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    Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) and Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTI) Combinations

    BOXED WARNING

    Hepatic disease, hepatitis, hepatitis B and HIV coinfection, hepatitis B exacerbation

    Avoid use of efavirenz; emtricitabine; tenofovir in patients with moderate to severe hepatic disease (Child-Pugh B or C), as postmarketing cases of hepatitis (including fulminant hepatitis progressing to hepatic failure requiring transplantation or resulting in death) have been reported in efavirenz-treated patients. Efavirenz-associated hepatotoxicity has been identified in patients with and without preexisting hepatic disease; therefore, all potential recipients of efavirenz; emtricitabine; tenofovir should undergo liver enzymes monitoring before and during treatment. Consider the benefit of continued therapy in patients who develop persistent elevations of serum transaminases 5-times the upper limit of normal. Discontinue treatment if elevations in serum transaminases are accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation. Efavirenz; emtricitabine; tenofovir is not indicated for the treatment of chronic hepatitis B virus (HBV) infection, and safety and efficacy of treatment have not been established in patients with hepatitis B and HIV coinfection. However, tenofovir monotherapy is indicated for the treatment of HBV infection. Perform hepatitis B virus (HBV) screening in any patient who presents with HIV infection to assure appropriate treatment. Patients who are coinfected with HIV and HBV 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. Patients with coexisting HBV and HIV infections who discontinue emtricitabine or tenofovir may experience severe acute hepatitis B exacerbation with some cases resulting in hepatic decompensation and hepatic failure. Therefore, close monitoring of transaminase concentrations (every 6 weeks for the first 3 months, and every 3 to 6 months thereafter) is recommended in coinfected patients who discontinue NRTI therapy. If appropriate, resumption of anti-hepatitis B treatment may be required; especially in patients with advanced hepatic disease or cirrhosis. 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 patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate. [32514] [46638] [34362]

    DEA CLASS

    Rx

    DESCRIPTION

    Combination of a non-nucleoside, a nucleoside, and a nucleotide reverse transcriptase inhibitor
    Used for the treatment of human immunodeficiency virus (HIV) infection
    Black Box Warning for patients coinfected with HIV and hepatitis B

    COMMON BRAND NAMES

    Atripla

    HOW SUPPLIED

    Atripla/Efavirenz, Emtricitabine, Tenofovir/Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Oral Tab: 600-200-300mg

    DOSAGE & INDICATIONS

    For the treatment of human immunodeficiency virus (HIV) infection.
    Oral dosage
    Adults weighing 40 kg or more

    1 tablet (efavirenz 600 mg; emtricitabine 200 mg; tenofovir 300 mg) PO once daily at bedtime. May be used alone or in conjunction with other antiretrovirals.

    Children and Adolescents weighing 40 kg or more

    1 tablet (efavirenz 600 mg; emtricitabine 200 mg; tenofovir 300 mg) PO once daily at bedtime. May be used alone or in conjunction with other antiretrovirals.

    MAXIMUM DOSAGE

    Adults

    40 kg or more: efavirenz 600 mg/day PO; emtricitabine 200 mg/day PO; tenofovir 300 mg/day PO.
    less than 40 kg: Use not recommended.

    Geriatric

    40 kg or more: efavirenz 600 mg/day PO; emtricitabine 200 mg/day PO; tenofovir 300 mg/day PO.
    less than 40 kg: Use not recommended.

    Adolescents

    40 kg or more: efavirenz 600 mg/day PO; emtricitabine 200 mg/day PO; tenofovir 300 mg/day PO.
    less than 40 kg: Use not recommended.

    Children

    40 kg or more: efavirenz 600 mg/day PO; emtricitabine 200 mg/day PO; tenofovir 300 mg/day PO.
    less than 40 kg: Use not recommended.

    Infants

    Use not recommended.

    Neonates

    Use not recommended.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Caution is advised when administering to patients with mild hepatic impairment (Child-Pugh A). Avoid use in patients with moderate to severe hepatic impairment (Child-Pugh B or C).

    Renal Impairment

    CrCl >= 50 mL/min: No dosage adjustment is needed.
    CrCl < 50 mL/min: Not recommended.
     
    Intermittent hemodialysis
    Hemodialysis can remove both emtricitabine and tenofovir from the blood, but is not expected to significantly remove efavirenz. It would be prudent to refrain from administering efavirenz; emtricitabine; tenofovir to patients requiring hemodialysis.

    ADMINISTRATION

    To reduce the nervous system side effects, bedtime dosing is recommended.

    Oral Administration

    Administer on an empty stomach.

