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  • CLASSES

    Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)s

    DEA CLASS

    Rx

    DESCRIPTION

    Non-nucleoside reverse transcriptase inhibitor
    Used for the treatment of HIV-1 infection in combination with other antiretroviral agents
    Advantages include once daily dosing and penetration into cerebrospinal fluid (CSF)

    COMMON BRAND NAMES

    Sustiva

    HOW SUPPLIED

    Efavirenz/Sustiva Oral Cap: 50mg, 200mg
    Efavirenz/Sustiva Oral Tab: 600mg

    DOSAGE & INDICATIONS

    For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents.
    Investigational Dosing for patients with CYP2B6 516 GG and GT Genotypes (Extensive Metabolizers)†.
    Oral dosage
    Infants 3 to 11 months weighing 3 to 4 kg

    200 mg PO once daily based on IMPAACT study P1070, a study in children younger than 3 years with HIV. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.

    Infants and Children 3 months to 2 years weighing 5 to 6 kg

    300 mg PO once daily based on IMPAACT study P1070, a study in children younger than 3 years with HIV. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.

    Infants and Children 3 months to 2 years weighing 7 to 13 kg

    400 mg PO once daily based on IMPAACT study P1070, a study in children younger than 3 years with HIV. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.

    Children 1 to 2 years weighing 14 to 16 kg

    500 mg PO once daily based on IMPAACT study P1070, a study in children younger than 3 years with HIV. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.

    Children 1 to 2 years weighing 17 kg or greater

    600 mg PO once daily based on IMPAACT study P1070, a study in children younger than 3 years with HIV. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.

    Investigational Dosing for patients with CYP2B6 516 TT Genotype (Slow Metabolizers)†.
    Oral dosage
    Infants and Children 3 months to 2 years weighing 3 to 6 kg

    50 mg PO once daily based on IMPAACT study P1070, a study in children younger than 3 years with HIV. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.

    Infants and Children 3 months to 2 years weighing 7 to 13 kg

    100 mg PO once daily based on IMPAACT study P1070, a study in children younger than 3 years with HIV. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.

    Infants and Children 3 months to 2 years weighing 14 kg or greater

    150 mg PO once daily based on IMPAACT study P1070, a study in children younger than 3 years with HIV. The HIV guidelines recommend that efavirenz should generally not be used in children younger than 3 years. However, if use is unavoidable in this population, the guidelines recommend a determination of CYP2B6 genotype to guide dosing. Efavirenz plasma trough concentrations should be obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment.

    Oral dosage
    Adults

    600 mg PO once daily at bedtime.

    Children and Adolescents weighing 40 kg or more

    600 mg PO once daily at bedtime.

    Children and Adolescents weighing 32.5 to 39 kg

    400 mg PO once daily at bedtime. However, 367 mg/m2/day has been suggested by some experts to avoid underdosing at the upper end of each weight band as suboptimal concentrations have been reported in trials using the FDA-approved dosing recommendations.

    Children weighing 25 to 32.4 kg

    350 mg PO once daily at bedtime. However, 367 mg/m2/day has been suggested by some experts to avoid underdosing at the upper end of each weight band as suboptimal concentrations have been reported in trials using the FDA-approved dosing recommendations.

    Children weighing 20 to 24 kg

    300 mg PO once daily at bedtime. However, 367 mg/m2/day has been suggested by some experts to avoid underdosing at the upper end of each weight band as suboptimal concentrations have been reported in trials using the FDA-approved dosing recommendations.

    Children weighing 15 to 19 kg

    250 mg PO once daily at bedtime. However, 367 mg/m2/day has been suggested by some experts to avoid underdosing at the upper end of each weight band as suboptimal concentrations have been reported in trials using the FDA-approved dosing recommendations. Although efavirenz is FDA-approved for use in children 3 months and older, the HIV guidelines state that efavirenz should generally not be used in children younger than 3 years due to lack of data on dosing and concerns about the possibility for underdosing or excessive exposure associated with the CYP2B6 genotype. If efavirenz use is unavoidable in this population, CYP2B6 genotyping should be performed, and therapeutic drug monitoring should be considered (efavirenz concentration obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment). Investigational dosing recommendations based on CYP2B6 genotype are available in guidelines for children younger than 3 years.

    Infants and Children 3 months and older weighing 7.5 to 14 kg

    200 mg PO once daily at bedtime. However, 367 mg/m2/day has been suggested by some experts to avoid underdosing at the upper end of each weight band as suboptimal concentrations have been reported in trials using the FDA-approved dosing recommendations. Although efavirenz is FDA-approved for use in children 3 months and older, the HIV guidelines state that efavirenz should generally not be used in children younger than 3 years due to lack of data on dosing and concerns about the possibility for underdosing or excessive exposure associated with the CYP2B6 genotype. If efavirenz use is unavoidable in this population, CYP2B6 genotyping should be performed, and therapeutic drug monitoring should be considered (efavirenz concentration obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment). Investigational dosing recommendations based on CYP2B6 genotype are available in guidelines for children younger than 3 years.

    Infants 3 months and older weighing 5 to 7.4 kg

    150 mg PO once daily at bedtime. However, 367 mg/m2/day has been suggested by some experts to avoid underdosing at the upper end of each weight band as suboptimal concentrations have been reported in trials using the FDA-approved dosing recommendations. Although efavirenz is FDA-approved for use in children 3 months and older, the HIV guidelines state that efavirenz should generally not be used in children younger than 3 years due to lack of data on dosing and concerns about the possibility for underdosing or excessive exposure associated with the CYP2B6 genotype. If efavirenz use is unavoidable in this population, CYP2B6 genotyping should be performed, and therapeutic drug monitoring should be considered (efavirenz concentration obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment). Investigational dosing recommendations based on CYP2B6 genotype are available in guidelines for children younger than 3 years.

    Infants 3 months and older weighing 3.5 to 4 kg

    100 mg PO once daily at bedtime. However, 367 mg/m2/day has been suggested by some experts to avoid underdosing at the upper end of each weight band as suboptimal concentrations have been reported in trials using the FDA-approved dosing recommendations. Although efavirenz is FDA-approved for use in children 3 months and older, the HIV guidelines state that efavirenz should generally not be used in children younger than 3 years due to lack of data on dosing and concerns about the possibility for underdosing or excessive exposure associated with the CYP2B6 genotype. If efavirenz use is unavoidable in this population, CYP2B6 genotyping should be performed, and therapeutic drug monitoring should be considered (efavirenz concentration obtained 2 weeks after therapy initiation and at age 3 years for possible dose adjustment). Investigational dosing recommendations based on CYP2B6 genotype are available in guidelines for children younger than 3 years.

    For human immunodeficiency virus (HIV) prophylaxis† after occupational exposure.
    Oral dosage
    Adults

    The World Health Organization (WHO) and the US Public Health Service guidelines suggest efavirenz 600 mg PO once daily at bedtime in combination with one of the following backbones (in order of preference) as acceptable alternative regimens for HIV post-exposure prophylaxis (PEP): tenofovir plus emtricitabine; tenofovir plus lamivudine; zidovudine plus lamivudine; zidovudine plus emtricitabine. However, prior to administering an efavirenz containing regimen, the US Public Health Service recommends consultation with a clinician experienced in the management of PEP. The New York State Department of Health AIDS Institute recommends against use of efavirenz because of the potential for CNS adverse effects, teratogenicity, and resistance. According to PEP guidelines, individuals potentially exposed to HIV should receive a 3-drug regimen for a total of 28 days; however if tolerability is a concern, use of a 2-drug regimen may be considered and is preferred to prophylaxis discontinuation. Begin prophylaxis as soon as possible, ideally within 2 hours of exposure. If initiation of prophylaxis is delayed (beyond 36 hours or 72 hours after exposure), efficacy of the antiretroviral regimen may be diminished and treatment should be determined on a case-by-case basis. Exposures for which PEP is indicated include: skin puncture by a sharp object that has been contaminated with blood, body fluid, or other infectious material; bite from a patient with visible bleeding in the mouth which causes bleeding by the exposed worker; splash of blood, body fluid, or other infectious material onto the workers mouth, nose, or eyes; exposure of blood, body fluid, or other infectious material on a workers non-intact skin (i.e., open wound, chapped skin, abrasion, dermatitis).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    600 mg/day PO.

    Geriatric

    600 mg/day PO.

    Adolescents

    40 kg or more: 600 mg/day PO.
    32.5 to 39 kg: 400 mg/day PO.
    25 to 32.4 kg: 350 mg/day PO.

    Children

    40 kg or more: 600 mg/day PO.
    32.5 to 39 kg: 400 mg/day PO.
    25 to 32.4 kg: 350 mg/day PO.
    20 to 24 kg: 300 mg/day PO.
    15 to 19 kg: 250 mg/day PO.
    7.5 to 14 kg: 200 mg/day PO.
    5 to 7.4 kg: 150 mg/day PO.

    Infants

    3 to 11 months weighing 7.5 to 14 kg: 200 mg/day PO.
    3 to 11 months weighing 5 to 7.4 kg: 150 mg/day PO.
    3 to 11 months weighing 3.5 to 4 kg: 100 mg/day PO.
    1 to 2 months or weighing less than 3.5 kg: Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild impairment (Child-Pugh class A, total score of 5 or 6): No dosage adjustment needed.
    Moderate impairment (Child-Pugh class B, total score of 7 to 9): Not recommended.
    Severe impairment (Child-Pugh class C, total score more than 10): Not recommended.

    Renal Impairment

    Efavirenz has not been studied in patients with renal impairment; however, since less than 1% is excreted into the urine unchanged, no dosage adjustment is required.

    ADMINISTRATION

    For storage information, see the specific product information within the How Supplied section
    To reduce the nervous system side effects, bedtime dosing is recommended.

    Oral Administration

    Administer on an empty stomach. Increased efavirenz concentrations observed following administration with food might lead to an increased frequency of adverse reactions.

    Oral Solid Formulations

    Swallow capsules and tablets intact with liquid; DO NOT crush the tablets.[28442]
     
    Capsule sprinkle method of administration
    Only for patients unable to swallow capsules or tablets.
    Open the capsule by holding horizontally over a small container and carefully twisting to open. Take precautions to avoid spillage or dispersion of the contents into the air.
    For patients able to tolerate solid foods, add a small amount (1 to 2 teaspoons) of age-appropriate soft food (applesauce, grape jelly, yogurt) to the container holding the entire capsule contents; gently mix and administer the dose.
    For young infants, the entire capsule content is mixed in a medicine cup with 2 teaspoons (10 mL) of reconstituted, room temperature infant formula. After carefully stirring with a small spoon, the mixture is drawn up into a 10 mL oral syringe and administered.
    After administration, an additional small amount (2 teaspoons) of food or formula must be added to the empty mixing container, stirred to disperse remaining drug residue, and administered to the patient.
    Administer the dose within 30 minutes of mixing.
    No additional food should be consumed for 2 hours after the dose.[28442]
    The mixture with grape jelly was rated as the most palatable formulation.[54609]

    STORAGE

    Sustiva:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    During baseline evaluation of people with HIV, discuss risk reduction measures and the need for status disclosure to sexual or needle-sharing partners, especially with untreated patients who are still at high risk of HIV transmission. Include the importance of adherence to therapy to achieve and maintain a plasma HIV RNA less than 200 copies/mL. Maintaining a plasma HIV RNA less than 200 copies/mL, including any measurable value below this threshold, with antiretroviral therapy prevents sexual transmission of HIV to their partners. Patients may recognize this concept as Undetectable = Untransmittable or U=U.
     
    Unplanned antiretroviral therapy interruption may be necessary for specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., less than 1 to 2 days) is necessary, in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption occurs in a pregnant patient or is because of a serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered; as stopping all simultaneously in a regimen containing drugs with differing half-lives may result in functional monotherapy of the drug with the longest half-life and may increase the risk for resistant mutations. Health care providers are advised to reinitiate a complete and effective antiretroviral regimen as soon as possible after an interruption of therapy. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities. [46638] [42452]

    Pregnancy

    Antiretroviral therapy should be provided to all women during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations are greater than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations are greater than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. According to the manufacturer, efavirenz may cause fetal harm (i.e., neural tube defects), and should be avoided during the first trimester of pregnancy. The manufacturer also recommends the use of 2 effective forms of birth control during treatment and for 12 weeks after stopping efavirenz.[28442] However, HIV treatment guidelines do not restrict the use of efavirenz-containing regimens in pregnant women or in women who are trying to conceive. In addition, guidelines recommend that women who become pregnant while receiving suppressive efavirenz-containing regimens continue their current regimens. The HIV guidelines base this decision on the results of a meta-analysis of 23 studies. Data from this meta-analysis found no increased risk of overall birth defects in infants born to women on efavirenz during the first trimester compared with those on other antiretroviral medications (relative risk 0.78; 95% CI, 0.56 to 1.08). Further, data from more than 13,00 periconception exposures to efavirenz in Botswana were sufficient to rule out an increased risk of neural tube defects with efavirenz. Available data from the Antiretroviral Pregnancy Registry (APR), which includes more than 1,160 first trimester exposures to efavirenz, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. When efavirenz exposure occurred in the first trimester, the prevalence of defects was 2.4% (95% CI: 1.6 to 3.5). Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Women who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for women on HAART less than 2 years, women with CD4 count less than 300 cells/mm3, or women with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing, and if indicated, phenotypic testing) at baseline in all women with HIV RNA concentrations greater than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in women receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for the development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a woman decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to efavirenz; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.[27468] [23512] [28442] [46638]

    Breast-feeding

    To reduce the risk of postnatal transmission, mothers with HIV within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy, including efavirenz. If a mother with HIV opts to breast-feed, the infant should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, health care workers may contact the Perinatal HIV Hotline (888-448-8765).[42452] Efavirenz has been shown to pass into human breast milk. One study found efavirenz plasma concentrations in breast-fed infants (taken 3 to 4 hours after the last dose) to be 13.1% of maternal plasma concentrations; the mean infant plasma concentrations were below those considered effective for HIV treatment in adults. Other antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.

    Hepatic disease, hepatitis, hepatitis B and HIV coinfection

    Efavirenz is not recommended in patients with moderate or severe hepatic impairment. Postmarketing cases of hepatitis, including fulminant hepatitis progressing to liver failure requiring transplantation or resulting in death, have been reported with efavirenz. Reports have included patients with underlying hepatic disease, including those with hepatitis B or C, and patients without preexisting hepatic disease or other identifiable risk factors. Monitoring of liver enzymes prior to and during treatment with efavirenz is recommended in all patients, particularly in patients with mild hepatic impairment. Consider treatment discontinuation in patients with persistent elevations of serum transaminases to greater than 5 times the upper limit of normal. Discontinue efavirenz if elevation of serum transaminases is accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation. Perform hepatitis B virus (HBV) screening in any patient who presents with HIV infection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still require treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    Hypercholesterolemia, hypertriglyceridemia

    Fat redistribution and hyperlipidemia have become increasingly recognized side effects with the use of antiretroviral agents. According to CDC guidelines, patients with hypertriglyceridemia or hypercholesterolemia should be evaluated for risks for cardiovascular events and pancreatitis. If a patient develops hyperlipidemia during antiretroviral treatment, possible interventions include dietary modification, use of lipid lowering agents, or modification of treatment regimen. Monitoring of serum cholesterol and triglycerides is recommended during efavirenz therapy.

