Efavirenz; lamivudine; tenofovir disoproxil fumarate is approved for the treatment of human immunodeficiency virus type 1 (HIV-1) in adult and pediatric patients weighing at least 35 kg (Symfi Lo) or 40 kg (Symfi). Symfi Lo contains a lower dose of efavirenz (400 mg) compared with Symfi (600 mg). Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI), lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI), and tenofovir disoproxil fumarate is an acyclic nucleoside analog (i.e., nucleotide reverse transcriptase inhibitor). This combination product allows for once daily dosing using a single tablet. Although lamivudine and tenofovir disoproxil fumarate both exhibit activity against the hepatitis B virus (HBV), this drug is not indicated to treat HBV. The FDA approved package labeling has a Black Box Warning stating that severe, acute exacerbations of hepatitis B have been reported in patients with HBV and HIV coinfection and have discontinued either lamivudine or tenofovir. If treatment for HIV with efavirenz; lamivudine; tenofovir disoproxil fumarate is discontinued in a patient with HBV coinfection, the patient should be closely monitored for several months for signs and symptoms of worsening hepatitis infection. Due to the similarities between emtricitabine and lamivudine, lamivudine containing products are not likely to be effective in individuals who display antimicrobial resistance to emtricitabine.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-To reduce the nervous system side effects, bedtime dosing is recommended.
-Women of childbearing potential should undergo pregnancy testing prior to drug initiation.
Route-Specific Administration
Oral Administration
-Administer on an empty stomach.
In a study comparing tenofovir disoproxil fumarate with stavudine (each given in combination with lamivudine and efavirenz) in treatment-naive patients, decreases in bone mineral density (BMD) from baseline were seen at the lumbar spine and hip regions in both treatment groups. At 144 weeks, percent decreases (mean +/- SD) in BMD from baseline at the lumbar spine were greater in patients receiving tenofovir (-2.2% +/- 3.9) compared with patients receiving stavudine (-1% +/- 4.6); percent decreases from baseline at the hip were similar in between both treatment groups (tenofovir, -2.8% +/- 3.5; stavudine -2.4% +/- 4.5). In both groups, the majority of the reduction in BMD occurred in the first 24 to 48 weeks of treatment and was sustained. There was a higher proportion of patients who met a protocol-defined value of BMD loss (5% decrease in spine or 7% decrease in hip) in the tenofovir group (28%) compared to the stavudine group (21%). In addition, there were significant increases in levels of biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide) in the tenofovir group compared to the stavudine group, suggesting increase bone turnover. Except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range. At week 144, clinically relevant bone fractures (excluding fingers and toes) were reported in 4 patients in the tenofovir group (1.3%) compared with 6 patients in the stavudine group (2%). In studies of pediatric patients with HIV, bone effects were similar to those noted in adult patients. Normally, BMD increases rapidly as children and adolescents age; however, in a study of patients ages 12 to 17 years, gains in BMD were found to be lower in tenofovir-treated patients than in patients receiving placebo. Additionally, 7 tenofovir-treated patients and 1 placebo-treated patient had significant (more than 4%) lumbar spine BMD loss in 48 weeks. Of note, skeletal growth height appeared to be unaffected by tenofovir treatment. Additionally, osteomalacia has been reported with postmarketing use of tenofovir. These results also increase the concern of developing osteopenia and osteoporosis. Assessment of BMD is recommended in patients with a history of bone fractures or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D has not been studied, such supplementation may be considered for HIV-associated osteopenia or osteoporosis. If bone abnormalities are suspected, appropriate consultation should be obtained.
Renal impairment and renal failure (unspecified), which may include hypophosphatemia, have been reported with the use of tenofovir disoproxil fumarate. The majority of the reported cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents. Postmarketing cases of interstitial nephritis (including acute cases), acute renal failure, renal failure, acute renal tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, and polyuria have all been reported in patients receiving tenofovir disoproxil fumarate. Adverse events that may occur due to proximal renal tubulopathy include rhabdomyolysis, osteomalacia, bone pain and fractures, hypokalemia, muscular weakness, myopathy, and hypophosphatemia; promptly evaluate renal function in patients experiencing these symptoms.