    STORAGE

    Atripla:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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]

    Females, hepatotoxicity or lactic acidosis, lactic acidosis, obesity

    Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported following use of emtricitabine and tenofovir disoproxil fumarate (DF), both alone and in combination with other antiretroviral medications. Treatment with efavirenz; emtricitabine; tenofovir DF should be suspended in any patient who develops clinical or laboratory findings suggestive of hepatotoxicity or lactic acidosis, which may include hepatomegaly and steatosis even in the absence of marked elevated hepatic enzymes. Although these adverse events may occur in any drug recipient, some risk factors include impaired hepatic function, obesity, and prolonged nucleoside exposure. In addition, a majority of these cases have been in females; it is unknown if being pregnant augments the incidence of this syndrome in patients receiving nucleoside analogs. However, because being pregnant itself can mimic some of the early symptoms of the lactic acid and hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester and any new symptoms should be evaluated thoroughly.

    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 more 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 more 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 12 weeks of pregnancy.[32514] 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 first trimester exposures to efavirenz (more than 1,160 exposures), emtricitabine (more than 3,950 exposures), and tenofovir disoproxil fumarate (more than 4,480 exposures), 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 exposure occurred in the first trimester, the prevalence of defects was 2.4% (95% CI: 1.6 to 3.5) for efavirenz, 2.6% (95% CI: 2.2 to 3.2) for emtricitabine, and 2.4% (95% CI: 2 to 2.9) for tenofovir disoproxil fumarate. Nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some of the early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester of pregnancy and any new symptoms should be evaluated thoroughly. 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; emtricitabine; tenofovir disoproxil fumarate; information about the registry can be obtained at www.apregistry.com or by calling 800-258-4263.[27468] [23512] [28442] [46638]

    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 the treatment regimen. Since monitoring of serum cholesterol and triglycerides is recommended during efavirenz therapy, it is prudent to consider such monitoring during treatment with efavirenz; emtricitabine; tenofovir.

    Children, infants, neonates

    Pediatric patients (i.e., neonates, infants, children) may experience an increase in the prevalence or severity of certain adverse reactions, including rash and bone mineral density; close monitoring is advised. In addition, efavirenz; emtricitabine; tenofovir is not recommended for use in patients weighing less than 40 kg.

    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; emtricitabine; tenofovir. 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.[28442] Limited data suggest small amounts of emtricitabine and tenofovir are excreted into 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. In another study, exposure to emtricitabine in exclusively breast-fed infants was estimated at approximately 2% of the recommended infant dose. This same study found tenofovir exposure in exclusively breast-fed infants to be equivalent to approximately 4.2 micrograms per day. Other antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.[32514] [46774] [46675] [46688] [46679] [46680] [46682]

    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 side effects, 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 the drugs 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 events including psychiatric adverse events.

    Exfoliative dermatitis, 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) have been observed. Discontinue treatment in patients with a rash associated with blistering, desquamation (e.g., exfoliative dermatitis), mucosal involvement, or fever, which may be due to the efavirenz component. Efavirenz 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/or 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.

    Seizure disorder, seizures

    Use efavirenz-containing regimens 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 levels.

    Asian patients, Black 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. In high-income countries (e.g., US, some European countries, Australia, Japan), approximately 10% to 17% of treatment-naive individuals have resistance mutations to at least 1 antiretroviral drug; up to 8% (but generally less than 5%) of transmitted viruses will exhibit resistance to drugs from more than 1 class. Therefore, 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. Emtricitabine will not likely be effective in individuals who display antimicrobial resistance to lamivudine, due to the similarities between the two drugs. Clinicians should not expect patients with the M184 mutation associated with lamivudine to benefit from an emtricitabine containing regimen. The M184 mutation confers high-level resistance, and emtricitabine, like lamivudine, selects for the M184 mutation. It is important that persons with detectable viral load who plan to switch therapy from lamivudine to emtricitabine have genotypic testing performed to determine whether the M184V mutation is present. A patient's treatment history is also extremely important; if lamivudine has failed in the past, the 184 is archived, thus rendering emtricitabine ineffective in this patient population. Of note, 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 21 days or more 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 Americans (Black 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 is not known. An alternative strategy is to substitute the efavirenz with a protease inhibitor (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.

    Hepatic disease, hepatitis, hepatitis B and HIV coinfection, hepatitis B exacerbation