    Alcoholism, bipolar disorder, depression, driving or operating machinery, mania, neurotoxicity, psychosis, schizophrenia, substance abuse, suicidal ideation

    A majority of patients receiving efavirenz during clinical trials experienced CNS adverse reactions, including dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, hallucinations, euphoria, confusion, agitation, amnesia, stupor, and depersonalization. In most cases, these symptoms were mild to moderate in severity and began during the 1st or 2nd day of therapy. Inform drug recipients that these common symptoms will likely improve with continued use of the drug (generally after the first 2 to 4 weeks of therapy) and are not predictive of subsequent onset of less frequent psychiatric symptoms. Use of ethanol or other psychoactive drugs may worsen these symptoms, while dosing at bedtime may improve the tolerability. Instruct patients to avoid driving or operating machinery until they know how efavirenz may affect them. Some patients may experience late-onset neurotoxicity, including ataxia and encephalopathy (i.e., impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), that develops months to years after starting efavirenz therapy. Of note, some cases of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased efavirenz concentrations despite standard dosing. Serious psychiatric adverse events (i.e., severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, paranoid reactions, catatonic reactions, manic reactions) have also been associated with efavirenz therapy. Promptly evaluate any patients who presents with signs or symptoms of a serious neurologic adverse reaction. Patients with a history of mental illness (e.g., bipolar disorder, depression, mania, schizophrenia, or psychosis), alcoholism, or substance abuse, may be at increased risk for CNS adverse reactions, including psychiatric adverse reactions.

    Autoimmune disease, Graves' disease, Guillain-Barre syndrome, immune reconstitution syndrome

    Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to efavirenz therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as progressive multifocal leukoencephalopathy (PML), mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, autoimmune hepatitis, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.

    Seizure disorder, seizures

    Use efavirenz with caution in patients with a history of seizures. Although infrequent, seizures have been observed in patients receiving efavirenz and these events have typically occurred in the presence of a known medical history of seizure disorder. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin, carbamazepine, and phenobarbital, may require periodic monitoring of anticonvulsant plasma concentrations.

    Hepatitis C and HIV coinfection

    HIV treatment guidelines recommend all patients presenting with HIV infection undergo routine screening for hepatitis C virus (HCV). For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experience with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid consuming alcohol, limit ingestion of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.

    Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, females, fever, geriatric, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, myocardial infarction, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE)

    Daily efavirenz doses of 600 mg PO administered for 14 days to healthy subjects with CYP2B6 polymorphisms, specifically the CYP2B6 *6/*6 genotype, has resulted in a mean QTc prolongation of 8.7 milliseconds. Consider alternatives to efavirenz in patients receiving medications that have the potential to cause torsade de pointes (TdP). Use efavirenz with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

    Asian patients, Hispanic patients, human immunodeficiency virus (HIV) infection resistance

    Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. The prevalence of transmitted drug resistance (TDR) in high-income countries ranges from 9% to 14% and varies by country. In most TDR surveys, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance and nucleoside reverse transcriptase inhibitor (NRTI) resistance are the most common mutation class types detected, followed by protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) resistance mutations, respectively. Resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. As with all other antiretroviral agents, antimicrobial resistance can develop when efavirenz is used either alone or in combination with other agents. Monotherapy with efavirenz is not recommended. Cross-resistance between reverse transcriptase inhibitors and protease inhibitors is unlikely because different enzyme targets are involved. In patients whom a planned discontinuation or interruption of efavirenz therapy is planned, there is an increased risk of NNRTI-resistant mutations. Pharmacokinetic data demonstrate the persistence of detectable drug levels for at least 21 days after discontinuation of efavirenz; simultaneously stopping all drugs in a regimen containing efavirenz may result in functional efavirenz monotherapy due to its long half-life. This is further complicated by evidence that certain genetic polymorphisms, more common among some ethnic groups (such as in African patients, Asian patients, and Hispanic patients), may result in slower rate of clearance. Some experts recommend stopping efavirenz before the other antiretroviral drugs, although the optimal interval between stopping efavirenz and other antiretroviral drugs is not known. An alternative strategy is to substitute the efavirenz with a PI prior to interruption of all antiretroviral drugs; if this strategy is used, the goal is to assure that the PI used also achieves complete viral suppression during this interval. Further research to determine the best approach to temporarily discontinuing efavirenz is needed.

    Children, serious rash

    Rash is a common adverse reaction associated with efavirenz therapy. In most patients, it is a self-limiting mild-to-moderate maculopapular eruption that develops within the first 2 weeks of treatment. However, in rare cases, serious rash (e.g., erythema multiforme, Stevens-Johnson syndrome) has been observed. Efavirenz should be discontinued in patients with a rash associated with blistering, desquamation (e.g., exfoliative dermatitis), mucosal involvement, or fever. It can be restarted following interruptions due to rash; however, for those patients experiencing a life-threatening cutaneous reaction (Stevens-Johnson syndrome), an alternative treatment is recommended. Use of appropriate antihistamines and corticosteroids may be considered when efavirenz is restarted; these agents may improve the tolerability and hasten the resolution of the rash. Compared with adults, children tend to have more frequent and severe rashes. Prophylaxis with antihistamines prior to initiating therapy with efavirenz in pediatric patients should be considered.

    Contraception requirements, pregnancy testing, reproductive risk

    According to the manufacturer, efavirenz may cause serious fetal harm when administered during the first trimester of pregnancy; therefore, it is recommended that all females of childbearing age undergo pregnancy testing prior to initiating an efavirenz-containing treatment regimen. Counsel females about the reproductive risk and contraception requirements during treatment; barrier contraception should be used in combination with other methods of contraception during therapy and for 12 weeks after efavirenz has been discontinued. HIV treatment guidelines, however, state that study data indicate efavirenz-containing regimens are safe treatment options for use in pregnant women and women who are trying to conceive.

    ADVERSE REACTIONS

    Severe

    erythema multiforme / Delayed / 0.1-2.2
    Stevens-Johnson syndrome / Delayed / 0.1-2.2
    seizures / Delayed / 0-1.0
    visual impairment / Early / 0-1.0
    hepatic failure / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    suicidal ideation / Delayed / 0.7-0.7
    teratogenesis / Delayed / Incidence not known

    Moderate

    hypercholesterolemia / Delayed / 10.0-54.0
    elevated hepatic enzymes / Delayed / 2.0-20.0
    depression / Delayed / 0-19.0
    erythema / Early / 5.0-16.0
    hypertriglyceridemia / Delayed / 6.0-11.0
    neutropenia / Delayed / 2.0-10.0
    hyperamylasemia / Delayed / 4.0-6.0
    hyperglycemia / Delayed / 2.0-5.0
    hallucinations / Early / 1.2-1.2
    ataxia / Delayed / 0-1.0
    psychosis / Early / 0-1.0
    hepatitis / Delayed / 0-1.0
    constipation / Delayed / 0-1.0
    myopathy / Delayed / 0-1.0
    dyspnea / Early / 0-1.0
    palpitations / Early / 0-1.0
    mania / Early / 0.2-0.2
    encephalopathy / Delayed / Incidence not known
    euphoria / Early / Incidence not known
    amnesia / Delayed / Incidence not known
    confusion / Early / Incidence not known
    lipodystrophy / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known