Infections reported in efavirenz; lamivudine; tenofovir disoproxil fumarate during clinical trials include upper respiratory tract infection (1% to 3%), naso-pharyngitis (2% to 3%), pneumonia (5%), gastroenteritis (2%), and herpes zoster (1% to 3%). Fever was noted in 1% to 8% of drug recipients, and neutropenia (neutrophils less than 750 cells/mm3) was observed in 2% to 3% of patients.
Severe acute hepatitis B exacerbation has been reported in patients coinfected with HIV and the hepatitis B virus (HBV) who have discontinued treatment with lamivudine or tenofovir disoproxil fumarate. If use of efavirenz; lamivudine; tenofovir disoproxil fumarate is stopped in a coinfected patient, closely monitor hepatic function with both clinical and laboratory follow-up for at least several months. If appropriate, treatment for hepatitis B infection may be warranted. Prior to initiating antiretroviral therapy for the treatment of HIV, it is recommended that all patients be tested for the presence of chronic HBV.
Elevated hepatic enzymes were observed in patients treated with efavirenz; lamivudine; tenofovir disoproxil fumarate during 2 clinical trials. In the first trial, Grade 3 to 4 increases in ALT and AST were identified in 4% and 5% of the 299 drug recipients, respectively. Among the 630 drug recipients in the second trial, 3% to 25% experienced Grade 3 to 4 increases in ALT and 2% had Grade 3 to 4 increase in AST. Postmarketing reports of hepatic failure requiring transplantation or resulting in death have been reported in patients treated with efavirenz-containing regimens. These reports included patients with and without pre-existing hepatic disease.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported during postmarketing use of nucleoside and nucleotide reverse transcriptase inhibitors, including lamivudine and tenofovir disoproxil fumarate. Many of these cases have occurred in women, obese patients, and patients with prolonged nucleoside exposure. If a patient develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity while receiving efavirenz; lamivudine; tenofovir disoproxil fumarate, treatment should be discontinued.
Psychiatric or central nervous system (CNS) related adverse events are likely due to the efavirenz component of efavirenz; lamivudine; tenofovir disoproxil fumarate. The most commonly reported psychiatric related adverse events in controlled trials involving antiretroviral-naive patients who received efavirenz; lamivudine; tenofovir disoproxil fumarate included abnormal dreams (2% to 11.3%), insomnia (3% to 6.5%), somnolence or drowsiness (3.1% to 3.9%), depression (3.1% to 11%), nightmares (1.9% to 2.6%), sleep disorder (1.3% to 2.2%), and anxiety (1.2% to 6%). Psychiatric related adverse events have been reported at a slightly higher frequency in patients receiving efavirenz 600 mg regimens compared with 400 mg regimens. Other serious psychiatric adverse reactions reported during efavirenz controlled trials (including 1,008 efavirenz-treated patients) included severe depression (2.4%), suicidal ideation (0.7%), nonfatal suicide attempts (0.5%), aggressive behavior (0.4%), paranoid reactions (i.e., paranoia or psychosis) (0.4%), manic reactions (i.e., mania) (0.2%), insomnia (16.3%), abnormal dreams (6.2%), drowsiness (7%), and impaired concentration (8.3%). There have also been postmarketing reports of death by suicide, delusions, catatonia, agitation, emotional lability, neurosis, and psychosis-like behavior. Patients who experience serious psychiatric events should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits.
Nervous system related reactions are likely due to the efavirenz component of efavirenz; lamivudine; tenofovir disoproxil fumarate. Symptoms usually begin on the first or second day of efavirenz therapy and resolve within 2 to 4 weeks; however, some patients may experience persistent CNS symptoms beyond 4 weeks. After 4 weeks of treatment, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9%. The most commonly reported nervous system related adverse events in controlled trials involving antiretroviral-naive patients who received efavirenz; lamivudine; tenofovir disoproxil fumarate included dizziness (3% to 35%), headache (1% to 14%), and peripheral neuropathy or peripheral neuritis (1%). Other adverse reactions reported during efavirenz controlled trials (including 1,008 efavirenz-treated patients) included dizziness (28.1%) and hallucinations (1.2%). Additional CNS side effects reported during postmarketing use of efavirenz-containing regimen include cerebellar coordination, abnormal coordination, ataxia, encephalopathy, convulsions or seizures, tremor, hypoesthesia, paresthesias, visual impairment (abnormal vision), tinnitus, and vertigo or balance disturbances. Dosing at bedtime may improve the tolerability of these reactions.