    Avoid use of efavirenz; emtricitabine; tenofovir in patients with moderate to severe hepatic disease (Child-Pugh B or C), as postmarketing cases of hepatitis (including fulminant hepatitis progressing to hepatic failure requiring transplantation or resulting in death) have been reported in efavirenz-treated patients. Efavirenz-associated hepatotoxicity has been identified in patients with and without preexisting hepatic disease; therefore, all potential recipients of efavirenz; emtricitabine; tenofovir should undergo liver enzymes monitoring before and during treatment. Consider the benefit of continued therapy in patients who develop persistent elevations of serum transaminases 5-times the upper limit of normal. Discontinue treatment if elevations in serum transaminases are accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation. Efavirenz; emtricitabine; tenofovir is not indicated for the treatment of chronic hepatitis B virus (HBV) infection, and safety and efficacy of treatment have not been established in patients with hepatitis B and HIV coinfection. However, tenofovir monotherapy is indicated for the treatment of HBV infection. Perform hepatitis B virus (HBV) screening in any patient who presents with HIV infection to assure appropriate treatment. Patients who are coinfected with HIV and HBV 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. Patients with coexisting HBV and HIV infections who discontinue emtricitabine or tenofovir may experience severe acute hepatitis B exacerbation with some cases resulting in hepatic decompensation and hepatic failure. Therefore, close monitoring of transaminase concentrations (every 6 weeks for the first 3 months, and every 3 to 6 months thereafter) is recommended in coinfected patients who discontinue NRTI therapy. If appropriate, resumption of anti-hepatitis B treatment may be required; especially in patients with advanced hepatic disease or cirrhosis. 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 patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate. [32514] [46638] [34362]

    Bone fractures, hypophosphatemia, renal disease, renal failure, renal impairment

    Both emtricitabine and tenofovir are eliminated by the kidney; use of efavirenz; emtricitabine; tenofovir should be avoided in patients with creatinine clearance less than 50 mL/min. Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been associated with tenofovir administration. The majority of such cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents; some cases, however, occur in patients with no identifiable risk factors. The manufacturer recommends that an estimated creatinine clearance, urine glucose, and urine protein be assessed in all patients prior to treatment, and as indicated during treatment. Serum phosphorous concentrations should also be assessed prior to, and periodically during treatment in patients chronic kidney disease. In addition, closely evaluate the renal function of patients who experience persistent or worsening bone pain, pain in extremities, bone fractures, and muscle pain or weakness while receiving the drug as these may be manifestations of proximal renal tubulopathy. Avoid use of the drug concurrently with or recently after administration of a nephrotoxic agent, including high-dose or multiple non-steroidal antiinflammatory drugs (NSAIDS), as cases of acute renal failure requiring hospitalization and renal replacement therapy have been reported. Discontinue use of efavirenz; emtricitabine; tenofovir in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.

    Osteomalacia, osteoporosis

    Bone mineral density (BMD) monitoring should be considered for patients with HIV who have a history of pathologic bone fracture or are at substantial risk for osteopenia, osteoporosis, or osteomalacia; osteomalacia has been reported in association with tenofovir use. In a post-marketing study comparing tenofovir with stavudine (each given in combination with lamivudine and efavirenz), decreases from baseline in BMD were seen at the lumbar spine and hip regions in both arms of the study. The clinical significance of the changes in BMD is unknown. Normally, BMD increases rapidly in pediatric patients; however, in studies of tenofovir-treated pediatric patients, bone effects were similar to those noted in adult patients. In a study involving adolescents aged 12 to 17 years, the mean rate of BMD gain was less in the tenofovir-treated patients compared to the placebo group. Six tenofovir-treated adolescents and 1 placebo-treated adolescent had significant (greater than 4%) lumbar spine BMD loss in 48 weeks. Skeletal growth height appeared to be unaffected. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be considered for all patients. If bone abnormalities are suspected, appropriate consultation should be obtained.

    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; emtricitabine; tenofovir 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 carinii 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.

    Hepatitis C and HIV coinfection

    HIV treatment guidelines recommend all patients presenting with HIV infection undergo testing for hepatitis C, with continued annual screening advised for those persons considered high risk for acquiring hepatitis C. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. For most patients, the benefits of concurrent therapy outweighs the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in all coinfected patients regardless of CD4 count. However, for antiretroviral naive patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    Bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, geriatric, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    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 ms. Health care providers are advised to consider alternatives to efavirenz in patients receiving medications that have the potential to cause Torsade de Pointes (TdP). Further, use efavirenz with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation.

    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 efavirenz; emtricitabine; tenofovir. 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; emtricitabine; tenofovir 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. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to efavirenz; emtricitabine; tenofovir; information about the registry can be obtained at http://apregistry.com or by calling 1-800-258-4263.

    ADVERSE REACTIONS

    Severe

    teratogenesis / Delayed / 2.8-3.6
    exfoliative dermatitis / Delayed / 0.1-2.2
    erythema multiforme / Delayed / 0.1-2.2
    Stevens-Johnson syndrome / Delayed / 0.1-2.2
    toxic epidermal necrolysis / Delayed / 0.1-2.2
    skin necrosis / Early / 0.1-2.2
    bone fractures / Delayed / 1.3-1.3
    suicidal ideation / Delayed / 0.7-0.7
    seizures / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    angioedema / Rapid / Incidence not known
    hepatic decompensation / Delayed / Incidence not known
    hepatitis B exacerbation / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    lactic acidosis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    Fanconi syndrome / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    diabetes insipidus / Delayed / Incidence not known