    Mild

    rash / Early / 26.0-32.0
    dizziness / Early / 28.1-28.1
    insomnia / Early / 0-16.3
    urticaria / Rapid / 5.0-16.0
    pruritus / Rapid / 5.0-16.0
    maculopapular rash / Early / 5.0-16.0
    diarrhea / Early / 3.0-14.0
    anxiety / Delayed / 0-13.0
    nausea / Early / 2.0-10.0
    headache / Early / 2.0-8.0
    fatigue / Early / 2.0-8.0
    drowsiness / Early / 7.0-7.0
    nightmares / Early / 6.2-6.2
    vomiting / Early / 3.0-6.0
    dyspepsia / Early / 4.0-4.0
    abdominal pain / Early / 2.0-3.0
    anorexia / Delayed / 1.0-2.0
    paresthesias / Delayed / 0-1.0
    vertigo / Early / 0-1.0
    tinnitus / Delayed / 0-1.0
    hypoesthesia / Delayed / 0-1.0
    tremor / Early / 0-1.0
    emotional lability / Early / 0-1.0
    photosensitivity / Delayed / 0-1.0
    flushing / Rapid / 0-1.0
    arthralgia / Delayed / 0-1.0
    myalgia / Early / 0-1.0
    asthenia / Delayed / 0-1.0
    paranoia / Early / 0.4-0.4
    agitation / Early / Incidence not known
    gynecomastia / Delayed / Incidence not known
    Cushingoid features / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Major) When possible, avoid concurrent use of dolutegravir with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and efavirenz is an inducer of CYP3A4.
    Abemaciclib: (Major) Avoid coadministration of efavirenz with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Consider alternative treatments. Abemaciclib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 53%, 41%, and 29% respectively.
    Abrocitinib: (Major) Avoid coadministration of abrocitinib with efavirenz as the combined exposure of abrocitinib and its 2 active metabolites may be increased, which may increase the risk for adverse reactions. Abrocitinib is a substrate of CYP2C19 and CYP2C9; efavirenz is a moderate CYP2C19 and CYP2C9 inhibitor.
    Acetaminophen: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Aspirin: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Aspirin; Diphenhydramine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Caffeine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with efavirenz can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If efavirenz is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Efavirenz is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Caffeine; Pyrilamine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Chlorpheniramine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Dextromethorphan: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Dextromethorphan; Doxylamine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Diphenhydramine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Guaifenesin; Phenylephrine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with efavirenz can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If efavirenz is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with efavirenz is necessary; consider increasing the dose of oxycodone as needed. If efavirenz is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Pamabrom; Pyrilamine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Pentazocine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Acetaminophen; Pseudoephedrine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Adagrasib: (Major) Concomitant use of adagrasib and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Adefovir: (Major) Patients who are concurrently taking adefovir with non-nucleoside reverse transcriptase inhibitors are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
    Alfentanil: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of other drugs metabolized by this enzyme, such as alfentanil.
    Alfuzosin: (Moderate) Consider alternatives to efavirenz when coadministering with alfuzosin as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Alfuzosin may also prolong the QT interval in a dose-dependent manner.
    Aliskiren; Amlodipine: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Alprazolam: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including alprazolam. Monitor patients closely for excessive side effects.
    Amiodarone: (Major) If possible, avoid coadministration of efavirenz and amiodarone, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as amiodarone. It would be prudent to monitor for changes in amiodarone efficacy.
    Amisulpride: (Major) Avoid coadministration of efavirenz and amisulpride due to the risk of QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Amisulpride causes dose- and concentration- dependent QT prolongation.
    Amlodipine: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Amlodipine; Atorvastatin: (Moderate) Efavirenz has the potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with atorvastatin with caution. (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Amlodipine; Benazepril: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Amlodipine; Celecoxib: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz. (Minor) Efavirenz inhibits CYP2C9 and CYP2C19 in the range of observed efavirenz plasma concentrations. Efavirenz may inhibit the metabolism of the celecoxib since it is a substrate for CYP2C9.
    Amlodipine; Olmesartan: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Amlodipine; Valsartan: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) The manufacturer of efavirenz recommends that alternatives to clarithromycin be considered when a macrolide antibiotic is required in patients receiving efavirenz. Coadministration of efavirenz and clarithromycin may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes TdP. QT prolongation has also been observed with use of efavirenz. In addition, concurrent use of efavirenz with clarithromycin 500 mg PO every 12 hours for seven days resulted in a significant decrease in the serum concentration of clarithromycin, but the clinical significance of this is not known. (Minor) Efavirenz inhibits and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C19.
    Anagrelide: (Major) If possible, avoid coadministration of efavirenz and anagrelide, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Ventricular tachycardia and TdP have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary.
    Apalutamide: (Major) Use caution if apalutamide and efavirenz are used concomitantly, as coadministration may significantly reduce plasma concentrations of efavirenz, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. When efavirenz is coadministered with another strong CYP3A4 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients weighing at least 50 kg). Apalutamide is a strong CYP3A4 inducer and efavirenz is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of efavirenz.
    Apomorphine: (Moderate) Consider alternatives to efavirenz when coadministering with apomorphine since concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    Aprepitant, Fosaprepitant: (Major) Use caution if efavirenz and aprepitant, fosaprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant as well as an increase in efavirenz-related adverse effects for several days after administration of a multi-day aprepitant regimen. Efavirenz is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of efavirenz. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Additionally, efavirenz is a moderate CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for weak-to-moderate inducers.
    Aripiprazole: (Moderate) Consider alternatives to efavirenz when coadministering with aripiprazole as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. In addition, decreased aripiprazole blood levels are expected when aripiprazole is coadministered with inducers of CYP3A4, such as efavirenz. Monitor the patient carefully for toxicity and efficacy if these agents are used in combination. Dosage adjustments of aripiprazole may be clinically warranted in some patients. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.
    Arsenic Trioxide: (Major) QT interval prolongation, TdP, and complete atrioventricular block have been reported with arsenic trioxide use. Avoid concomitant use of arsenic trioxide with other drugs that may cause QT interval prolongation, such as efavirenz; select an alternative antiretroviral that does not prolong the QT interval prior to starting arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms.
    Artemether; Lumefantrine: (Major) If possible, avoid coadministration of efavirenz and artemether; lumefantrine, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Artemether; lumefantrine is also associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if efavirenz must be used with or after artemether; lumefantrine treatment. In addition, coadministration may decrease concentrations of artemether; lumefantrine and/or dihydroartemisinin (active metabolite of artemether). The antimalarial efficacy of artemether; lumefantrine may be decreased. In a drug interaction study, when artemether; lumefantrine was co-administered with efavirenz, the Cmax and AUC of artemether; lumefantrine decreased by 21% and 51%, respectively. If these drugs are co-administered, monitor for decreased antimalarial efficacy of artemether; lumefantrine.
    Asenapine: (Major) According to the manufacturer of asenapine, the drug should be avoided in combination with other agents known to cause QT prolongation, such as efavirenz. Both asenapine and efavirenz have been associated with QT prolongation.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer.
    Aspirin, ASA; Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as efavirenz, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer. (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as efavirenz, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
    Aspirin, ASA; Omeprazole: (Minor) Efavirenz inhibits and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C19.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with efavirenz is necessary; consider increasing the dose of oxycodone as needed. If efavirenz is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Atazanavir: (Major) Due to induction of the CYP3A4 isoenzyme by efavirenz, coadministration results in significantly decreased atazanavir AUC and Cmin. Do not coadminister these drugs to treatment-experienced patients. Coadministration is acceptable in treatment-naive patients weighing at least40 kg as a regimen of atazanavir 400 mg with ritonavir 100 mg given once daily with food and efavirenz 600 mg given once daily on an empty stomach.
    Atazanavir; Cobicistat: (Major) Due to induction of the CYP3A4 isoenzyme by efavirenz, coadministration results in significantly decreased atazanavir AUC and Cmin. Do not coadminister these drugs to treatment-experienced patients. Coadministration is acceptable in treatment-naive patients weighing at least40 kg as a regimen of atazanavir 400 mg with ritonavir 100 mg given once daily with food and efavirenz 600 mg given once daily on an empty stomach. (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates.
    Atogepant: (Major) Use an atogepant dose of 30 or 60 mg PO once daily if coadministered with efavirenz. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
    Atomoxetine: (Moderate) Consider alternatives to efavirenz when coadministering with atomoxetine as the combination may increase the risk for QT prolongation. QT prolongation has been observed with use of efavirenz. QT prolongation has also occurred during therapeutic use of atomoxetine and following overdose.
    Atorvastatin: (Moderate) Efavirenz has the potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with atorvastatin with caution.
    Atorvastatin; Ezetimibe: (Moderate) Efavirenz has the potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with atorvastatin with caution.
    Atovaquone: (Major) Avoid concurrent administration of efavirenz and atovaquone; proguanil. Use of these drugs together results in a 75% decreased in atovaquone AUC and a 43% decrease in proguanil AUC. Consider use of an alternative malaria prophylaxis.
    Atovaquone; Proguanil: (Major) Avoid concurrent administration of efavirenz and atovaquone; proguanil. Use of these drugs together results in a 75% decreased in atovaquone AUC and a 43% decrease in proguanil AUC. Consider use of an alternative malaria prophylaxis.
    Avacopan: (Major) Avoid concomitant use of avacopan and efavirenz due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
    Avanafil: (Moderate) Avanafil is a substrate of and primarily metabolized by CYP3A4. Efavirenz is an inducer of CYP3A4; coadministration may result in decreased avanafil concentrations. The concomitant use of avanafil and CYP inducers is not recommended.
    Avapritinib: (Major) Avoid coadministration of avapritinib with efavirenz due to the risk of a decrease in the efficacy of avapritinib. Avapritinib is a CYP3A4 substrate and efavirenz is a strong CYP3A4 inducer. Coadministration with efavirenz is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
    Axitinib: (Major) Avoid coadministration of axitinib with efavirenz if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and efavirenz is a moderate CYP3A4 inducer.
    Azithromycin: (Major) Avoid coadministration of azithromycin with efavirenz due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. QTc prolongation has been observed with the use of efavirenz.
    Barbiturates: (Major) Complex interactions may occur when barbiturates (e.g., phenobarbital) are administered to patients receiving treatment for HIV infection; if treating seizure disorder, a different anticonvulsant should be used whenever possible. If a barbiturate must be used in a patient being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments to the barbiturate or the antiretroviral medications are unknown. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenobarbital is an inducer of CYP3A4, and a substrate and inducer of CYP2C9 and CYP2C19. Use caution if these drugs are to be coadministered, with increased monitoring of both efavirenz and barbiturate concentrations.
    Bedaquiline: (Major) Avoid concurrent use of efavirenz with bedaquiline. Efavirenz is a CYP3A4 inducer, which may result in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect. In addition, both drugs have been reported to prolong the QT interval. If coadministration is necessary, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
    Belumosudil: (Moderate) Monitor patients for signs of reduced efficacy when belumosudil is coadministered with efavirenz; concomitant use may result in decreased belumosudil exposure. Belumosudil is a CYP3A4 substrate and efavirenz is a moderate CYP3A inducer. Coadministration with efavirenz is predicted to decrease belumosudil exposure by 35% in healthy subjects.
    Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of efavirenz with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and efavirenz is a CYP2C19 inhibitor.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with efavirenz may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If concomitant use is necessary, consider increasing the benzhydrocodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Discontinuation of efavirenz may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If efavirenz is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. Efavirenz is an inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Bortezomib: (Moderate) Agents that induce CYP3A4, such as efavirenz, may decrease the exposure to bortezomib and possibly decrease the efficacy of the drug; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of a potential interaction resulting from the concurrent administration of bortezomib with efavirenz is not known.
    Bosentan: (Minor) Bosentan is metabolized by CYP2C9 and CYP3A4 isoenzymes. Although not studied, efavirenz may induce these isoenzymes and thereby alter the plasma concentrations of bosentan. It is prudent to monitor bosentan therapy for loss of efficacy during coadministration.
    Brentuximab vedotin: (Moderate) Concomitant administration of brentuximab vedotin and efavirenz may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and efavirenz is a potent CYP3A4 inducer; therefore, the efficacy of brentuximab may be reduced.
    Brexpiprazole: (Moderate) Decreased brexpiprazole blood levels may occur when brexpiprazole is coadministered with inducers of CYP3A4, such as efavirenz. Monitor the patient carefully for efficacy if these agents are used in combination. Dosage adjustments of brexpiprazole may be clinically warranted in some patients. Similar precautions apply to combination products containing efavirenz such as efavirenz; emtricitabine; tenofovir.
    Brigatinib: (Major) Avoid coadministration of brigatinib with efavirenz due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with efavirenz, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of efavirenz, resume the brigatinib dose that was tolerated prior to initiation of efavirenz. Brigatinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
    Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and efavirenz are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; efavirenz is a moderate inducer of CYP3A4.
    Bupivacaine; Lidocaine: (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and thus, may decrease serum concentrations of lidocaine. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range (e.g., systemic lidocaine).
    Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with efavirenz is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and efavirenz is a moderate CYP2C9 inhibitor.
    Buprenorphine: (Major) If possible, avoid coadministration of efavirenz and buprenorphine, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as buprenorphine. Efavirenz has been shown to decrease the AUC of buprenorphine by 50% and the norbuprenorphine AUC by 71%. No withdrawal symptoms have been reported and no dosage adjustments are recommended; however, monitor patients for withdrawal symptoms.
    Buprenorphine; Naloxone: (Major) If possible, avoid coadministration of efavirenz and buprenorphine, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as buprenorphine. Efavirenz has been shown to decrease the AUC of buprenorphine by 50% and the norbuprenorphine AUC by 71%. No withdrawal symptoms have been reported and no dosage adjustments are recommended; however, monitor patients for withdrawal symptoms.
    Bupropion: (Major) Concurrent use of efavirenz 600 mg/day and bupropion in healthy volunteers resulted in a reduction of the AUC and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged and the Cmax of hydroxybupropion was increased by 50%. Healthcare providers are advised to increase the dose of bupropion based on clinical response during concurrent use with efavirenz; however, the maximum recommended dose of bupropion should not be exceeded.
    Bupropion; Naltrexone: (Major) Concurrent use of efavirenz 600 mg/day and bupropion in healthy volunteers resulted in a reduction of the AUC and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged and the Cmax of hydroxybupropion was increased by 50%. Healthcare providers are advised to increase the dose of bupropion based on clinical response during concurrent use with efavirenz; however, the maximum recommended dose of bupropion should not be exceeded.
    Buspirone: (Moderate) Substances that are inducers of hepatic cytochrome P450 isoenzyme CYP3A4, such as efavirenz, may increase the rate of buspirone metabolism. In a study of healthy volunteers, co-administration of buspirone with rifampin decreased the plasma concentrations (83.7% decrease in Cmax; 89.6% decrease in AUC) and pharmacodynamic effects of buspirone. If a patient has been titrated to a stable dosage on buspirone, a dose adjustment of buspirone may be necessary to maintain anxiolytic effect.
    Butalbital; Acetaminophen: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Butalbital; Acetaminophen; Caffeine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Cabotegravir; Rilpivirine: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP).
    Cannabidiol: (Moderate) Consider a dose adjustment of efavirenz when coadministered with cannabidiol due to an increased risk of adverse reactions and/or decreased efficacy. Efavirenz is a CYP2B6 substrate; cannabidiol may induce or inhibit CYP2B6.
    Capmatinib: (Major) Avoid coadministration of efavirenz and rifampin due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and efavirenz is a strong CYP3A4 inducer. Coadministration with efavirenz decreased capmatinib exposure by 44%.
    Carbamazepine: (Major) Coadministration of carbamazepine and efavirenz is not recommended due to the potential for loss of virologic response and possible resistance to efavirenz or the class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Efavirenz may also decrease plasma concentrations of carbamazepine. Monitor carbamazepine and efavirenz concentration, or if possible, use an alternative anticonvulsant. In drug interaction studies, coadministration of carbamazepine and efavirenz resulted in a 27% decrease in carbamazepine AUC and a 36% decrease in the efavirenz AUC.
    Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as efavirenz, has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear.
    Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as efavirenz, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
    Caspofungin: (Major) Consider dosing caspofungin as 70 mg IV once daily in adult patients and 70 mg/m2 IV once daily (Max: 70 mg/day) in pediatric patients receiving efavirenz. Administering inducers of hepatic cytochrome P450, such as efavirenz, concurrently with caspofungin may reduce the plasma concentrations of caspofungin.
    Celecoxib: (Minor) Efavirenz inhibits CYP2C9 and CYP2C19 in the range of observed efavirenz plasma concentrations. Efavirenz may inhibit the metabolism of the celecoxib since it is a substrate for CYP2C9.
    Celecoxib; Tramadol: (Moderate) The (+) enantiomer of tramadol preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. Efavirenz is an inducer of CYP3A4 and CYP2B6. Coadministration may affect the metabolism of tramadol leading to altered tramadol exposure. Decreased serum tramadol concentrations and reduced efficacy may occur. In addition, both medications have been associated with the development of seizures; caution is advised. (Minor) Efavirenz inhibits CYP2C9 and CYP2C19 in the range of observed efavirenz plasma concentrations. Efavirenz may inhibit the metabolism of the celecoxib since it is a substrate for CYP2C9.
    Ceritinib: (Major) Avoid coadministration of ceritinib with efavirenz if possible due to the risk of QT prolongation; plasma concentrations of efavirenz may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Monitor for an increase in efavirenz-related adverse reactions. Efavirenz is a CYP3A4 substrate that has been associated with QT prolongation. Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
    Chlordiazepoxide: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including chlordiazepoxide. Monitor patients closely for excessive side effects.
    Chlordiazepoxide; Amitriptyline: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including chlordiazepoxide. Monitor patients closely for excessive side effects.
    Chlordiazepoxide; Clidinium: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including chlordiazepoxide. Monitor patients closely for excessive side effects.
    Chloroquine: (Major) Avoid coadministration of chloroquine with efavirenz due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. QTc prolongation has been observed with the use of efavirenz.
    Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with efavirenz can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If efavirenz is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Efavirenz is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with efavirenz can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If efavirenz is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Chlorpromazine: (Major) If possible, avoid coadministration of efavirenz and chlorpromazine, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP.
    Cilostazol: (Major) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as cilostazol.
    Ciprofloxacin: (Moderate) Consider alternatives to efavirenz when coadministering with ciprofloxacin as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Rare cases of QT prolongation and TdP have been reported with ciprofloxacin during post-marketing surveillance.
    Cisapride: (Contraindicated) QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. QT prolongation has also been observed with efavirenz. Because of the potential for QT prolongation and TdP, use of efavirenz with cisapride is contraindicated.
