF does not have a clinically important effect on the pharmacokinetics of sofosbuvir, efavirenz, or emtricitabine, but results in decreased velpatasvir plasma concentrations and AUC and increased tenofovir plasma concentrations and AUC.

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

HCV Protease Inhibitors

Simeprevir

Concomitant use of simeprevir (150 mg once daily for 14 days) and efavirenz (600 mg once daily for 14 days) substantially decreased plasma concentrations and AUC of simeprevir and may result in loss of simeprevir therapeutic effects. There was no clinically important effect on efavirenz concentrations or AUC.

Concomitant use of simeprevir and efavirenz is not recommended.

HCV Replication Complex Inhibitors

Daclatasvir

Concomitant use of daclatasvir (120 mg once daily) and efavirenz (600 mg daily) results in decreased daclatasvir trough concentrations.

If daclatasvir and efavirenz are used concomitantly, daclatasvir should be given in a dosage of 90 mg once daily.

Elbasvir and Grazoprevir

Concomitant use of efavirenz (600 mg once daily) and elbasvir (50 mg once daily) or grazoprevir (200 mg once daily) results in substantially decreased elbasvir or grazoprevir concentrations due to potent CYP3A induction by efavirenz, which may lead to loss of virologic response to the HCV antiviral. Concomitant use does not have a clinically important effect on efavirenz exposures.

Concomitant use of the fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir) and efavirenz is contraindicated.

Ledipasvir and Sofosbuvir

If the fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) is used concomitantly with efavirenz, clinically important pharmacokinetic interactions are not expected. Concomitant use of the fixed combination efavirenz/emtricitabine/tenofovir DF and ledipasvir or sofosbuvir results in decreased ledipasvir concentrations, but does not have a clinically important effect on sofosbuvir or efavirenz concentrations.

Dosage adjustments are not necessary if ledipasvir/sofosbuvir and efavirenz are used concomitantly. If ledipasvir/sofosbuvir and efavirenz/emtricitabine/tenofovir DF are used concomitantly, patients should be monitored for tenofovir-associated adverse effects.

Ombitasvir, Paritaprevir, and Ritonavir

Concomitant use of efavirenz and the fixed combination of ombitasvir, paritaprevir, and ritonavir (ombitasvir/paritaprevir/ritonavir) with or without dasabuvir is poorly tolerated and has resulted in elevated liver enzymes.

Concomitant use of efavirenz and ombitasvir/paritaprevir/ritonavir with or without dasabuvir is contraindicated.

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 agents, but is not expected to affect efavirenz concentrations.

If efavirenz or efavirenz/emtricitabine/tenofovir DF is used concomitantly with an immunosuppressive agent metabolized by CYP3A (e.g., cyclosporine, sirolimus, tacrolimus), dosage of the immunosuppressive agent may need to be adjusted. When efavirenz or efavirenz/emtricitabine/tenofovir DF is initiated or discontinued, plasma concentrations of the immunosuppressive agent should be monitored for at least 2 weeks until stable concentrations are reached.

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.

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.

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. Some experts recommend that alternatives to clarithromycin (e.g., azithromycin) be considered in patients receiving efavirenz.

Phosphodiesterase Type 5 Inhibitors

Avanafil

Data are not available regarding concomitant use of avanafil and efavirenz; concomitant use is not recommended.

Dietary and Herbal Supplements

St. John's Wort (Hypericum perforatum)

St. John's wort (Hypericum perforatum) and efavirenz should not be used concomitantly since such use is expected to result in suboptimal antiretroviral concentrations and may be associated with loss of virologic response and development of resistance. St. John's wort is an extract of hypericum and contains at least 7 different components that may contribute to its pharmacologic effects, including hypericin, pseudohypericin, and hyperforin. There is evidence that hypericum extracts can induce several different CYP isoenzymes, including CYP3A4 and CYP1A2, and also may induce the P-glycoprotein transport system. Therefore, it has be recommended that concomitant use of St. John's wort and PIs or NNRTIs metabolized by CYP isoenzymes be avoided. For further information on drug interactions between St. John's wort and drugs metabolized by CYP isoenzymes,

Pharmacokinetics

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. 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.

Results to date indicate that pharmacokinetic parameters of the drug in healthy individuals are similar to those in HIV-infected individuals. Pharmacokinetic studies have not revealed gender- or race-related differences in the pharmacokinetics of efavirenz. 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. The pharmacokinetics of efavirenz have not been specifically studied in patients with renal impairment, and only very limited data are available to date.