In efavirenz controlled trials, rash occurred in 26% of patients (n = 266 of 1,008) who received efavirenz in combination with other antiretroviral agents. Skin rash usually consists of mild-to-moderate maculopapular rash that occur with the first 2 weeks of initiating therapy. In most cases, the rash resolves with continuing efavirenz therapy within 1 month. However in 0.9% of patients (n = 9 of 1,008), the rash was associated with blistering, moist desquamation, and skin ulcer. Further, Grade 4 rashes (e.g., erythema multiforme, Stevens-Johnson syndrome) have been noted in 0.1% of efavirenz recipients (includes patients from all studies and expanded access). Treatment should be discontinued in patients with blistering, desquamation, mucosal involvement, or pyrexia. A discontinuation rate for rash was 1.7% (n = 17 of 1,008) in efavirenz clinical trials. In controlled trials involving antiretroviral-naive patients who received efavirenz; lamivudine; tenofovir disoproxil fumarate, dermatologic adverse events were observed in 9% to 32% of drug recipients. These dermatologic adverse events included maculopapular rash, erythematous rash, pruritic rash, macular rash, papular rash, morbilliform rash, vesicular rash, vesiculobullous rash, pustular rash, generalized rash, allergic dermatitis, eosinophilic pustular folliculitis, pruritus, and urticaria. During postmarketing experience, case of photosensitivity (photoallergic dermatitis) and alopecia have been noted with use of efavirenz and lamivudine, respectively.
According to the manufacturer, efavirenz may cause teratogenesis when administered to a pregnant woman. There are retrospective case reports of neural tube defects in infants whose mothers were exposed to efavirenz-containing regimens in the first trimester of pregnancy; however, a causal relationship has not been established. Based on this data, the manufacturer recommends use of effective contraception during treatment and for 12 weeks after treatment discontinuation. However, HIV treatment guidelines do not restrict use of efavirenz-containing regimens at anytime during pregnancy. In addition, it is recommended 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 1st trimester compared with those on other antiretroviral medications (relative risk 0.78; 95% CI, 0.56 to 1.08).
QT prolongation has been observed in patients receiving efavirenz. In a pharmacodynamic study, 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. Other cardiovascular adverse event reported during postmarketing use of efavirenz include palpitations and flushing.
Hypercholesterolemia and hypertriglyceridemia were observed in patients treated with efavirenz; lamivudine; tenofovir disoproxil fumarate during 2 clinical trials. In the first trial, 2% to 5% of the 630 drug recipients experienced Grade 3 to 4 increases in cholesterol concentration. Among the 299 drug recipients in the second trial, 19% had fasting cholesterol higher than 240 mg/dL and 1% has fasting triglycerides higher than 750 mg/dL.
Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral-experienced pediatric patients receiving lamivudine alone and in combination with other antiretroviral agents. Cases of pancreatitis have also been observed during postmarketing use of tenofovir disoproxil fumarate. During efavirenz; lamivudine; tenofovir disoproxil fumarate clinical trials, serum amylase concentrations greater than 175 units/L were observed in 9% of drug recipients.
While more commonly associated with protease inhibitor therapy, a lipodystrophy syndrome consisting of redistribution or accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, accumulation of facial fat, lipomas, breast enlargement, gynecomastia, and other cushingoid features has been reported in patients receiving long-term highly active antiretroviral therapy (HAART). The mechanism by which nucleoside analogues may cause body fat changes is not known. It has been suggested that nucleoside analogs may damage the mitochondria of adipocytes. An increased incidence of body fat changes is noted in those patients receiving long-term nucleoside therapy and in female patients. Lipodystrophy was observed in 1% of patients treated with efavirenz; lamivudine; tenofovir disoproxil fumarate during clinical trials.