    Moderate

    hypercholesterolemia / Delayed / 22.0-22.0
    depression / Delayed / 2.4-9.0
    impaired cognition / Early / 8.3-8.3
    hyperamylasemia / Delayed / 8.0-8.0
    hypertriglyceridemia / Delayed / 4.0-4.0
    neutropenia / Delayed / 3.0-3.0
    hematuria / Delayed / 3.0-3.0
    hyperglycemia / Delayed / 1.0-3.0
    hypoglycemia / Early / 0-3.0
    elevated hepatic enzymes / Delayed / 2.0-3.0
    hallucinations / Early / 1.2-1.2
    skin ulcer / Delayed / 0.8-1.1
    psychosis / Early / 0.4-0.4
    mania / Early / 0.2-0.2
    bullous rash / Early / 5.0
    glycosuria / Early / 1.0
    hyperbilirubinemia / Delayed / 3.0
    peripheral neuropathy / Delayed / 5.0
    neuritis / Delayed / 5.0
    confusion / Early / Incidence not known
    ataxia / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    amnesia / Delayed / Incidence not known
    euphoria / Early / Incidence not known
    erythema / Early / Incidence not known
    lipodystrophy / Delayed / Incidence not known
    hepatomegaly / Delayed / Incidence not known
    steatosis / Delayed / Incidence not known
    osteopenia / Delayed / Incidence not known
    osteoporosis / Delayed / Incidence not known
    osteomalacia / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    myasthenia / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    myopathy / Delayed / Incidence not known
    hypophosphatemia / Delayed / Incidence not known
    bone pain / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    dyspnea / Early / Incidence not known
    palpitations / Early / Incidence not known
    QT prolongation / Rapid / Incidence not known