    Citalopram: (Major) Citalopram causes dose-dependent QT interval prolongation. According to the manufacturer, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. QT prolongation has been observed with use of efavirenz. If concurrent therapy is considered essential, ECG monitoring is recommended. In addition, because citalopram is a substrate for CYP2C19, the maximum daily dose of citalopram should not exceed 20 mg/day in patients receiving CYP2C19 inhibitors such as efavirenz. During concurrent use of citalopram and efavirenz, clinicians should monitor patients for a potential increase in side effects or toxicity.
    Clarithromycin: (Major) The manufacturer of efavirenz recommends that alternatives to clarithromycin be considered when a macrolide antibiotic is required in patients receiving efavirenz. Coadministration of efavirenz and clarithromycin may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes TdP. QT prolongation has also been observed with use of efavirenz. In addition, concurrent use of efavirenz with clarithromycin 500 mg PO every 12 hours for seven days resulted in a significant decrease in the serum concentration of clarithromycin, but the clinical significance of this is not known.
    Clofazimine: (Moderate) Concomitant use of clofazimine and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Clonazepam: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations, if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including (e.g., clonazepam). Monitor patients closely for excessive side effects.
    Clorazepate: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations, if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including (e.g., clorazepate). Monitor patients closely for excessive side effects.
    Clozapine: (Moderate) Consider alternatives to efavirenz when coadministering with clozapine as concurrent use may increase the risk of QT prolongation; decreased clozapine exposure may also occur. Monitor for loss of clozapine efficacy and consider increasing the clozapine dose if necessary. QTc prolongation has been observed with the use of efavirenz. Clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. In addition, efavirenz is an and inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
    Cobicistat: (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates.
    Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with efavirenz due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and efavirenz is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
    Codeine: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer.
    Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer. (Moderate) Consider alternatives to efavirenz when coadministering with promethazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer. (Moderate) Consider alternatives to efavirenz when coadministering with promethazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
    Conjugated Estrogens: (Moderate) Estrogens are partially metabolized by CYP3A4. Efavirenz induces CYP3A4 and, therefore, may decrease plasma concentrations of estrogens. Patients receiving estrogens should be monitored for a decrease in estrogen efficacy when coadministered with efavirenz.
    Conjugated Estrogens; Bazedoxifene: (Moderate) Estrogens are partially metabolized by CYP3A4. Efavirenz induces CYP3A4 and, therefore, may decrease plasma concentrations of estrogens. Patients receiving estrogens should be monitored for a decrease in estrogen efficacy when coadministered with efavirenz.
    Conjugated Estrogens; Medroxyprogesterone: (Moderate) Estrogens are partially metabolized by CYP3A4. Efavirenz induces CYP3A4 and, therefore, may decrease plasma concentrations of estrogens. Patients receiving estrogens should be monitored for a decrease in estrogen efficacy when coadministered with efavirenz.
    Crizotinib: (Major) Avoid concomitant use of crizotinib and efavirenz due to the risk of QT prolongation. Crizotinib can cause concentration-dependent QT prolongation. QTc prolongation has also been observed with the use of efavirenz.
    Cyclosporine: (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range, such as cyclosporine. Monitoring of serum cyclosporine concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz.
    Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as efavirenz. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
    Dapsone: (Moderate) Closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia if coadministration with efavirenz is necessary. Dapsone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis).
    Daridorexant: (Major) Avoid concomitant use of daridorexant and efavirenz. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. During drug interaction studies, concomitant use of efavirenz decreased daridorexant overall exposure by over 50%.
    Darifenacin: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as darifenacin.
    Darunavir: (Moderate) Concurrent administration of darunavir with efavirenz results in decreased darunavir concentrations (13% reduction in AUC and 31% reduction in Cmin) and increased efavirenz concentration (21% increase in AUC and 17% increase in Cmin). No dosage adjustment recommendations are required for either medication. Use this combination with caution.
    Darunavir; Cobicistat: (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates. (Moderate) Concurrent administration of darunavir with efavirenz results in decreased darunavir concentrations (13% reduction in AUC and 31% reduction in Cmin) and increased efavirenz concentration (21% increase in AUC and 17% increase in Cmin). No dosage adjustment recommendations are required for either medication. Use this combination with caution.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates. (Moderate) Concurrent administration of darunavir with efavirenz results in decreased darunavir concentrations (13% reduction in AUC and 31% reduction in Cmin) and increased efavirenz concentration (21% increase in AUC and 17% increase in Cmin). No dosage adjustment recommendations are required for either medication. Use this combination with caution.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with efavirenz is contraindicated. The use of this drug combination was pooly tolerated by recipients and resulted in hepatic enzyme elevations. (Contraindicated) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with efavirenz is contraindicated. The use of this drug combination was pooly tolerated by recipients and resulted in hepatic enzyme elevations. (Contraindicated) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with efavirenz is contraindicated. The use of this drug combination was pooly tolerated by recipients and resulted in hepatic enzyme elevations. (Moderate) Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Concurrent use is is expected to result in increased concentrations of both drugs.
    Dasatinib: (Moderate) Consider alternatives to efavirenz when coadministering with dasatinib as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Treatment with dasatinib has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
    Deflazacort: (Major) Avoid concomitant use of deflazacort and efavirenz. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; efavirenz is a moderate inducer of CYP3A4. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
    Degarelix: (Moderate) Consider alternatives to efavirenz when coadministering with degarelix. QTc prolongation has been observed with the use of efavirenz. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
    Delavirdine: (Major) The combined use of two NNRTIs has not been shown to be beneficial; thus, efavirenz and delavirdine should not be coadministered.
    Desflurane: (Major) Although data are limited, coadministration of efavirenz and halogenated anesthetics may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs can prolong the QT interval.
    Desogestrel; Ethinyl Estradiol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Deutetrabenazine: (Moderate) Consider alternatives to efavirenz when coadministering with deutetrabenazine due to the risk for additive QT prolongation. QTc prolongation has been observed with the use of efavirenz. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
    Dextromethorphan; Bupropion: (Major) Concurrent use of efavirenz 600 mg/day and bupropion in healthy volunteers resulted in a reduction of the AUC and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged and the Cmax of hydroxybupropion was increased by 50%. Healthcare providers are advised to increase the dose of bupropion based on clinical response during concurrent use with efavirenz; however, the maximum recommended dose of bupropion should not be exceeded.
    Dextromethorphan; Quinidine: (Major) Coadministration of efavirenz and quinidine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Quinidine administration is associated with QT prolongation and TdP. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as quinidine.
    Diazepam: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including diazepam. In addition, efavirenz inhibits CYP2C9 in vitro; diazepam is also metabolized via this isoenzyme. Monitor patients closely for excessive side effects.
    Diclofenac: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as efavirenz; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Diclofenac; Misoprostol: (Moderate) If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as efavirenz; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
    Dienogest; Estradiol valerate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Diltiazem: (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
    Disopyramide: (Major) If possible, avoid coadministration of efavirenz and disopyramide, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Disopyramide administration is associated with QT prolongation and TdP. In addition, efavirenz can induce CYP3A4, an isoenzyme that is partially responsible for the metabolism of disopyramide. Use these drugs together with caution due to the potential for decreased disopyramide efficacy.
    Disulfiram: (Moderate) The pathway to disulfiram activation is mediated by CYP3A4/5 (major), CYP1A2, CYP2B6, and CYP2E1.Efavirenz is an in vivo inducer of CYP3A4 and CY2B6. Increased disulfiram activation may occur if these drugs are administred together.
    Docetaxel: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as docetaxel.
    Dofetilide: (Major) Coadministration of dofetilide and efavirenz is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QTc prolongation has been observed with the use of efavirenz.
    Dolasetron: (Moderate) Consider alternatives to efavirenz when coadministering with dolasetron as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir: (Major) When possible, avoid concurrent use of dolutegravir with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and efavirenz is an inducer of CYP3A4.
    Dolutegravir; Lamivudine: (Major) When possible, avoid concurrent use of dolutegravir with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and efavirenz is an inducer of CYP3A4.
    Dolutegravir; Rilpivirine: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP). (Major) When possible, avoid concurrent use of dolutegravir with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and efavirenz is an inducer of CYP3A4.
    Donepezil: (Moderate) Consider alternatives to efavirenz when coadministering with donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QTc prolongation has been observed with the use of efavirenz.
    Donepezil; Memantine: (Moderate) Consider alternatives to efavirenz when coadministering with donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QTc prolongation has been observed with the use of efavirenz.
    Doravirine: (Contraindicated) Concurrent treatment with efavirenz and doravirine is not recommended. Both medications are non-nucleoside reverse transcriptase inhibitors (NNRTIs), and using these drugs together would represent duplicate therapy. In addition, taking these drugs together results in decreased doravirine exposure. Doravirine is a CYP3A4 substrate; efavirenz is a CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Contraindicated) Concurrent treatment with efavirenz and doravirine is not recommended. Both medications are non-nucleoside reverse transcriptase inhibitors (NNRTIs), and using these drugs together would represent duplicate therapy. In addition, taking these drugs together results in decreased doravirine exposure. Doravirine is a CYP3A4 substrate; efavirenz is a CYP3A4 inducer.
    Doxercalciferol: (Moderate) Although these interactions have not been specifically studied, hepatic enzyme inducers such as efavirenz may affect the 25-hydroxylation of doxercalciferol and may necessitate dosage adjustments of doxercalciferol.
    Doxorubicin Liposomal: (Major) Avoid coadministration of efavirenz with doxorubicin due to decreased doxorubicin plasma concentrations. Efavirenz is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    Doxorubicin: (Major) Avoid coadministration of efavirenz with doxorubicin due to decreased doxorubicin plasma concentrations. Efavirenz is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with efavirenz is necessary, and monitor for changes in the efficacy or adverse effect profile of dronabinol (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate. Efavirenz is a moderate inhibitor of CYP2C9 in vitro, and a CYP3A4 inducer. Concomitant use may result in altered plasma concentrations of dronabinol.
    Dronedarone: (Contraindicated) Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Efavirenz has also been associated with QT prolongation. Because of the potential for QT prolongation and TdP, use of efavirenz with dronedarone is contraindicated.
    Droperidol: (Major) If possible, avoid coadministration of efavirenz and droperidol, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP; droperidol labeling advises against coadministration with drugs that prolong the QT interval. In addition, efavirenz may induce the CYP3A4 metabolism of droperidol; potentially reducing the efficacy of droperidol by decreasing its systemic exposure.
    Drospirenone: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Drospirenone; Estetrol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Drospirenone; Estradiol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Drospirenone; Ethinyl Estradiol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Duvelisib: (Major) Avoid concomitant use of duvelisib with efavirenz. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib. If concomitant use is necessary, increase the dose of duvelisib on day 12 of coadministration from 25 mg PO twice daily to 40 mg PO twice daily; or from 15 mg PO twice daily to 25 mg PO twice daily. When efavirenz has been discontinued for at least 14 days, resume duvelisib at the dose taken prior to initiating treatment with efavirenz. Duvelisib is a CYP3A substrate; efavirenz is a moderate CYP3A inducer. Coadministration of duvelisib with another moderate CYP3A inducer for 12 days decreased duvelisib exposure by 35%.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with efavirenz is contraindicated. Efavirenz is a CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
    Eletriptan: (Contraindicated) Concomitant use of eletriptan and efavirenz is not recommended. Eletriptan is metabolized by CYP3A4, and inhibition of CYP3A4 by efavirenz may result in elevated eletriptan concentrations and serious adverse events.
    Eliglustat: (Moderate) Consider alternatives to efavirenz when coadministering with eliglustat as concurrent use may increase the risk of QT prolongation; eliglustat exposure may also decrease. Efavirenz is a moderate CYP3A4 inducer; QTc prolongation has been observed with the use of efavirenz. Eliglustat is a CYP3A4 inducer that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir: (Major) Avoid coadministration of elvitegravir with efavirenz or efavirenz; emtricitabine; tenofovir, as concurrent use is expected to decrease elvitegravir plasma concentrations. Efavirenz is a substrate and inducer of CYP3A4; elvitegravir is a CYP3A4 substrate. Use of these drugs together may result in loss of antiviral efficacy and potentially the development of viral resistance.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of elvitegravir with efavirenz or efavirenz; emtricitabine; tenofovir, as concurrent use is expected to decrease elvitegravir plasma concentrations. Efavirenz is a substrate and inducer of CYP3A4; elvitegravir is a CYP3A4 substrate. Use of these drugs together may result in loss of antiviral efficacy and potentially the development of viral resistance. (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of elvitegravir with efavirenz or efavirenz; emtricitabine; tenofovir, as concurrent use is expected to decrease elvitegravir plasma concentrations. Efavirenz is a substrate and inducer of CYP3A4; elvitegravir is a CYP3A4 substrate. Use of these drugs together may result in loss of antiviral efficacy and potentially the development of viral resistance. (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates.
    Empagliflozin; Linagliptin: (Moderate) Concomitant use of linagliptin with efavirenz may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; efavirenz is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Concomitant use of linagliptin with efavirenz may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; efavirenz is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP).
    Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP).
    Enalapril; Felodipine: (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
    Encorafenib: (Major) Avoid coadministration of encorafenib and efavirenz due to decreased encorafenib exposure and potential loss of efficacy. Additive risk of QT prolongation is also possible. Encorafenib is a CYP3A4 substrate that is associated with dose-dependent prolongation of the QT interval; efavirenz is a moderate CYP3A4 inducer that has been associated with QT prolongation. Coadministration with CYP3A4 inducers has not been studied with encorafenib; however, in clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction.
    Entrectinib: (Major) Avoid coadministration of entrectinib with efavirenz due to additive risk of QT prolongation and decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate that has been associated with QT prolongation; efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
    Enzalutamide: (Major) Use caution if enzalutamide and efavirenz are used concomitantly, as coadministration may significantly reduce plasma concentrations of efavirenz, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. When efavirenz is coadministered with another strong CYP3A4 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients >= 50 kg). Enzalutamide is a strong CYP3A4 inducer and efavirenz is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of efavirenz.
    Eplerenone: (Moderate) Efavirenz is a CYP3A4 inducer and may causes a decrease in eplerenone serum concentration. It is not known if the interaction is clinically significant.
    Erdafitinib: (Major) If coadministration of erdafitinib and efavirenz is necessary at the initiation of erdafitinib therapy, administer the dose of erdafitinib as recommended (8 mg once daily with potential to increase the dose to 9 mg on days 14 to 21 based on phosphate levels and tolerability). If efavirenz must be added to erdafitinib therapy after the initial dose increase period (days 14 to 21), increase the dose of erdafitinib up to 9 mg. If efavirenz is discontinued, continue erdafitinib at the same dose in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Eribulin: (Major) Although data are limited, coadministration of efavirenz and eribulin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Eribulin has also been associated with QT prolongation. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Erlotinib: (Moderate) There may be a risk of reduced erlotinib efficacy when coadministered with efavirenz; however, the risk has not been clearly defined. If coadministration is necessary, consider increasing the erlotinib dose by 50 mg increments at 2-week intervals as tolerated, to a maximum of 450 mg. Erlotinib is a CYP3A4 substrate, and efavirenz is a moderate CYP3A4 inducer.
    Erythromycin: (Major) Consider alternative therapy as the coadministration of efavirenz and erythromycin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Erythromycin is associated with QT prolongation and TdP. In addition, concurrent use may increase the systemic concentration of efavirenz as efavirenz is a CYP3A4 substrate, while erythromycin is a CYP3A4 inhibitor.
    Escitalopram: (Moderate) Consider alternatives to efavirenz when coadministering with escitalopram as concurrent use may increase the risk of QT prolongation. QT prolongation has been observed with use of efavirenz. Escitalopram has also been associated with a risk of QT prolongation and TdP.
    Esomeprazole: (Minor) Although drug interaction studies have not been conducted, efavirenz may inhibit the metabolism of substrates for CYP2C9 or CYP2C19 such as esomeprazole. In vitro studies have shown that efavirenz inhibits CYP2C9 and CYP2C19 in the range of observed efavirenz plasma concentrations.
    Estazolam: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including estazolam. Monitor patients closely for excessive side effects.
    Estradiol: (Moderate) Estrogens are CYP3A4 substrates and efavirenz is a CYP3A4 inducer; concomitant use of efavirenz-containing products (including efavirenz; emtricitabine; tenofovir) may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., menopausal symptoms, breakthrough bleeding, reduced efficacy) if these drugs are used together.
    Estradiol; Levonorgestrel: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations. (Moderate) Estrogens are CYP3A4 substrates and efavirenz is a CYP3A4 inducer; concomitant use of efavirenz-containing products (including efavirenz; emtricitabine; tenofovir) may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., menopausal symptoms, breakthrough bleeding, reduced efficacy) if these drugs are used together.
    Estradiol; Norethindrone: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations. (Moderate) Estrogens are CYP3A4 substrates and efavirenz is a CYP3A4 inducer; concomitant use of efavirenz-containing products (including efavirenz; emtricitabine; tenofovir) may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., menopausal symptoms, breakthrough bleeding, reduced efficacy) if these drugs are used together.
    Estradiol; Norgestimate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Ethanol: (Major) Advise patients to avoid alcohol while taking efavirenz. It is possible that CNS symptoms such as dizziness, trouble sleeping, drowsiness, difficulty concentrating and/or abnormal dreams may be more severe if efavirenz is taken with alcohol.
    Ethinyl Estradiol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Ethinyl Estradiol; Norelgestromin: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Ethinyl Estradiol; Norethindrone Acetate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Ethinyl Estradiol; Norgestrel: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Ethosuximide: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as ethosuximide.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Etonogestrel; Ethinyl Estradiol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Etravirine: (Major) Concomitant use of etravirine with efavirenz may cause a significant decrease in etravirine plasma concentrations and, thus, a loss of therapeutic effect. Additionally, the combined use of two NNRTIs has not been shown to be beneficial; etravirine and other NNRTIs should not be coadministered.
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with efavirenz is necessary. The dose of everolimus may need to be increased. Everolimus is a sensitive CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with CYP3A4 inducers may increase the metabolism of everolimus and decrease everolimus blood concentrations.
    Ezetimibe; Simvastatin: (Moderate) Efavirenz has potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with simvastatin with caution.
    Fedratinib: (Major) Avoid coadministration of fedratinib with efavirenz as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer. Coadministration of fedratinib with efavirenz decreased the overall exposure of fedratinib by 47%.