Absorption

Following oral administration of a single 100- to 1600-mg dose of efavirenz in healthy adults, peak plasma drug concentrations of 0.51-2.9 mcg/mL were attained within 5 hours. While administration of single oral doses of up to 1600 mg of efavirenz was associated with dose-related increases in peak plasma concentration and AUC, the increases were less than proportional and suggest reduced absorption of the drug at higher doses. 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. 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. Following continued administration of efavirenz, plasma concentrations are lower than expected from single-dose studies, presumably because of increased clearance of the drug. 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.

Following oral administration of efavirenz 600 mg once daily in HIV-infected adults, peak plasma concentration, trough plasma concentration, and AUC of the drug at steady-state averaged 4.1 mcg/mL, 1.8 mcg/mL, and 58.1 mcg&bul;hour/mL, respectively. Predicted steady-state peak plasma concentrations of efavirenz following administration of efavirenz capsules (or capsule contents mixed with soft food or infant formula) in HIV-infected pediatric patients weighing 3.5-5 kg (100 mg once daily), 7.5-10 kg (200 mg once daily), 15-20 kg (250 mg once daily), 20-25 kg (300 mg once daily), or 32.5-40 kg (400 mg once daily) are 5.81, 7.75, 6.47, 7.04, or 6.96 mcg/mL, respectively.

Following oral administration of a single 400-mg oral dose of efavirenz in individuals with chronic liver disease or healthy individuals, peak plasma concentrations averaged 1.2 or 1.8 mcg/mL, respectively, and AUC averaged 94.4 or 96.3 mcg&bul;hour/mL, respectively.

Oral bioavailability of efavirenz may be affected by administration with food. 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. 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. Therefore, the manufacturer states that efavirenz should be administered on an empty stomach. 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.(See Dosage and Administration: Administration.)

Distribution

Distribution of efavirenz into body tissues and fluids has not been fully characterized. In rats and rhesus monkeys, the volume of distribution of efavirenz following IV administration is 2.4-4.4 L/kg suggesting extensive tissue distribution.

Following oral administration of efavirenz 200-600 mg once daily for 1 month or longer in HIV-infected adults, CSF concentrations of efavirenz were 0.26-1.19% of corresponding plasma concentrations. Low concentrations of efavirenz are found in CSF; however, the proportion of drug in CSF is about threefold higher than the nonprotein-bound fraction in plasma. In a study in HIV-infected patients who received efavirenz 600 mg once daily for 5 weeks or longer mean CSF concentrations of efavirenz were 0.011 mcg/mL (range: 0.002-0.019 mcg/mL) and concurrent mean plasma concentrations were 1.97 mcg/mL (range: 0.792-2.95 mcg/mL).

Efavirenz is about 99.5-99.75% bound to plasma proteins, principally albumin.

Efavirenz crosses the placenta in animals (e.g., rats, rabbits, primates) and concentrations of the drug in fetal blood in these species are similar to those in maternal blood. Efavirenz is distributed into human milk.

Elimination

Efavirenz appears to induce its own metabolism. 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. In addition, following continued administration of efavirenz, plasma concentrations are lower than expected from single-dose studies, presumably because of increased clearance.

The terminal elimination half-life of efavirenz is prolonged in patients with chronic liver disease. Following oral administration of a single 400-mg dose of efavirenz, an elimination half-life of 152 or 118 hours was reported in individuals with or without chronic liver disease, respectively.

In one HIV-infected adult with anuric end-stage renal failure who was receiving efavirenz in a dosage of 600 mg once daily, peak and trough plasma concentrations were 2.58 and 0.65 mcg/mL and the plasma half-life was decreased to 10 hours.

The metabolic fate of efavirenz has not been fully determined, but the drug is metabolized in the liver. Efavirenz is principally metabolized by the cytochrome P-450 (CYP) isoenzymes 3A and 2B6 to several hydroxylated metabolites, which undergo subsequent glucuronidation.

Efavirenz is excreted principally in the feces, both as unchanged drug and metabolites. Excretion of efavirenz has been evaluated in individuals receiving 400 mg daily for 1 month. Following oral administration of 400 mg of radiolabeled efavirenz on day 8, 14-34% of the dose was excreted in urine (less than 1% as unchanged drug), and 16-61% was excreted in feces (predominantly as unchanged drug).

Because efavirenz is highly protein bound and less than 1% of the drug is excreted unchanged in urine, it is unlikely that substantial amounts of the drug would be removed from the body by hemodialysis or peritoneal dialysis. The pharmacokinetics of efavirenz were evaluated in an HIV-infected adult with anuric end-stage renal failure undergoing hemodialysis and results confirm that hemodialysis does not affect the pharmacokinetics of the drug.

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