    Mild

    rash / Early / 26.0-32.0
    dizziness / Early / 8.0-28.1
    insomnia / Early / 5.0-16.3
    pruritus / Rapid / 8.8-10.7
    diarrhea / Early / 9.0-9.0
    nausea / Early / 9.0-9.0
    fatigue / Early / 9.0-9.0
    sinusitis / Delayed / 8.0-8.0
    infection / Delayed / 5.0-8.0
    drowsiness / Early / 7.0-7.0
    nightmares / Early / 6.2-6.2
    headache / Early / 6.0-6.0
    pharyngitis / Delayed / 5.0-5.0
    anxiety / Delayed / 5.0-5.0
    vomiting / Early / 2.0-2.0
    vesicular rash / Delayed / 0.8-1.1
    paranoia / Early / 0.4-0.4
    paresthesias / Delayed / 5.0
    maculopapular rash / Early / 5.0
    anorexia / Delayed / 2.0
    abdominal pain / Early / 5.0
    dyspepsia / Early / 5.0
    rhinitis / Early / 5.0
    arthralgia / Delayed / 5.0
    cough / Delayed / 5.0
    back pain / Delayed / 5.0
    myalgia / Early / 5.0
    fever / Early / 5.0
    tinnitus / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    agitation / Early / Incidence not known
    tremor / Early / Incidence not known
    vertigo / Early / Incidence not known
    emotional lability / Early / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    skin discoloration / Delayed / Incidence not known
    flushing / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known
    gynecomastia / Delayed / Incidence not known
    breast enlargement / Delayed / Incidence not known
    Cushingoid features / Delayed / Incidence not known
    asthenia / Delayed / Incidence not known
    weakness / Early / Incidence not known
    polyuria / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and 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.
    Abacavir; Lamivudine, 3TC: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
    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. (Moderate) Coadministration of tenofovir disoproxil fumarate with abrocitinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and abrocitinib is a P-gp inhibitor.
    Acalabrutinib: (Moderate) Coadministration of acalabrutinib and tenofovir disoproxil fumerate may increase may increase the absorption and plasma concentration of tenofovir disoproxil fumerate. Monitor patients for tenofovir-related adverse reactions and discontinue use in patients who experience an adverse reaction. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Tenofovir disoproxil fumerate is a BCRP substrate.
    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: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus. (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; Magnesium Salicylate; Phenyltoloxamine: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus. (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; Phenyltoloxamine; Salicylamide: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus. (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; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (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; Propoxyphene: (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.
    Acyclovir: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as acyclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and acyclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as acyclovir. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration with drugs that decrease renal function may increase concentrations of tenofovir. In addition, use with drugs that are also eliminated by active tubular secretion may increase concentrations of the co-administered drug. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate; a majority of the cases occurred in patients who had underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir containing products should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Adefovir: (Major) Avoid coadministration of tenofovir disoproxil fumarate with adefovir. Both tenofovir and adefovir are primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration may increase concentrations of both drugs resulting in additive nephrotoxicity. Additionally, in the treatment of chronic hepatitis B, tenofovir should not be administered in combination with adefovir to avoid multi-drug resistance. If coadministration is necessary, patients should be carefully monitored for changes in serum creatinine and phosphorus, and urine glucose and protein. (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). (Moderate) Patients who are concurrently taking adefovir with emtricitabine 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.
    Alogliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    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.
    Amikacin: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as aminoglycosides. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and aminoglycosides are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Aminoglycosides: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as aminoglycosides. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and aminoglycosides are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Aminosalicylate sodium, Aminosalicylic acid: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
    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. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as amiodarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    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) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (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. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (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. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Minor) Efavirenz inhibits and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C19.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Minor) Additive nephrotoxicity can also occur if amphotericin B is given concomitantly with tenofovir. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Amphotericin B lipid complex (ABLC): (Minor) Additive nephrotoxicity can also occur if amphotericin B is given concomitantly with tenofovir. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Amphotericin B liposomal (LAmB): (Minor) Additive nephrotoxicity can also occur if amphotericin B is given concomitantly with tenofovir. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Amphotericin B: (Minor) Additive nephrotoxicity can also occur if amphotericin B is given concomitantly with tenofovir. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Amprenavir: (Minor) When amprenavir was coadministered with efavirenz, the systemic exposure AUC and Cmax of amprenavir were decreased by 36% and 43%, respectively. However, the clinical significance of this interaction has not been established.
    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: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus. (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; Caffeine: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus. (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.
    Aspirin, ASA; Caffeine; Orphenadrine: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
    Aspirin, ASA; Carisoprodol: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus. (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: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus. (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; Citric Acid; Sodium Bicarbonate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
    Aspirin, ASA; Dipyridamole: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
    Aspirin, ASA; Omeprazole: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus. (Minor) Efavirenz inhibits and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C19.
    Aspirin, ASA; Oxycodone: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus. (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.
    Aspirin, ASA; Pravastatin: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
    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. (Moderate) Tenofovir decreases atazanavir AUC and Cmin. If atazanavir and tenofovir, PMPA are to be coadministered, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir 300 mg once per day with food in patients >= 40 kg; atazanavir should not be coadministered with tenofovir without ritonavir. Data are insufficient to recommend atazanavir dosing in children < 40 kg who are also receiving concomitant tenofovir. In three post-marketing clinical trials, atazanavir AUC and Cmin were decreased by approximately 25% and 23 to 40%, respectively, when atazanavir was coadministered with tenofovir, PMPA as compared to atazanavir alone. Coadministration of atazanavir and tenofovir without ritonavir could lead to loss or lack of virologic response and possible resistance to atazanavir. In addition, atazanavir appears to increase tenofovir plasma concentrations, which could lead to adverse effects associated with tenofovir, including renal disorders. Increased tenofovir concentrations have been noted in the following combination regimens: tenofovir with ritonavir 'boosted' atazanavir; tenofovir, atazanavir, and lopinavir; ritonavir. Patients who receive tenofovir with atazanavir and any form/dose of ritonavir should be monitored for tenofovir-associated adverse events, with tenofovir being discontinued in patients who develop such adverse events. Although there are varying results in reports of an interaction between tenofovir and lopinavir; ritonavir, the clinical significance of an interaction is suspected to be insignificant. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food.