    Felodipine: (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
    Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of efavirenz is necessary. If efavirenz is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like efavirenz with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Finasteride; Tadalafil: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
    Finerenone: (Major) Avoid concurrent use of finerenone and efavirenz due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Coadministration with efavirenz decreased overall exposure to finerenone by 80%.
    Fingolimod: (Moderate) Consider alternatives to efavirenz when coadministering with fingolimod as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Fingolimod initiation results in decreased heart rate and may prolong the QT interval.
    Flecainide: (Major) Coadministration of efavirenz and flecainide may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
    Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and CYP3A4 inducers, such as efavirenz is not recommended.
    Fluconazole: (Moderate) Consider alternatives to efavirenz when coadministering with flucanazole as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP).
    Fluoxetine: (Moderate) Consider an alternative to efavirenz if coadministration with fluoxetine is necessary as concurrent use may increase the risk of QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. QTc prolongation has also been observed with the use of efavirenz.
    Fluphenazine: (Minor) Consider alternatives to efavirenz when coadministering with fluphenazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Fluphenazine is associated with a possible risk for QT prolongation.
    Flurazepam: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including flurazepam. Monitor patients closely for excessive side effects.
    Fluvastatin: (Moderate) Efavirenz inhibits CYP2C9, which is the isoenzyme primarily responsible for the metabolism of fluvastatin. Coadministration of fluvastatin with efavirenz may increase the risk of myopathy and rhabdomyolysis.
    Fluvoxamine: (Moderate) Consider alternatives to efavirenz when coadministering with fluvoxamine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been reported with the use of efavirenz. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
    Food: (Major) Advise patients to avoid cannabis use during efavirenz treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoid delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP2C9 substrates and efavirenz is a moderate CYP2C9 inhibitor.
    Fosamprenavir: (Major) Appropriate doses of unboosted fosamprenavir when coadministered with efavirenz have not been established. When fosamprenavir plus ritonavir is administered once daily and given in combination with efavirenz, the dose of ritonavir must be increased by 100 mg/day (300 mg total). No change in the ritonavir dose is required when efavirenz is administered with fosamprenavir plus ritonavir twice daily. Systemic concentrations of fosamprenavir are reduced when administered concurrently with efavirenz. Fosamprenavir is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as efavirenz. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). QTc prolongation has also been observed with the use of efavirenz. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fostamatinib: (Moderate) Monitor for efavirenz toxicities that may require efavirenz dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a CYP3A4 substrate may increase the concentration of the CYP3A4 substrate. The active metabolite of fostamatinib, R406, is a CYP3A4 inhibitor; efavirenz is a substrate for CYP3A4. Coadministration of fostamatinib with a sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%.
    Fostemsavir: (Moderate) Consider alternatives to efavirenz when coadministering with fostemsavir. QTc prolongation has been observed with the use of efavirenz. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, 4 times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Ganaxolone: (Major) Avoid concurrent use of ganaxolone and efavirenz due to the risk of decreased ganaxolone efficacy. If concomitant use is unavoidable, consider increasing ganaxolone dose without exceeding the maximum daily dose. Ganaxolone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Gemifloxacin: (Moderate) Consider alternatives to efavirenz when coadministering with gemifloxacin as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and efavirenz together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. QTc prolongation has been observed with the use of efavirenz. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin.
    Gilteritinib: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and efavirenz is necessary. Gilteritinib has been associated with QT prolongation. QTc prolongation has been observed with the use of efavirenz.
    Glasdegib: (Major) Avoid coadministration of glasdegib with efavirenz due to additive risk of QT prolongation and decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate that has been associated with QT prolongation; efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation. Coadministration of a moderate CYP3A4 inducer like efavirenz is predicted to reduce the glasdegib AUC by 55%. If concurrent use cannot be avoided, increase the glasdegib dosage (i.e., from 100 mg PO daily to 200 mg PO daily; or from 50 mg PO daily to 100 mg PO daily). Resume the previous dose of glasdegib after efavirenz has been discontinued for 7 days.
    Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir with efavirenz is not recommended due to the potential loss of efficacy of glecaprevir. Glecaprevir is a substrate of CYP3A4; efavirenz is a CYP3A4 inducer. Coadministration may decrease plasma concentrations of glecaprevir.
    Glimepiride: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like efavirenz. Monitor serum glucose concentrations if glimepiride is coadministered with efavirenz. Dosage adjustments may be necessary.
    Glimepiride; Rosiglitazone: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like efavirenz. Monitor serum glucose concentrations if glimepiride is coadministered with efavirenz. Dosage adjustments may be necessary.
    Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving efavirenz as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Granisetron: (Moderate) Consider alternatives to efavirenz when coadministering with granisetron as concurrent use may increase the risk of QT prolongation. QT prolongation has been observed with use of efavirenz. Granisetron has also been associated with QT prolongation.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with efavirenz can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If efavirenz is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with efavirenz can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If efavirenz is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Guanfacine: (Major) Efavirenz may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if efavirenz is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If efavirenz is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and efavirenz is a moderate CYP3A4 inducer.
    Halogenated Anesthetics: (Major) Although data are limited, coadministration of efavirenz and halogenated anesthetics may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs can prolong the QT interval.
    Haloperidol: (Moderate) Consider alternatives to efavirenz when coadministering with haloperidol as concurrent use may increase the risk of QT prolongation and reduce haloperidol efficacy. Efavirenz is a moderate CYP3A4 inducer that has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Haloperidol plasma concentration is significantly reduced when prolonged treatment (1 to 2 weeks) with enzyme-inducing drugs is added to therapy.
    Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving efavirenz as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with efavirenz can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If efavirenz is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Hydantoins: (Major) Complex interactions may occur when hydantoins (phenytoin, fosphenytoin, and possibly ethotoin) are administered to patients receiving treatment for HIV infection; if possible, a different anticonvulsant should be used. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. If phenytoin is used in patients being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments for phenytoin or the antiretroviral medications are unknown. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenytoin is a substrate and inducer of CYP3A4, CYP2C9, and CYP2C19. Use of these drugs in combination may decrease the serum concentrations of both phenytoin and efavirenz.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with efavirenz can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If efavirenz is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with efavirenz can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If efavirenz is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with efavirenz can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If efavirenz is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    Hydroxyzine: (Moderate) Consider alternatives to efavirenz when coadministering with hydroxyzine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes.
    Ibrexafungerp: (Major) Avoid concurrent administration of ibrexafungerp with efavirenz. Use of these drugs together is expected to significantly decrease ibrexafungerp exposure, which may reduce its efficacy. Ibrexafungerp is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
    Ibrutinib: (Moderate) Use ibrutinib and efavirenz together with caution; decreased ibrutinib levels may occur resulting in reduced ibrutinib efficacy. Monitor patients for signs of decreased ibrutinib efficacy if these agents are used together. Ibrutinib is a CYP3A4 substrate; efavirenz is a moderate CYP3A inducer. Simulations suggest that coadministration with a moderate CYP3A4 inducer may decrease ibrutinib exposure by 3-fold.
    Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with efavirenz is necessary; consider increasing the dose of oxycodone as needed. If efavirenz is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Ibutilide: (Major) Coadministration of efavirenz and ibutilide may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Ibutilide administration can cause QT prolongation and TdP; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with efavirenz, a CYP3A substrate, as efavirenz toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with efavirenz is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; efavirenz is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as efavirenz. In addition, efavirenz may induce the CYP3A4 metabolism of iloperidone, potentially reducing the efficacy of iloperidone by decreasing its systemic exposure.
    Indinavir: (Major) Efavirenz increases the CYP3A4 metabolism of indinavir resulting in lower indinavir concentrations. When administered together, the optimal indinavir dose is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased metabolism. An increased dose of indinavir (1000 mg every 8 hours) given with efavirenz (600 mg once daily) results in decreased indinavir AUC and Cmin, approximately 40% and 50%, respectively, compared to when indinavir (800 mg every 8 hours) is given alone.
    Infigratinib: (Major) Avoid concurrent use of infigratinib and efavirenz. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Infigratinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with efavirenz due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. QTc prolongation has been observed with the use of efavirenz.
    Interferon Alfa-2a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferon Alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferon Alfa-2b; Ribavirin: (Moderate) The concomitant use of ribavirin and antiretroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferon Alfacon-1: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferon Alfa-n3: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferon Beta-1a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferon Beta-1b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferon Gamma-1b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Interferons: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Isavuconazonium: (Major) Coadministration of isavuconazonium with efavirenz is not recommended as there is a potential for elevated efavirenz concentrations and decreased concentrations of isavuconazonium. Decreased isavuconazonium concentrations may lead to a reduction of antifungal efficacy and the potential for treatment failure. Efavirenz is a substrate and inducer of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme.
    Isoflurane: (Major) Although data are limited, coadministration of efavirenz and halogenated anesthetics may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs can prolong the QT interval.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) When efavirenz and rifampin are coadministered, decreased efavirenz concentrations are seen and decreased antiretroviral efficacy is expected. These drugs may be coadministered to patients weighing 50 kg or more if the efavirenz dose is increased to 800 mg PO daily. A small study evaluated this interaction by administering the drugs (both at 600 mg PO daily x 7 days) to 12 subjects, and found decreased mean efavirenz Cmax, AUC, and Cmin of 20%, 26%, and 32%. Of note, reduced efavirenz metabolism is seen in patients with genetic polymorphisms of cytochrome P450 2B6 (primarily in patients of African, Asian, and Hispanic descent). Increasing the dose in these patients can result in a significant increase in efavirenz toxicity; some patients may even require lower doses.
    Isoniazid, INH; Rifampin: (Major) When efavirenz and rifampin are coadministered, decreased efavirenz concentrations are seen and decreased antiretroviral efficacy is expected. These drugs may be coadministered to patients weighing 50 kg or more if the efavirenz dose is increased to 800 mg PO daily. A small study evaluated this interaction by administering the drugs (both at 600 mg PO daily x 7 days) to 12 subjects, and found decreased mean efavirenz Cmax, AUC, and Cmin of 20%, 26%, and 32%. Of note, reduced efavirenz metabolism is seen in patients with genetic polymorphisms of cytochrome P450 2B6 (primarily in patients of African, Asian, and Hispanic descent). Increasing the dose in these patients can result in a significant increase in efavirenz toxicity; some patients may even require lower doses.
    Isradipine: (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
    Istradefylline: (Moderate) Monitor for efavirenz-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. Efavirenz is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
    Itraconazole: (Major) Use of efavirenz is not recommended for 2 weeks before or during itraconazole therapy. Consider an alternative antifungal medication. Administering itraconazole with inducers of CYP3A4, such as efavirenz, may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy could be reduced. Efavirenz is also partially metabolized by CYP3A4; taking efavirenz with itraconazole (a potent CYP3A4 inhibitor) may increase exposure to efavirenz. In addition, both drugs are associated with QT prolongation; coadministration may increase this risk.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with efavirenz due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QTc prolongation has been observed with the use of efavirenz.
    Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and efavirenz due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may decrease the exposure of ketoconazole, reducing its efficacy. Ketoconazole is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) The manufacturer of efavirenz recommends that alternatives to clarithromycin be considered when a macrolide antibiotic is required in patients receiving efavirenz. Coadministration of efavirenz and clarithromycin may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes TdP. QT prolongation has also been observed with use of efavirenz. In addition, concurrent use of efavirenz with clarithromycin 500 mg PO every 12 hours for seven days resulted in a significant decrease in the serum concentration of clarithromycin, but the clinical significance of this is not known.
    Lapatinib: (Moderate) Consider alternatives to efavirenz when coadministering with lapatinib as concurrent use may increase the risk of QT prolongation; increased efavirenz exposure is also possible. QTc prolongation has been observed with the use of efavirenz. Prolongation of the QTc interval has been observed with the use of efavirenz, a CYP3A4 substrate. Lapatinib is a weak CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib.
    Larotrectinib: (Major) Avoid concurrent use of larotrectinib and efavirenz due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If efavirenz is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of efavirenz. Larotrectinib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Coadministration with efavirenz is predicted to decrease larotrectinib exposure by 72%.
    Lefamulin: (Major) Avoid coadministration of lefamulin with efavirenz as concurrent use may increase the risk of QT prolongation and decrease lefamulin exposure and efficacy. If coadministration cannot be avoided, monitor for decreased efficacy and ECG during treatment. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation.
    Lemborexant: (Major) Avoid coadministration of lemborexant and efvirenz as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer.
    Lenacapavir: (Major) Avoid concurrent use of lenacapavir and efavirenz due to the risk of decreased lenacapavir exposure which may result in loss of therapeutic effect and development of resistance. Lenacapavir is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Concomitant use with efavirenz reduced lenacapavir overall exposure by 56%.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with efavirenz due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Lesinurad: (Moderate) Use lesinurad and efavirenz together with caution; efavirenz may increase the systemic exposure of lesinurad. Efavirenz is an inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
    Lesinurad; Allopurinol: (Moderate) Use lesinurad and efavirenz together with caution; efavirenz may increase the systemic exposure of lesinurad. Efavirenz is an inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
    Letermovir: (Major) Concurrent administration of letermovir and efavirenz is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Also, a clinically relevant increase in the plasma concentration of efavirenz may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Efavirenz is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
    Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving efavirenz as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Leuprolide; Norethindrone: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations. (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving efavirenz as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Levamlodipine: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Levofloxacin: (Moderate) Consider alternatives to efavirenz when coadministering with levofloxacin. QTc prolongation has been observed with the use of efavirenz. Levofloxacin has also been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and efavirenz due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may decrease the exposure of ketoconazole, reducing its efficacy. Ketoconazole is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Levonorgestrel: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Levonorgestrel; Ethinyl Estradiol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Lidocaine: (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and thus, may decrease serum concentrations of lidocaine. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range (e.g., systemic lidocaine).
    Lidocaine; Epinephrine: (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and thus, may decrease serum concentrations of lidocaine. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range (e.g., systemic lidocaine).
    Lidocaine; Prilocaine: (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and thus, may decrease serum concentrations of lidocaine. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range (e.g., systemic lidocaine).
    Linagliptin: (Moderate) Concomitant use of linagliptin with efavirenz may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; efavirenz is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
    Linagliptin; Metformin: (Moderate) Concomitant use of linagliptin with efavirenz may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; efavirenz is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
    Lithium: (Moderate) Consider alternatives to efavirenz when coadministering with lithium. QTc prolongation has been observed with the use of efavirenz. Lithium has been associated with QT prolongation.
    Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with efavirenz due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. QTc prolongation has been observed with the use of efavirenz.
    Lonafarnib: (Contraindicated) Coadministration of lonafarnib and efavirenz is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Loperamide: (Moderate) Concomitant use of loperamide and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Loperamide; Simethicone: (Moderate) Concomitant use of loperamide and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir; ritonavir with efavirenz due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Additionally, increase the dose of lopinavir; ritonavir to 500/125 mg and administer twice daily in adults; do not use once daily administration. Induction of CYP3A4 by efavirenz may decrease lopinavir concentrations. Both drugs have been associated with QT prolongation. (Moderate) Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Concurrent use is is expected to result in increased concentrations of both drugs.
    Lorlatinib: (Major) Avoid concomitant use of lorlatinib and efavirenz due to decreased plasma concentrations of both drugs, which may reduce efficacy and increase the potential for viral resistance. If concomitant use is necessary, increase the dose of lorlatinib to 125 mg PO once daily. Both lorlatinib and efavirenz are CYP3A4 substrates and moderate CYP3A4 inducers. Administration with another moderate CYP3A inducer decreased lorlatinib exposure by 23%.
    Losartan: (Minor) Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of drugs that are substrates for CYP2C9 or CYP2C19 including losartan.
    Losartan; Hydrochlorothiazide, HCTZ: (Minor) Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of drugs that are substrates for CYP2C9 or CYP2C19 including losartan.
    Lovastatin: (Minor) Efavirenz has potential to induce CYP3A4 isoenzymes which may decrease the efficacy of lovastatin.
    Lovastatin; Niacin: (Minor) Efavirenz has potential to induce CYP3A4 isoenzymes which may decrease the efficacy of lovastatin.
    Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor can reduce the efficacy of efavirenz by decreasing its systemic exposure. If these agents must be used together, monitor efavirenz plasma concentrations; an efavirenz dosage adjustment may be required to obtain the desired therapeutic effect. Efavirenz is a substrate of CYP3A4 and CYP2B6. Lumacaftor is a strong CYP3A inducer, and in vitro data suggest that lumacaftor may also induce CYP2B6. When efavirenz is coadministered with rifampin, a strong CYP3A4 and CYP2B6 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients >= 50 kg).
    Lumateperone: (Major) Avoid coadministration of lumateperone and efavirenz as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer.
    Lurasidone: (Moderate) Because lurasidone is primarily metabolized by CYP3A4, decreased plasma concentrations of lurasidone may occur when the drug is co-administered with inducers of CYP3A4. Concurrent use of lurasidone and CYP3A4 inducers, such as efavirenz or combination products containing efavirez (e.g. efavirenz; emtricitabine; tenofovir), may lead to a decrease in efficacy of lurasidone. If lurasidone is used with a moderate CYP3A4 inducer, it may be necessary to increase the lurasidone dose after chronic treatment (7 days or more).
    Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and efavirenz due to the risk of decreased lurbinectedin exposure which may reduce its efficacy. Lurbinectedin is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
    Macimorelin: (Major) Discontinue efavirenz and allow a sufficient washout period to pass before administering the macimorelin. Use of these drugs together can significantly decrease macimorelin plasma concentrations, and may result in a false positive test for growth hormone deficiency. No drug-drug interaction studies have been conducted; however, macimorelin is primarily metabolized by CYP3A4 and efavirenz is a CYP3A4 inducer. In addition, use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. QTc prolongation has been observed with the use of efavirenz.
    Maprotiline: (Moderate) Consider alternatives to efavirenz when coadministering with maprotiline as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Maraviroc: (Major) Coadministration of maraviroc, a CYP3A substrate, and efavirenz, a strong CYP3A inducer, without a concomitant strong CYP3A inhibitor, significantly decreases maraviroc concentrations, therefore, the adult maraviroc dose should be increased to 600 mg PO twice daily when coadministered with efavirenz without a concomitant strong CYP3A inhibitor. Coadministration of maraviroc and efavirenz is contraindicated in patients with CrCl less than 30 mL/min. For pediatric patients, concomitant use of maraviroc with a strong CYP3A inducer, without a strong CYP3A inhibitor, is not recommended. If the patient's medication regimen also contains a strong CYP3A inhibitor, the CYP3A inhibitor's actions are expected to exceed that of the inducer; overall, increased maraviroc concentrations are expected.
    Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with efavirenz due to risk for reduced mavacamten efficacy. Concomitant use decreases mavacamten exposure. Mavacamten is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
    Mefloquine: (Moderate) Consider alternatives to efavirenz when coadministering with mefloquine. QTc prolongation has been observed with the use of efavirenz. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. In addition, efavirenz may induce the CYP3A4 metabolism of mefloquine; potentially reducing the efficacy of mefloquine. Concomitant administration may increase the risk of Plasmodium falciparum resistance during treatment of malaria.
    Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with efavirenz is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and efavirenz is a moderate CYP2C9 inhibitor.
    Meperidine; Promethazine: (Moderate) Consider alternatives to efavirenz when coadministering with promethazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
    Mestranol; Norethindrone: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Metformin; Repaglinide: (Minor) Repaglinide is metabolized in the liver by cytochrome P450 isoenzyme CYP3A4. Patients taking repaglinide concomitantly with a CYP3A4 inducer such as efavirenz or efavirenz-containing products (e.g. efavirenz; emtricitabine; tenofovir) should be monitored for reduced effectiveness of repaglinide and possible symptoms indicating hyperglycemia.
    Methadone: (Major) Coadministration of efavirenz and methadone may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Methadone is considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In addition, efavirenz induces methadone metabolism via CYP3A4 and is associated with significant decreases in methadone concentrations. Clinical reports suggest that patients who are stabilized on methadone-maintenance therapy may experience opiate withdrawal symptoms when efavirenz is added to their HIV-regimen. Methadone-maintained patients should be monitored for evidence of withdrawal and the methadone dose should be adjusted accordingly.
    Metronidazole: (Moderate) Concomitant use of metronidazole and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Midostaurin: (Major) Avoid the concomitant use of midostaurin and efavirenz as midostaurin exposure may be decreased, which may reduce its efficacy; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Midostaurin is a CYP3A4 substrate and efavirenz is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
    Mifepristone: (Major) Avoid use together when possible; consider alternatives to efavirenz. The use of these drugs together may increase the risk for QT prolongation or other efavirenz-induced side effects and may reduce mifepristone efficacy. Concurrent use will increase the systemic exposure of efavirenz and decrease mifepristone exposure. Efavirenz is a CYP2B6 substrate and CYP3A4 inducer, while mifepristone is a CYP3A4 substrate and CYP2B6 inhibitor. In addition, careful monitoring for mifepristone efficacy is necessary. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used. Also monitor for evavirenz-associated adverse reactions, such as nervous system or psychiatric symptoms, fast irregular heart rate, QT prolongation, hepatotoxicity, and rash. QT prolongation has been observed with use of efavirenz. Mifepristone, when given chronically for hormonal conditions such as Cushing's syndrome. has also been associated with dose-dependent prolongation of the QT interval.
    Mirtazapine: (Moderate) Consider alternatives to efavirenz when coadministering with mirtazapine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. QTc prolongation have been reported with the use of efavirenz. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.
    Mitapivat: (Major) Avoid coadministration of mitapivat with efavirenz if possible, due to decreased mitapivat efficacy. If concomitant use is necessary, up-titration of mitapivat may be required. Monitor hemoglobin and titrate the mitapivat dose based on response; do not exceed 100 mg PO twice daily. Mitapivat is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Efavirenz decreased mitapivat overall and peak exposure by approximately 60% and 30%, respectively, after mitapivat 5 or 20 mg twice daily. Efavirenz decreased mitapivat overall and peak exposure by 55% and 24%, respectively, after mitapivat 50 mg twice daily.
    Mitotane: (Major) Use caution if mitotane and efavirenz are used concomitantly, as coadministration may significantly reduce plasma concentrations of efavirenz, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. When efavirenz is coadministered with rifampin, another strong CYP3A4 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients >= 50 kg). Mitotane is a strong CYP3A4 inducer and efavirenz is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of efavirenz.
    Mobocertinib: (Major) Avoid concomitant use of mobocertinib and efavirenz. Concomitant use may decrease mobocertinib exposure resulting in decreased efficacy. Use may also increase the risk of QT prolongation and torsade de pointes (TdP). Mobocertinib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Use of a moderate CYP3A inducer is predicted to decrease the overall exposure of mobocertinib and its active metabolites by 58%.
    Moxifloxacin: (Major) Coadministration of efavirenz and moxifloxacin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, torsade de pointes has been reported during post-marketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with efavirenz is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Nanoparticle Albumin-Bound Sirolimus: (Major) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range, such as sirolimus. Monitoring of serum sirolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz.
    Naproxen; Esomeprazole: (Minor) Although drug interaction studies have not been conducted, efavirenz may inhibit the metabolism of substrates for CYP2C9 or CYP2C19 such as esomeprazole. In vitro studies have shown that efavirenz inhibits CYP2C9 and CYP2C19 in the range of observed efavirenz plasma concentrations.
    Nefazodone: (Major) Nefazodone inhibits the CYP3A4 metabolism of efavirenz. Nefazodone has been used to treat depression in patients on antiretroviral medications concurrently. However, it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects.
    Neratinib: (Major) Avoid concomitant use of efavirenz with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that efavirenz may decrease neratinib exposure by 52%.
    Nevirapine: (Major) Coadministration of nevirapine and efavirenz is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. Concomitant use may also cause a decrease in plasma concentrations of efavirenz and, thus, a loss of therapeutic effect. The pharmacokinetics of nevirapine appear to be unaffected. Nevirapine is a CYP3A substrate and weak CYP3A inducer. Efavirenz is a CYP3A substrate and moderate CYP3A inducer.
    Niacin; Simvastatin: (Moderate) Efavirenz has potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with simvastatin with caution.
    Nicardipine: (Moderate) Use caution and careful monitoring when coadministering efavirenz with certain calcium-channel blockers. Efavirenz induces CYP3A4, potentially altering serum concentrations of calcium-channel blockers metabolized via CYP3A4. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments are made based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, lercanidipine, nicardipine, and verapamil); adjust based on clinical response.
    Nifedipine: (Moderate) Use caution and careful monitoring when coadministering efavirenz with certain calcium-channel blockers. Efavirenz induces CYP3A4, potentially altering serum concentrations of calcium-channel blockers metabolized via CYP3A4. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments are made based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, lercanidipine, nicardipine, and verapamil); adjust based on clinical response.
    Nilotinib: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as efavirenz, is not advised; nilotinib prolongs the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. In addition, concomitant use of nilotinib, a substrate and an inhibitor of CYP3A4, and efavirenz, a substrate and inducer of CYP3A4, may result in decreased nilotinib plasma concentrations and/or increased efavirenz concentrations. Selecting an alternate agent with less potential for CYP3A4 induction should be considered. Closely monitor patients if these drugs are used together; increasing the nilotinib dosage will most likely not account for the loss of exposure based on the nonlinear pharmacokinetics of nilotinib.
    Nimodipine: (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
    Nirmatrelvir; Ritonavir: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of efavirenz is necessary. Concomitant use of nirmatrelvir and efavirenz may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. (Moderate) Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Concurrent use is is expected to result in increased concentrations of both drugs.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with efavirenz due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and efavirenz is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    Non-oral combination contraceptives: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin, levonorgestrel, and etonogestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased by 80% and 83%, respectively. Etonogestrel AUC decreased by 63% to 82%. There have been postmarketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Norethindrone: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Norethindrone; Ethinyl Estradiol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Norgestimate; Ethinyl Estradiol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Norgestrel: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Octreotide: (Moderate) Use octreotide with caution in combination with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Moderate) Consider alternatives to efavirenz when coadministering with ofloxacin as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Quinolones have been associated with a risk of QT prolongation and torsade de pointes (TdP). Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Olanzapine; Fluoxetine: (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval. (Moderate) Consider an alternative to efavirenz if coadministration with fluoxetine is necessary as concurrent use may increase the risk of QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. QTc prolongation has also been observed with the use of efavirenz.
    Olanzapine; Samidorphan: (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
    Olaparib: (Major) Avoid coadministration of olaparib with efavirenz due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and efavirenz is a moderate CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with efavirenz is predicted to decrease the olaparib Cmax by 31% and the AUC by 60%.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Olutasidenib: (Major) Avoid concurrent use of olutasidenib and efavirenz due to the risk of decreased olutasidenib exposure which may reduce its efficacy. Olutasidenib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
    Ombitasvir; Paritaprevir; Ritonavir: (Contraindicated) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with efavirenz is contraindicated. The use of this drug combination was pooly tolerated by recipients and resulted in hepatic enzyme elevations. (Contraindicated) Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with efavirenz is contraindicated. The use of this drug combination was pooly tolerated by recipients and resulted in hepatic enzyme elevations. (Moderate) Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Concurrent use is is expected to result in increased concentrations of both drugs.
    Omeprazole: (Minor) Efavirenz inhibits and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C19.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Due to decreased exposure of rifabutin, the FDA-approved labeling recommends that the daily dose of rifabutin be increased by 50% when coadministered with efavirenz. For patients being treated for tuberculosis, guidelines recommend a daily dose of 450 to 600 mg. For rifabutin regimens given two or three times per week, consider doubling the rifabutin dose. Rifabutin is a substrate of CYP3A4; efavirenz is a moderate CYP3A4 inducer. (Minor) Efavirenz inhibits and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C19.
    Omeprazole; Sodium Bicarbonate: (Minor) Efavirenz inhibits and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C19.
    Ondansetron: (Major) Coadministration of efavirenz and ondansetron may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If these drugs must be coadministered, ECG monitoring is recommended. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as ondansetron.
    Oral Contraceptives: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Oritavancin: (Major) Efavirenz is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of efavirenz may be reduced if these drugs are administered concurrently.
    Orlistat: (Major) Monitor HIV RNA concentrations frequently during concurrent use of orlistat and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Discontinue orlistat if an increased HIV viral load is confirmed. Loss of virological control has been reported in persons with HIV infection taking orlistat with antiretrovirals, including NNRTIs. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the antiretroviral agent.
    Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with efavirenz as concurrent use may increase the risk of QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation. QTc prolongation has been observed with the use of efavirenz.
    Osimertinib: (Major) Avoid coadministration of efavirenz with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QTc prolongation has been observed with the use of efavirenz.
    Oxaliplatin: (Major) Consider alternatives to efavirenz when treatment with oxaliplatin is necessary. QTc prolongation has been observed with the use of efavirenz. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
    Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A4. Drugs that induce CYP3A4, such as efavirenz, may cause decreased serum concentrations of oxybutynin. The clinical significance of such interactions is not known; however patients receiving oxybutynin with efavirenz or efavirenz-containing products (e.g. efavirenz; emtricitabine; tenofovir) concomitantly should be monitored for efficacy.
    Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with efavirenz is necessary; consider increasing the dose of oxycodone as needed. If efavirenz is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking efavirenz due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. QTc prolongation has been observed with the use of efavirenz.
    Paclitaxel: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as paclitaxel.
    Pacritinib: (Major) Avoid concurrent use of pacritinib with efavirenz due to the risk of decreased pacritinib exposure which may impair efficacy. Concomitant use may also increase the risk of QT/QTc prolongation and torsade de pointes (TdP). Pacritinib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
    Palbociclib: (Moderate) Monitor for an increase in efavirenz-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while efavirenz is a CYP3A4 substrate.
    Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval, such as efavirenz, is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or greater during therapy; permanently discontinue if QT prolongation does not resolve. In addition, efavirenz may induce the CYP3A4 metabolism of panobinostat, potentially reducing the efficacy of panobinostat by decreasing its systemic exposure.
    Paricalcitol: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as paricalcitol.
    Pasireotide: (Moderate) Consider alternatives to efavirenz when coadministering with pasireotide as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval, such as efavirenz, is not advised; pazopanib has been reported to prolong the QT interval. If pazopanib and the other drug must be continued, closely monitor the patient for QT interval prolongation. In addition, concurrent use may increase the systemic concentration of efavirenz and decrease the concentration of pazopanib. Efavirenz is a CYP3A4 substrate and inducer, while pazopanib is a CYP3A4 substrate and mild inhibitor.
    Peginterferon Alfa-2a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Peginterferon Alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Peginterferon beta-1a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Pemigatinib: (Major) Avoid coadministration of pemigatinib and efavirenz due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease pemigatinib exposure by more than 50%.
    Pentamidine: (Major) Although data are limited, coadministration of efavirenz and pentamidine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs
    Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with efavirenz due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of efavirenz occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Efavirenz is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Perindopril; Amlodipine: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Perphenazine: (Minor) Consider alternatives to efavirenz when coadministering with perphenazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Perphenazine is associated with a possible risk for QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Consider alternatives to efavirenz when coadministering with perphenazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Perphenazine is associated with a possible risk for QT prolongation.
    Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with efavirenz. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as efavirenz. In addition, pimavanserin is primarily metabolized by CYP3A4 and CYP3A5 and the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as efavirenz. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
    Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Efavirenz has also been associated with QT prolongation. Because of the potential for QT prolongation and TdP, use of efavirenz with pimozide is contraindicated.
    Pioglitazone; Glimepiride: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like efavirenz. Monitor serum glucose concentrations if glimepiride is coadministered with efavirenz. Dosage adjustments may be necessary.
    Piroxicam: (Moderate) Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of piroxicam, a substrate for CYP2C9.
    Pitolisant: (Major) Avoid coadministration of pitolisant with efavirenz as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. QTc prolongation has been observed with the use of efavirenz.
    Ponesimod: (Major) In general, do not initiate ponesimod in patients taking efavirenz due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. QTc prolongation has been observed with the use of efavirenz.
    Posaconazole: (Contraindicated) The concurrent use of posaconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as efavirenz, is contraindicated. Posaconazole has been associated with QT prolongation and torsade de pointes. In addition, concomitant use may increase the risk for breakthrough fungal infection. Efavirenz is believed to interact with posaconazole by inducing UDP glucuronidation. When posaconazole was administered with efavirenz, the mean reductions in Cmax were 45% and the mean reductions in AUC were 50% for posaconazole.
    Praziquantel: (Major) In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Therefore, use of praziquantel with efavirenz, a CYP3A4 inducer, should be done with caution as concomitant use may produce therapeutically ineffective concentrations of praziquantel.
    Pretomanid: (Major) Avoid coadministration of pretomanid with efavirenz as concurrent use decreased pretomanid exposure by 66% which may lead to decreased efficacy; concurrent use may also increase the risk for hepatotoxicity. Pretomanid is a CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications.
    Primaquine: (Moderate) Consider alternatives to efavirenz when coadministering with primaquine. QT prolongation has been observed with use of both efavirenz and primaquine.
    Procainamide: (Major) Coadministration of efavirenz and procainamide may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Procainamide is associated with a well-established risk of QT prolongation and TdP.
    Prochlorperazine: (Minor) Consider alternatives to efavirenz when coadministering with prochlorperazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Prochlorperazine is associated with a possible risk for QT prolongation.
    Promethazine: (Moderate) Consider alternatives to efavirenz when coadministering with promethazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
    Promethazine; Dextromethorphan: (Moderate) Consider alternatives to efavirenz when coadministering with promethazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
    Promethazine; Phenylephrine: (Moderate) Consider alternatives to efavirenz when coadministering with promethazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
    Propafenone: (Major) Although data are limited, coadministration of efavirenz and propafenone may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. In addition, efavirenz is an inducer of CYP3A4; propafenone concentrations may be decreased with coadministration.
    Quetiapine: (Major) Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. According to the manufacturer, use of quetiapine should be avoided in combination with drugs known to increase the QT interval, such as efavirenz. In addition, efavirenz may induce the CYP3A4 metabolism of quetiapine, and thus, decrease the serum concentration of quetiapine.
    Quinidine: (Major) Coadministration of efavirenz and quinidine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Quinidine administration is associated with QT prolongation and TdP. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as quinidine.
    Quinine: (Major) Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Avoid concurrent use of quinine with other drugs that may cause QT prolongation and TdP, such as efavirenz. In addition, concurrent use may alter the systemic concentration of efavirenz and decrease the concentration of quinine. Efavirenz is a CYP3A4 substrate and inducer, while quinine is a CYP3A4 substrate, inducer, and inhibitor.
    Ranolazine: (Contraindicated) Do not use ranolazine in combination with CYP3A inducers like efavirenz as ranolazine exposure and therapeutic response may be decreased; additive effects on the QT interval are also possible. Efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation. Ranolazine is a CYP3A substrate that is associated with dose- and plasma concentration-related increases in the QTc interval. Although the effect of moderate inducers is not reported by the ranolazine manufacturer, coadministration with a strong CYP3A inducer decreased the ranolazine plasma concentrations by 95%.
    Red Yeast Rice: (Moderate) Since certain red yeast rice products (i.e., pre-2005 Cholestin formulations) contain lovastatin, clinicians should use red yeast rice cautiously in combination with drugs known to interact with lovastatin. CYP3A4 inducers, such as efavirenz, can theoretically reduce the effectiveness of HMG-CoA reductase activity via induction of CYP3A4 metabolism.
    Relugolix: (Moderate) Consider alternatives to efavirenz when coadministering with relugolix. QTc prolongation has been observed with the use of efavirenz. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations. (Moderate) Consider alternatives to efavirenz when coadministering with relugolix. QTc prolongation has been observed with the use of efavirenz. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
    Repaglinide: (Minor) Repaglinide is metabolized in the liver by cytochrome P450 isoenzyme CYP3A4. Patients taking repaglinide concomitantly with a CYP3A4 inducer such as efavirenz or efavirenz-containing products (e.g. efavirenz; emtricitabine; tenofovir) should be monitored for reduced effectiveness of repaglinide and possible symptoms indicating hyperglycemia.
    Ribavirin: (Moderate) The concomitant use of ribavirin and antiretroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Ribociclib: (Major) Avoid coadministration of ribociclib with efavirenz due to an increased risk for QT prolongation. Additionally, the systemic exposure of efavirenz may be increased resulting in an increase in treatment-related adverse reactions. Efavirenz is a CYP3A4 substrate that has been associated with QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with efavirenz due to an increased risk for QT prolongation. Additionally, the systemic exposure of efavirenz may be increased resulting in an increase in treatment-related adverse reactions. Efavirenz is a CYP3A4 substrate that has been associated with QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Concomitant use may increase the risk for QT prolongation.
    Rifabutin: (Major) Due to decreased exposure of rifabutin, the FDA-approved labeling recommends that the daily dose of rifabutin be increased by 50% when coadministered with efavirenz. For patients being treated for tuberculosis, guidelines recommend a daily dose of 450 to 600 mg. For rifabutin regimens given two or three times per week, consider doubling the rifabutin dose. Rifabutin is a substrate of CYP3A4; efavirenz is a moderate CYP3A4 inducer.
    Rifampin: (Major) When efavirenz and rifampin are coadministered, decreased efavirenz concentrations are seen and decreased antiretroviral efficacy is expected. These drugs may be coadministered to patients weighing 50 kg or more if the efavirenz dose is increased to 800 mg PO daily. A small study evaluated this interaction by administering the drugs (both at 600 mg PO daily x 7 days) to 12 subjects, and found decreased mean efavirenz Cmax, AUC, and Cmin of 20%, 26%, and 32%. Of note, reduced efavirenz metabolism is seen in patients with genetic polymorphisms of cytochrome P450 2B6 (primarily in patients of African, Asian, and Hispanic descent). Increasing the dose in these patients can result in a significant increase in efavirenz toxicity; some patients may even require lower doses.
    Rifapentine: (Moderate) Monitor for decreased efficacy of efavirenz if coadministered with rifapentine. Concurrent use may decrease the plasma concentrations of efavirenz leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Efavirenz is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer.
    Rilpivirine: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP).
    Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and efavirenz. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Rimegepant: (Major) Avoid coadministration of rimegepant with efavirenz; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Ripretinib: (Major) Avoid coadministration of ripretinib with efavirenz. If concomitant use is unavoidable, increase the frequency of ripretinib dosing from 150 mg once daily to 150 mg twice daily; monitor for clinical response and tolerability. Resume once daily dosing of ripretinib 14 days after discontinuation of efavirenz. Coadministration is predicted to decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A and efavirenz is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
    Risperidone: (Major) Coadministration of efavirenz and risperidone may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Risperidone has been associated with a possible risk for QT prolongation and/or TdP. Reports of QT prolongation and TdP during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting. If coadministration is chosen, and the patient has known risk factors for cardiac disease or arrhythmia, then the patient should be closely monitored clinically. In addition, efavirenz may induce the CYP3A4 metabolism of risperidone, potentially reducing the efficacy of risperidone by decreasing its systemic exposure.
    Ritonavir: (Moderate) Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Concurrent use is is expected to result in increased concentrations of both drugs.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and efavirenz may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Efavirenz is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
    Roflumilast: (Moderate) Coadminister efavirenz or efavirenz-containing products (e.g. efavirenz; emtricitabine; tenofovir) and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Efavirenz induces CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
    Romidepsin: (Moderate) Consider alternatives to efavirenz and monitoring electrolytes and ECGs at baseline and periodically during treatment if administered with romidepsin as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. QTc prolongation has been observed with the use of efavirenz.
    Ropeginterferon alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
    Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as efavirenz, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
    Saquinavir: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as efavirenz. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Also, appropriate dosing recommendations for concomitant efavirenz and saquinavir, coadministered with or without ritonavir, have not been established. The concurrent administration of saquinavir soft gel capsule and efavirenz has resulted in decrease in saquinavir AUC and Cmax by 62% and 50%, respectively. A case report of 2 patients who had efavirenz (600 mg once daily) added to their ritonavir/saquinavir-SGC regimen (400/600 mg twice daily), showed modest increases in saquinavir AUC after the addition of efavirenz. The AUC of ritonavir increased in one patient and decreased in the other. Increasing the dose of saquinavir to 800 mg every 12 hours decreased the AUC of ritonavir and increased the AUC of efavirenz in both patients after 14 days. However, the increased dose of saquinavir produced a less than proportional increase in the saquinavir AUC.
    Segesterone Acetate; Ethinyl Estradiol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
    Selpercatinib: (Major) Avoid coadministration of selpercatinib and efavirenz due to the risk of decreased selpercatinib exposure which may reduce its efficacy; additive QT prolongation may also occur. Selpercatinib is a CYP3A4 substrate that is associated with concentration-dependent QT prolongation; efavirenz is a moderate CYP3A4 inducer that is associated with QTc prolongation. Coadministration with efavirenz is predicted to decrease selpercatinib exposure by 40% to 70%.
    Selumetinib: (Major) Avoid coadministration of selumetinib and efavirenz due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with efavirenz is predicted to decrease selumetinib exposure by 38%.
    Sertraline: (Moderate) Consider alternatives to efavirenz when coadministering with sertraline. If use together is necessary, use caution and monitor patients for QT prolongation. QTc prolongation has been observed with the use of efavirenz. Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure).
    Sevoflurane: (Major) Although data are limited, coadministration of efavirenz and halogenated anesthetics may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs can prolong the QT interval.
    Sibutramine: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as sibutramine.
    Sildenafil: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as sildenafil.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and efavirenz. Induction of CYP3A4 by efavirenz significantly reduces the plasma concentrations of simeprevir, potentially resulting in treatment failure. Concurrent treatment for 14 days has resulted in decreased Cmax, AUC, and Cmin of simeprevir by 51% (90% CI: 46% to 56%), 71% (90% CI: 67% to 74%), and 91% (90% CI: 88% to 92%), respectively.
    Simvastatin: (Moderate) Efavirenz has potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with simvastatin with caution.
    Simvastatin; Sitagliptin: (Moderate) Efavirenz has potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with simvastatin with caution.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving efavirenz due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Efavirenz has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and efavirenz is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, efavirenz decreased the exposure of siponimod by up to 52% according to in silico evaluation.
    Sirolimus: (Major) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range, such as sirolimus. Monitoring of serum sirolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz.
    Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with efavirenz, as concurrent administration significantly decreases velpatasvir plasma concentrations and may result in loss of antiviral efficacy. In a drug interaction study, use of these drugs together resulted in an approximate 50% reduction in velpatasvir exposure. Velpatasvir is substrate of P-glycoprotein (P-gp) and to a lesser extent CYP3A; efavirenz induces P-gp and CYP3A.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with efavirenz, as concurrent administration significantly decreases velpatasvir plasma concentrations and may result in loss of antiviral efficacy. In a drug interaction study, use of these drugs together resulted in an approximate 50% reduction in velpatasvir exposure. Velpatasvir is substrate of P-glycoprotein (P-gp) and to a lesser extent CYP3A; efavirenz induces P-gp and CYP3A. (Major) Avoid coadministration of voxilaprevir with moderate to potent inducers of CYP3A4, such as efavirenz. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy. Voxilaprevir is metabolized by CYP3A4.
    Solifenacin: (Moderate) Consider alternatives to efavirenz when coadministering with solifenacin as concurrent use may increase the risk of QT prolongation; decreased solifenacin exposure is also possible. QTc prolongation has been observed with the use of efavirenz. Solifenacin has been associated with dose-dependent prolongation of the QT interval and TdP has been reported with post-marketing use, although causality was not determined. In addition, efavirenz may induce the CYP3A4 metabolism of solifenacin; potentially reducing the efficacy of solifenacin by decreasing its systemic exposure.
    Sonidegib: (Major) Avoid the concomitant use of sonidegib and efavirenz; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and efavirenz is a CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
    Sorafenib: (Major) Avoid coadministration of sorafenib with efavirenz due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. QTc prolongation has also been observed with the use of efavirenz.
    Sotalol: (Major) Concomitant use of sotalol and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    St. John's Wort, Hypericum perforatum: (Contraindicated) Concurrent use of St. John's Wort, Hypericum perforatum and efavirenz is contraindicated. When coadministered, there is a potential for treatment failure and the development of efavirenz or NNRTI resistance. St. John's Wort is a strong inducer of CYP3A4, which is partially responsible for the metabolism of efavirenz. Coadministration may result in decreased efavirenz serum concentrations, which could cause impaired virologic response.
    Stiripentol: (Moderate) Consider a dose adjustment of efavirenz when coadministered with stiripentol. Coadministration may alter plasma concentrations of efavirenz resulting in an increased risk of adverse reactions and/or decreased efficacy. Efavirenz is a CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if efavirenz must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with efavirenz is necessary; consider increasing the dose of sufentanil injection as needed. If efavirenz is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Sunitinib: (Major) Consider alternatives to efavirenz when coadministering with sunitinib. QTc prolongation has been observed with the use of efavirenz. Sunitinib can also prolong the QT interval.
    Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with efavirenz. Monitoring of serum tacrolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz. Tacrolimus is a CYP3A4 substrate that may prolong the QT interval and cause torsade de pointes (TdP). Efavirenz induces CYP3A4; QTc prolongation has been observed with the use of efavirenz.
    Tadalafil: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
    Tamoxifen: (Moderate) Consider alternatives to efavirenz when coadministering with tamoxifen as concurrent use may increase the risk of QT prolongation. Prolongation of the QTc interval has been observed with the use of efavirenz. Tamoxifen has also been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and efavirenz. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors may increase exposure to tasimelteon with the potential for adverse reactions. Because efavirenz may inhibit or induce CYP3A4, the clinical outcome of this combination is unknown.
    Tazemetostat: (Major) Avoid coadministration of tazemetostat with efavirenz as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
    Telavancin: (Moderate) Consider alternatives to efavirenz when coadministering with telavancin. QTc prolongation has been observed with the use of efavirenz. Telavancin has been associated with QT prolongation.
    Telithromycin: (Moderate) Consider alternatives to efavirenz when coadministering with telithromycin as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Telithromycin is associated with QT prolongation and TdP. In addiiton, concentrations of efavirenz may be increased and the concentrations of telithromycin may be decreased with coadministration. Efavirenz is a CYP3A4 substrate and inducer, while telithromycin is a CYP3A4 substrate and a strong CYP3A4 inhibitor.
    Telmisartan; Amlodipine: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
    Terbinafine: (Moderate) Caution is advised when administering terbinafine with efavirenz. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9, CYP2C19, and CYP3A4; efavirenz is inhibitor of CYP2C9 and CYP2C19, and an inhibitor/inducer of CYP3A4. Monitor patients for adverse reactions and breakthrough fungal infections if these drugs are coadministered.
    Tetrabenazine: (Major) Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc, such as efavirenz.
    Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Thioridazine is considered contraindicated for use along with agents that may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Efavirenz has also been associated with QT prolongation. Because of the potential for QT prolongation and TdP, use of efavirenz with thioridazine is contraindicated.
    Ticagrelor: (Moderate) If possible, avoid use of ticagrelor with efavirenz or efavirenz-containing products (i.e., efavirenz; emtricitabine; tenofovir); coadministration may result in decreased efficacy of ticagrelor, and potentially increased adverse events of efavirenz. Ticagrelor is a substrate and weak inhibitor of CYP3A4/5. Efavirenz has been shown to induce CYP3A in vivo and is partially metabolized by CYP3A4.
    Tolbutamide: (Minor) Efavirenz inhibits CYP2C9 and CYP2C19. Efavirenz may inhibit the metabolism of tolbutamide since it is a substrate for CYP2C9 or CYP2C19.
    Tolterodine: (Moderate) Consider alternatives to efavirenz when coadministering with tolterodine due to increased risk for QT prolongation. QTc prolongation has been observed with the use of efavirenz. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as tolterodine.
    Toremifene: (Major) Avoid coadministration of efavirenz with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Tramadol: (Moderate) The (+) enantiomer of tramadol preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. Efavirenz is an inducer of CYP3A4 and CYP2B6. Coadministration may affect the metabolism of tramadol leading to altered tramadol exposure. Decreased serum tramadol concentrations and reduced efficacy may occur. In addition, both medications have been associated with the development of seizures; caution is advised.
    Tramadol; Acetaminophen: (Moderate) The (+) enantiomer of tramadol preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. Efavirenz is an inducer of CYP3A4 and CYP2B6. Coadministration may affect the metabolism of tramadol leading to altered tramadol exposure. Decreased serum tramadol concentrations and reduced efficacy may occur. In addition, both medications have been associated with the development of seizures; caution is advised. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Trandolapril; Verapamil: (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
    Trazodone: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval, such as efavirenz. In addition, efavirenz may induce the CYP3A4 metabolism of trazodone; potentially reducing the efficacy of trazodone by decreasing its systemic exposure.
    Triclabendazole: (Moderate) Concomitant use of triclabendazole and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Trifluoperazine: (Minor) Consider alternatives to efavirenz when coadministering with trifluoperazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Trifluoperazine is associated with a possible risk for QT prolongation.
    Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving efavirenz as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Ubrogepant: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with efavirenz as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer.
    Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and efavirenz is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
    Vandetanib: (Major) Avoid coadministration of vandetanib with efavirenz due to an increased risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Prolongation of the QTc interval has also been observed with the use of efavirenz.
    Vardenafil: (Moderate) Consider the potential for additive QT effects if vardenafil is administered with efavirenz. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval. QTc prolongation has been observed with the use of efavirenz.
    Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. ECG monitoring is recommended if vemurafenib and another QT prolonging drug, such as efavirenz, must be coadministered; closely monitor the patient for QT interval prolongation. In addition, concomitant use may result in decreased vemurafenib and efavirenz concentrations. Both drugs are substrates and inducers of CYP3A4.
    Venetoclax: (Major) Avoid the concomitant use of venetoclax and efavirenz; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
    Venlafaxine: (Moderate) Consider alternatives to efavirenz when coadministering with venlafaxine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Venlafaxine administration is associated with a possible risk of QT prolongation; torsade de pointes (TdP) has reported with postmarketing use.
    Verapamil: (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
    Voclosporin: (Major) Avoid coadministration of voclosporin with efavirenz. Coadministration may decrease voclosporin exposure resulting in decreased efficacy. Concomitant use may also increase the risk of QT prolongation. Voclosporin is a sensitive CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease voclosporin exposure by 70%.
    Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of vonoprazan and efavirenz due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
    Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of vonoprazan and efavirenz due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) The manufacturer of efavirenz recommends that alternatives to clarithromycin be considered when a macrolide antibiotic is required in patients receiving efavirenz. Coadministration of efavirenz and clarithromycin may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes TdP. QT prolongation has also been observed with use of efavirenz. In addition, concurrent use of efavirenz with clarithromycin 500 mg PO every 12 hours for seven days resulted in a significant decrease in the serum concentration of clarithromycin, but the clinical significance of this is not known.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and efavirenz. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with efavirenz, a CYP3A inducer.
    Voriconazole: (Major) Coadministration of standard doses of voriconazole and efavirenz (400 mg PO daily or higher) is contraindicated. If efavirenz and voriconazole must be coadministered, dosage adjustments of both drugs are required. During coadministration, increase the voriconazole maintenance dose to 400 mg PO every 12 hours and decrease the efavirenz dose to 300 mg PO once daily, using the capsule formulation; efavirenz tablets should not be broken. When coadministered, efavirenz (400 mg PO daily) significantly decreased the steady state Cmax and AUC of voriconazole by 61% and 77%, respectively and voriconazole significantly increased the steady state Cmax and AUC of efavirenz by 38% and 44%, respectively. If administered at standard doses, this would pose the risk of voriconazole therapeutic failure and increased efavirenz-related toxicities. In addition, concurrent use may increase the risk for QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. QT prolongation has also been observed during use of efavirenz.
    Vorinostat: (Moderate) Consider alternatives to efavirenz when coadministering with vorinostat as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Vorinostat therapy is associated with a risk of QT prolongation.
    Voxelotor: (Major) Avoid coadministration of voxelotor and efavirenz as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. If coadministration is unavoidable, increase voxelotor dosage to 2,000 mg PO once daily in patients 12 years and older. In patients 4 to 11 years old, weight-based dosage adjustments are recommended; consult product labeling for specific recommendations. Voxelotor is a substrate of CYP3A; efavirenz is a moderate CYP3A inducer. Coadministration of voxelotor with a moderate CYP3A inducer is predicted to decrease voxelotor exposure by up to 24%.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with efavirenz is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Efavirenz is a moderate CYP2C9 inhibitor and warfarin is a CYP2C9 substrate. Additionally, efavirenz is a moderate CYP3A4 inducer and warfarin is a CYP3A4 substrate.
    Zanubrutinib: (Major) Avoid the concomitant use of zanubrutinib and efavirenz. Coadministration may result in decreased zanubrutinib exposure and reduced efficacy. Zanubrutinib is a CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer. The AUC of zanubrutinib is predicted to decrease by 60% when coadministered with efavirenz.
    Ziprasidone: (Major) Concomitant use of ziprasidone and efavirenz should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QTc prolongation has been observed with the use of efavirenz. Consider alternatives to efavirenz when coadministering with a drug with a known risk of TdP.
    Zolpidem: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as efavirenz. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.