    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 daruanavir and atazanavir are CYP3A4 substrates. (Moderate) Tenofovir decreases atazanavir AUC and Cmin. If atazanavir and tenofovir, PMPA are to be coadministered, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir 300 mg once per day with food in patients >= 40 kg; atazanavir should not be coadministered with tenofovir without ritonavir. Data are insufficient to recommend atazanavir dosing in children < 40 kg who are also receiving concomitant tenofovir. In three post-marketing clinical trials, atazanavir AUC and Cmin were decreased by approximately 25% and 23 to 40%, respectively, when atazanavir was coadministered with tenofovir, PMPA as compared to atazanavir alone. Coadministration of atazanavir and tenofovir without ritonavir could lead to loss or lack of virologic response and possible resistance to atazanavir. In addition, atazanavir appears to increase tenofovir plasma concentrations, which could lead to adverse effects associated with tenofovir, including renal disorders. Increased tenofovir concentrations have been noted in the following combination regimens: tenofovir with ritonavir 'boosted' atazanavir; tenofovir, atazanavir, and lopinavir; ritonavir. Patients who receive tenofovir with atazanavir and any form/dose of ritonavir should be monitored for tenofovir-associated adverse events, with tenofovir being discontinued in patients who develop such adverse events. Although there are varying results in reports of an interaction between tenofovir and lopinavir; ritonavir, the clinical significance of an interaction is suspected to be insignificant. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food.
    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.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
    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.
    Bacitracin: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as bacitracin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    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.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
    Bepridil: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as bepridil. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Berotralstat: (Moderate) Coadministration of tenofovir disoproxil fumarate with berotralstat may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and berotralstat is a P-gp inhibitor.
    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: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus. (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.
    Boceprevir: (Moderate) Avoid concurrent administration of efavirenz and boceprevir, as use of these drugs together may result in hepatitis C treatment failures and efavirenz-related adverse events. When administered in combination, the mean plasma concentration (AUC) of boceprevir was deceased by 19%, and the mean AUC of efavirenz was increased by 20%. Predictions about the interaction can be made based on the metabolic pathways of efavirenz and boceprevir. Efavirenz is an inducer and substrate of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor and substrate of this isoenzyme. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as boceprevir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    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%. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with brigatinib is necessary. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
    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.
    Brompheniramine; 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.
    Brompheniramine; 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.
    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) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (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. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    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).
    Cabozantinib: (Minor) Monitor for an increase in both cabozantinib- and tenofovir-related adverse reactions if coadministration is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and tenofovir is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib. Cabozantinib is also P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates such as tenofovir. The clinical relevance of either of these interactions is unknown.
    Canagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Cannabidiol: (Moderate) Coadministration of tenofovir disoproxil fumarate with cannabidiol may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and cannabidiol is a P-gp inhibitor. (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%. (Moderate) Coadministration of tenofovir disoproxil fumarate with capmatinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) and BCRP substrate and capmatinib is a P-gp and BCRP inhibitor.
    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.
    Carbinoxamine; Hydrocodone; Phenylephrine: (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.
    Carbinoxamine; 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.
    Carboplatin: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as carboplatin. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    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.
    Carvedilol: (Moderate) Increased concentrations of tenofovir may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and tenofovir is a P-gp substrate.
    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: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (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) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (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; Dihydrocodeine; Pseudoephedrine: (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; 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.
    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.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (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.
    Chlorpheniramine; 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.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    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.
    Choline Salicylate; Magnesium Salicylate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
    Cidofovir: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as cidofovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and cidofovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Since tenofovir, PMPA is primarily eliminated by the kidneys, concurrent administration of tenofovir disoproxil with cidofovir may increase serum concentrations of tenofovir via competition for renal tubular secretion.
    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.
    Cisplatin: (Major) Avoid tenofovir administration with concurrent or recent treatment with cisplatin. Cisplatin can cause nephrotoxicity. Tenofovir is primarily eliminated by the kidneys; drugs that decrease renal function may increase concentrations of tenofovir. Also, cases of acute renal failure after initiation of other nephrotoxic drugs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir treatment; some patients required hospitalization and renal replacement therapy.
    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. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as clarithromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Clindamycin: (Moderate) Concomitant use of tenofovir and clindamycin may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
    Clofarabine: (Major) Avoid the concomitant use of clofarabine and tenofovir; coadministration may result in additive nephrotoxicity. Additionally, taking these drugs together may alter clofarabine concentrations; clofarabine and tenofovir are both substrates of OAT1 and OAT3.
    Clofazimine: (Major) Avoid coadministration of efavirenz and clofazimine 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. QT prolongation and TdP have been reported in patients receiving clofazimine in combination with QT prolonging medications.
    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 daruanavir 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.
    Colchicine: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as colchicine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Colistimethate, Colistin, Polymyxin E: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as colistimethate sodium. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Colistin: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as colistimethate sodium. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus, and urine glucose and protein.
    Conivaptan: (Moderate) Use caution when administering conivaptan and tenofovir concurrently. Conivaptan is an inhibitor of P-glycoprotein (P-gp). Co-administration of conivaptan with P-gp substrates, such as tenofovir, PMPA, can increase tenofovir exposure leading to increased or prolonged therapeutic effects and adverse events.
    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: (Major) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, such as cyclosporine, should be carefully monitored for changes in serum creatinine and phosphorus. (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.
    Dapagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    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).
    Darifenacin: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as darifenacin.
    Darolutamide: (Moderate) Caution is advised with the coadministration of darolutamide and tenofovir disoproxil fumarate due to the potential for increased plasma concentrations of tenofovir disoproxil fumarate increasing the risk of adverse effects. Tenofovir disoproxil fumarate is a substrate of breast cancer resistance protein (BCRP) and darolutamide is a BCRP inhibitor.
    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. (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
    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 daruanavir 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. (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
    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 daruanavir 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. (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
    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 with efavirenz is contraindicated. The use of this drug combination was pooly tolerated by recipients and resulted in hepatic enzyme elevations. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as ritonavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Moderate) Concurrent administration of tenofovir, PMPA with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated tenofovir plasma concentrations. Tenofovir is a substrate for the breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). Dasabuvir, paritaprevir, and ritonavir are BCRP inhibitors, and ritonavir inhibits P-gp. Caution and close monitoring are advised if these drugs are administered together. (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; 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. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as quinidine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    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.
    Dichlorphenamide: (Major) Use of dichlorphenamide and tenofovir disoproxil fumarate is not recommended because of increased tenofovir exposure and a risk of tenofovir-related adverse effects. Monitor closely for signs of drug toxicity if coadministration cannot be avoided. For example, it is important to monitor renal and hepatic function for all patients during treatment with tenofovir, as the drug may cause hepatotoxicity or nephrotoxicity. Increased tenofovir exposure is possible. Tenofovir is a sensitive OAT1 substrate. Dichlorphenamide inhibits OAT1.
    Diclofenac: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (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. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    Diclofenac; Misoprostol: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (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. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    Didanosine, ddI: (Major) HIV guidelines recommend against concurrent use of tenofovir, PMPA and didanosine; however, these medications can be used together, if necessary, in patients with a creatinine clearance 60 mL/min or more if the didanosine dose is reduced; decrease the didanosine dose to 250 mg in patients weighing 60 kg or more and to 200 mg in patients weighing 25 to 59 kg. Concurrent administration of tenofovir, PMPA and didanosine, ddI increases the concentration of both didanosine and its active metabolite (dideoxyadenosine 5-triphosphate) which may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. In addition, this combination has been associated with CD4 cell count decline despite viral suppression, high rates of early virologic failure, and rapid selection of resistance mutations. The mechanism of the interaction is not known, but the interaction occurs with both buffered and non-buffered didanosine formulations. When coadministered, tenofovir and didanosine EC may be taken under fasted conditions or with a light meal (under 400 kcal, containing 20% or less fat); coadministration of didanosine buffered tablet formulation with tenofovir should be under fasted conditions. Coadministration of tenofovir and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine therapy should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop.
    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.
    Diflunisal: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (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.
    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.
    Diphenhydramine; Hydrocodone; Phenylephrine: (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.
    Diphenhydramine; Ibuprofen: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    Diphenhydramine; Naproxen: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    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. (Major) Dofetilide should be co-administered with tenofovir, PMPA with caution since both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia. Careful patient monitoring and dose adjustment of dofetilide is recommended. (Moderate) Use caution when administering dofetilide concurrently with emtricitabine as both drugs are actively secreted via cationic secretion and could compete for common renal tubular transport systems. This results in a possible increase in plasma concentrations of either drug. Increased concentrations of dofetilide may increase the risk for side effects including proarrhythmia.
    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) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and 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. (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
    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. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as dronedarone. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    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%.
    Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy. (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, one study with etravirine did not show a significant effect of Echinacea on drug exposure. More study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
    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.
    Elexacaftor; tezacaftor; ivacaftor: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ivacaftor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Eliglustat: (Moderate) Coadministration of tenofovir, PMPA and eliglustat may result in increased concentrations of tenofovir. Monitor patients closely for tenofovir-related adverse effects including nausea, diarrhea, headache, asthenia, and nephrotoxicity. Tenofovir is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor. For coadministration with P-gp substrates, eliglustat's product labeling recommends monitoring therapeutic drug concentrations of the P-gp substrate, if possible, or consideration of a dosage reduction and titrating to clinical effect. (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 daruanavir 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 daruanavir 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) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (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; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    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.
    Enasidenib: (Moderate) Coadministration of tenofovir disoproxil fumarate with enasidenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
    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.
    Enflurane: (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.
    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.
    Ertugliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    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. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as erythromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Erythromycin; Sulfisoxazole: (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. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as erythromycin. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    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: (Moderate) 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.
    Ethiodized Oil: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as radiopaque contrast agents. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    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.
    Etodolac: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    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. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as etravirine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    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.
    Ezogabine: (Moderate) Consider alternatives to efavirenz when coadministering with Ezogabine. QTc prolongation has been observed with the use of efavirenz. Ezogabine has been associated with QT prolongation.
    Famotidine; Ibuprofen: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    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.
    Fenoprofen: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    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.
    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.