    PREGNANCY AND LACTATION

    Pregnancy

    Antiretroviral therapy should be provided to all women during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations are greater than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations are greater than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. According to the manufacturer, efavirenz may cause fetal harm (i.e., neural tube defects), and should be avoided during the first trimester of pregnancy. The manufacturer also recommends the use of 2 effective forms of birth control during treatment and for 12 weeks after stopping efavirenz.[28442] However, HIV treatment guidelines do not restrict the use of efavirenz-containing regimens in pregnant women or in women who are trying to conceive. In addition, guidelines recommend that women who become pregnant while receiving suppressive efavirenz-containing regimens continue their current regimens. The HIV guidelines base this decision on the results of a meta-analysis of 23 studies. Data from this meta-analysis found no increased risk of overall birth defects in infants born to women on efavirenz during the first trimester compared with those on other antiretroviral medications (relative risk 0.78; 95% CI, 0.56 to 1.08). Further, data from more than 13,00 periconception exposures to efavirenz in Botswana were sufficient to rule out an increased risk of neural tube defects with efavirenz. Available data from the Antiretroviral Pregnancy Registry (APR), which includes more than 1,160 first trimester exposures to efavirenz, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. When efavirenz exposure occurred in the first trimester, the prevalence of defects was 2.4% (95% CI: 1.6 to 3.5). Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Women who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for women on HAART less than 2 years, women with CD4 count less than 300 cells/mm3, or women with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing, and if indicated, phenotypic testing) at baseline in all women with HIV RNA concentrations greater than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at delivery. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in women receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for the development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a woman decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to efavirenz; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.[27468] [23512] [28442] [46638]

    According to the manufacturer, efavirenz may cause serious fetal harm when administered during the first trimester of pregnancy; therefore, it is recommended that all females of childbearing age undergo pregnancy testing prior to initiating an efavirenz-containing treatment regimen. Counsel females about the reproductive risk and contraception requirements during treatment; barrier contraception should be used in combination with other methods of contraception during therapy and for 12 weeks after efavirenz has been discontinued. HIV treatment guidelines, however, state that study data indicate efavirenz-containing regimens are safe treatment options for use in pregnant women and women who are trying to conceive.

    MECHANISM OF ACTION

    Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. It binds directly to a site on reverse transcriptase that is near but distinct from where nucleoside reverse transcriptase inhibitors (NRTIs) bind. This binding causes disruption of the enzyme's active site, thereby blocking RNA-dependent and DNA-dependent DNA polymerase activities. Unlike NRTIs, efavirenz does not compete with template or nucleoside triphosphates, nor does it require phosphorylation to be active. HIV-2 reverse transcriptase is not inhibited by efavirenz. The 90% to 95% inhibitory concentrations range from 1.7 to 25 nM.[28442] [44852]
     
    In efavirenz resistant patients, mutations in reverse transcriptase occurred most frequently at amino acid position 103. Other reverse transcriptase mutations occurring at 1 or more amino acid positions 98, 100, 101, 106, 108, 188, 190, 255, and 227 are also associated with resistance to efavirenz. Of these failure isolates, 61% had an 88-fold (median) decrease in cell culture efavirenz susceptibility. Cross-resistance to NNRTIs has been observed in vitro. HIV-1 strains previously characterized as efavirenz-resistant were also phenotypically resistant to nevirapine and delavirdine.[28442]
     
    Avoid use of efavirenz in patients infected with HIV-2, as HIV-2 is intrinsically resistant to NNRTIs. To identify the HIV strain, The Centers for Disease Control and Prevention guidelines for HIV diagnostic testing recommend initial HIV testing using an HIV-1 and HIV-2 antigen and antibody combination immunoassay and subsequent testing using an HIV-1 and HIV-2 antibody differentiation immunoassay.[46638]

    PHARMACOKINETICS

    Efavirenz is administered orally. It is highly protein bound (99%), predominantly to albumin. In HIV-infected patients (n = 9) receiving 200 to 600 mg once daily for at least 1 month, CSF concentrations ranged from 0.26% to 1.19% (mean 0.69%) of the corresponding plasma concentration. This is approximately 3-times higher than the non-protein bound fraction of efavirenz in plasma. Efavirenz is metabolized by cytochrome P450 (CYP) 3A and CYP2B6 to hydroxylated metabolites with subsequent glucuronidation of these metabolites. It has a terminal half-life of 52 to 76 hours after a single dose and 40 to 55 hours after multiple doses. A mass balance/excretion study showed approximately 14% to 34% of radiolabeled efavirenz and metabolites were excreted in urine and 16% to 61% in feces. Nearly all of the urinary excretion was in the form of metabolites, while efavirenz accounted for the majority of the total radioactivity measured in the feces.[28442]
     
    Affected cytochrome P450 isoenzymes: CYP2C9, CYP2C19, CYP3A, CYP2B6
    Efavirenz has been shown in vivo to induce CYP3A and CYP2B6, which is its most prominent effect, thus increasing the biotransformation of drugs metabolized by this enzyme, including itself. In vitro studies have shown it inhibits CYP2C9 and CYP2C19 enzymes with Ki values (8.5 to 17 micro-M) in the range of observed plasma concentrations. Efavirenz inhibited CYP2D6 and CYP1A2 only at concentrations well above those achieved clinically (Ki values 82 to 160 micro-M). Coadministration with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A, or CYP2B6 isoenzymes may result in altered plasma concentrations of the coadministered drug. Drugs that induce CYP3A or CYP2B6 activity would be expected to increase the clearance of efavirenz.[28442]

    Oral Route

    Peak efavirenz plasma concentrations were seen 3 to 5 hours after administration of single doses of 200, 400, and 600 mg to HIV-infected volunteers. Steady-state plasma concentrations in these volunteers were reached in 6 to 10 days. For the capsules, a high-fat/high-caloric meal (e.g., 894 kcal, 54% of total calories from fat) increased the AUC and Cmax by 22% and 39%, respectively; a reduced-fat/normal-caloric meal (e.g., 440 kcal, 4% calories from fat) increased the AUC and Cmax by 17% and 51%, respectively, as compared to fasting conditions. For the tablets, a high-fat/high-caloric meal (e.g., 1000 kcal, 50% to 60% calories from fat) increased the AUC by 28% and increased the Cmax by 79% compared to fasting conditions. Administration of the capsule contents with 2 teaspoons of applesauce, grape jelly, yogurt, or infant formula resulted in an AUC that was bioequivalent to administration of the intact capsule under fasting conditions.[28442]