    Flurbiprofen: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    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: (Moderate) The pharmacokinetic parameters of anti-retroviral medications (anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs), anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs), anti-retroviral nucleotide reverse transcriptase inhibitors, and anti-retroviral protease inhibitors) metabolized through the CYP isoenzyme system are slightly altered by smoked and oral marijuana. Despite this interaction, marijuana is not expected to adversely affect anti-retroviral efficacy. However, the incidence of marijuana associated adverse effects may change following coadministration with anti-retroviral drugs. Many anti-retrovirals are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with anti-retrovirals, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile. (Moderate) The pharmacokinetic parameters of anti-retroviral medications (anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs), anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs), anti-retroviral nucleotide reverse transcriptase inhibitors, and anti-retroviral protease inhibitors) metabolized through the CYP isoenzyme system are slightly altered by smoked and oral marijuana. Despite this interaction, marijuana is not expected to adversely affect anti-retroviral efficacy. However, the incidence of marijuana associated adverse effects may change following coadministration with anti-retroviral drugs. Many anti-retrovirals are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with anti-retrovirals, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile. (Moderate) The pharmacokinetic parameters of anti-retroviral medications (anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs), anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs), anti-retroviral nucleotide reverse transcriptase inhibitors, and anti-retroviral protease inhibitors) metabolized through the CYP isoenzyme system are slightly altered by smoked and oral marijuana. Despite this interaction, marijuana is not expected to adversely affect anti-retroviral efficacy.However, the incidence of marijuana associated adverse effects may change following coadministration with anti-retroviral drugs. Many anti-retrovirals are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with anti-retrovirals, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Fosamprenavir: (Major) Systemic concentrations of fosamprenavir are reduced when administered concurrently with efavirenz. Avoid administering these drugs concurrently, unless fosamprenavir is boosted with ritonavir. 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.
    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. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as foscarnet. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and foscarnet are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir is administered in combination with nephrotoxic agents, such as foscarnet. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir, and/or the co-administered drug. Drugs that decrease renal function may increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir; a majority of the cases occurred in patients who had underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir containing products should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    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%. (Moderate) Monitor for tenofovir toxicities that may require tenofovir disoproxil dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a BCRP or P-gp substrate may increase the concentration of the BCRP or P-gp substrate. Fostamatinib is a P-gp inhibitor, and the active metabolite of fostamatinib, R406, is a BCRP inhibitor; tenofovir disoproxil is a substrate for BCRP and P-gp. Coadministration of fostamatinib with another BCRP substrate increased the substrate AUC by 95% and Cmax by 88%. Coadministration of fostamatinib with another P-gp substrate increased the substrate AUC by 37% and Cmax by 70%.
    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.
    Ganciclovir: (Moderate) Concurrent use of nephrotoxic agents with ganciclovir should be done cautiously to avoid additive nephrotoxicity. Other nephrotoxic agents include tenofovir. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as ganciclovir. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and ganciclovir are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    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.
    Gentamicin: (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as aminoglycosides. Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and aminoglycosides are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (Moderate) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
    Gilteritinib: (Moderate) Coadministration of tenofovir disoproxil fumarate with gilteritinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. (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.
    Glipizide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    Glyburide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as emtricitabine, may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended. (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion, such as tenofovir, PMPA may decrease metformin elimination by competing for common renal tubular transport systems. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of metformin and/or the interfering cationic drug are recommended.
    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.
    Grapefruit juice: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as grapefruit juice. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    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.
    Halothane: (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.
    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) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (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. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    Hydrocodone; Phenylephrine: (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; Potassium Guaiacolsulfonate: (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; Potassium Guaiacolsulfonate; 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.
    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) Avoid coadministration of efavirenz and hydroxychloroquine due to the risk of increased 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. Hydroxychloroquine prolongs the QT interval. QTc prolongation has been observed with the use of efavirenz.
    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.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent; patients receiving concomitant nephrotoxic agents, like salicylates should be carefully monitored for changes in serum creatinine and phosphorus.
    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: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    Ibuprofen; Oxycodone: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs. (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.
    Ibuprofen; Pseudoephedrine: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    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.
    Indomethacin: (Moderate) Avoid administering tenofovir, PMPA concurrently with or recently after a nephrotoxic agent, such as high-dose or multiple nonsteroidal antiinflammatory drugs (NSAIDs). Cases of acute renal failure, some requiring hospitalization and renal replacement therapy, have been reported after high-dose or multiple NSAIDs were initiated in patients who appeared stable on tenofovir. Consider alternatives to NSAIDs in patients at risk for renal dysfunction. If these drugs must be coadministered, carefully monitor the estimated creatinine creatinine, serum phosphorus, urine glucose, and urine protein prior to, and periodically during, treatment. (Moderate) Monitor for changes in serum creatinine and adverse reactions, such as lactic acidosis or hepatotoxicity if emtricitabine is administered in combination with nephrotoxic agents, such as high-dose nonsteroidal antiinflammatory drugs (NSAIDs). Consider the potential for drug interaction prior to and during concurrent use of these medications. Both emtricitabine and NSAIDs are excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. While no drug interactions due to competition for renal excretion have been observed, coadministration of these medications may increase concentrations of both drugs.
    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: (Major) The concomitant use of ribavirin and anti-retroviral 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 emtricitabine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. (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 anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs 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. (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.
    Iodixanol: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as radiopaque contrast agents. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Iohexol: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as radiopaque contrast agents. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease renal function may also increase concentrations of tenofovir. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir with a majority of the cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents. Monitor patients receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus.
    Iopamidol: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as radiopaque contrast agents. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the co-administered drug. Drugs that decrease r