Gastrointestinal adverse events reported by patients receiving efavirenz; lamivudine; tenofovir disoproxil fumarate during clinical trials include abdominal pain (7%), diarrhea (2% to 11%), dyspepsia (4%), nausea (8%), and vomiting (1% to 5%). In addition, reports of constipation and malabsorption have been noted during postmarketing use of efavirenz.
Musculoskeletal adverse events reported by patients receiving efavirenz; lamivudine; tenofovir disoproxil fumarate during clinical trials include arthralgia (5%), back pain (9%), generalized pain (13%), and myalgia (3%). In addition, 12% of drug recipients experienced increases in creatine kinase (Males: greater than 990 units/L; Females: greater than 845 units/L). During postmarketing use of efavirenz, cases of myopathy have been reported. Cases of rhabdomyolysis and muscle weakness have been noted during postmarketing use of lamivudine. Use of tenofovir disoproxil fumarate during the postmarketing period has been associated with rhabdomyolysis, muscle weakness, and myopathy.
Asthenia was reported by 6% of patients treated with efavirenz; lamivudine; tenofovir disoproxil fumarate during clinical trials.
Hematuria (more than 100 RBC/HPF) was observed in 7% of patients treated with efavirenz; lamivudine; tenofovir disoproxil fumarate during clinical trials. Other Grade 3 to 4 laboratory abnormalities observed in drug recipients during clinical trials were changes in total bilirubin (0.3% to 3%) and phosphorous (2% to 3%) concentrations. Cases of hypokalemia and hypophosphatemia have been noted during postmarketing use of tenofovir disoproxil fumarate.
Allergic reactions, including angioedema and anaphylactoid reactions, have been noted during the postmarketing use of efavirenz, lamivudine, and tenofovir disoproxil fumarate.
Dyspnea has been noted during the postmarketing use of efavirenz and tenofovir disoproxil fumarate.
Hyperglycemia and case of anemia (including pure red cell aplasia and severe anemias progressing on therapy) have been noted during the postmarketing use of lamivudine.
During baseline evaluation of people with HIV, discuss risk reduction measures and the need for status disclosure to sexual or needle-sharing partners, especially with untreated patients who are still at high risk of HIV transmission. Include the importance of adherence to therapy to achieve and maintain a plasma HIV RNA less than 200 copies/mL. Maintaining a plasma HIV RNA less than 200 copies/mL, including any measurable value below this threshold, with antiretroviral therapy prevents sexual transmission of HIV to their partners. Patients may recognize this concept as Undetectable = Untransmittable or U=U. Instruct patients to achieve sustained viral suppression (i.e., 2 recorded measurements of plasma viral loads that are below the limits of detection and taken at least 3 months apart) before attempting to conceive a child in order to maximize their health, prevent HIV sexual transmission, and minimize the risk of HIV transmission to the infant once conception occurs. For partners with different HIV status when the person with HIV is on antiretroviral therapy and has achieved sustained viral suppression, sexual intercourse without a condom allows conception without sexual HIV transmission to the person without HIV. Expert consultation is recommended.
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. Healthcare 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.
Antiretroviral therapy should be provided to all patients 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. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. 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. However, HIV treatment guidelines do not restrict the use of efavirenz-containing regimens in pregnant patients or in those who are trying to conceive. In addition, guidelines recommend that patients 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 mothers 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 (1,193 exposures), lamivudine (5,613 exposures), and tenofovir disoproxil fumarate (4,840 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 3.4) for efavirenz, 3.1% (95% CI: 2.6 to 3.6) for lamivudine, and 2.6% (95% CI: 2.2 to 3.1) 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 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 patients 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. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than or equal to 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 patients on HAART less than 2 years and have CD4 counts less than 300 cells/mm3, patients with inconsistent adherence, or patients with detectable viral loads. For patients on HAART less than 2 years but have CD4 counts greater than or equal to 300 cells/mm3, monitor CD4 counts every 6 months. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of planned delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. 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 patients 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 patients 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 patients 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 patient 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; lamivudine; tenofovir disoproxil fumarate; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.
HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission. Advise patients who receive a diagnosis of HIV infection while breast-feeding (acute HIV) to immediately discontinue breast-feeding and switch to replacement feeding in order to reduce the risk of postnatal HIV transmission to the infant. Replacement feeding is also recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants 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, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). All 3 drug components have been shown to pass into human breast milk. One study found efavirenz plasma concentrations in breast-fed infants (taken 3 to 4 hours after the last dose) to be 13.1% of maternal plasma concentrations; the mean infant plasma concentrations were below those considered effective for HIV treatment in adults. Lamivudine was found to be secreted in human breast milk during a study involving 20 breast-feeding women with HIV who were administered either 300 mg of lamivudine twice daily as a single agent (n = 10) or lamivudine 150 mg twice daily in combination with zidovudine (n = 10). The mean breast milk concentrations of lamivudine in the respective groups were similar at 1.22 mg/L (range less than 0.5 to 6.09 mg/L) and 0.9 mg/L (range less than 0.5 to 8.2 mg/L). In another study, tenofovir exposure in exclusively breast-fed infants was found 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.
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; lamivudine; tenofovir disoproxil fumarate therapy. 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; lamivudine; tenofovir disoproxil fumarate therapy 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 appears to be a significant risk of pancreatitis in pediatric patients treated with lamivudine-containing regimens. Administer efavirenz; lamivudine; tenofovir disoproxil fumarate with caution to children with a history of prior antiretroviral nucleoside exposure, pancreatitis, or other significant risk factors for pancreatitis. Stop treatment immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur.
Prior to and during treatment with efavirenz; lamivudine; tenofovir disoproxil fumarate monitor all patients for elevated hepatic enzymes. In patients found to have moderate to severe hepatic disease (i.e., Child-Pugh B and C), use of the drug is not recommended. The drug may be administered to patients with mild hepatic impairment (i.e., Child-Pugh A); however, close monitoring for changes in hepatic function and for adverse events is advised. Postmarketing use of efavirenz-containing regimens has been associated with cases of hepatic failure that required transplantation or resulted in death. These reported included patients with underlying hepatic disease, including coinfection with hepatitis B or C, and patients without pre-existing hepatic disease or other identifiable risk factors. If a drug recipient develops persistently elevated serum transaminases more than 5-times the upper limit of normal, consider the benefit of continued therapy against the unknown risks of significant liver toxicity. If the elevated serum transaminases are accompanied by clinical signs or symptoms of hepatitis or hepatic decompensation, use of the drug must be stopped. Efavirenz; lamivudine; tenofovir disoproxil fumarate is not indicated for the treatment of chronic hepatitis B virus (HBV) infection; however, both the lamivudine and tenofovir components are active against the hepatitis B virus. Perform hepatitis B virus (HBV) screening in any patient who presents with HIV infection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. Patients with coexisting HBV and HIV infections who discontinue lamivudine 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. 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.
HIV treatment guidelines recommend all patients presenting with HIV infection undergo routine screening for hepatitis C virus (HCV). For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experience with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. If efavirenz; lamivudine; tenofovir disoproxil fumarate is to be used in combination with interferon alfa with or without ribavirin, closely monitor the patient for treatment-associated toxicities (especially hepatic decompensation). In vitro studies have shown antiretroviral use with ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogs, such as lamivudine. Although no evidence of pharmacokinetic or pharmacodynamic interactions were observed, some patients who received these drugs concurrently experienced fatal hepatic decompensation. If adverse events are identified, consider treatment discontinuation or ribavirin and interferon alfa dose reductions as medically appropriate. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid consuming alcohol, limit ingestion of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.
Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported following use of lamivudine and tenofovir disoproxil fumarate (DF), both alone and in combination with other antiretroviral medications. Treatment with efavirenz; lamivudine; 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.
Tenofovir disoproxil fumarate is principally eliminated by the kidney; use of efavirenz; lamivudine; tenofovir should be avoided in patients with impaired renal function (i.e., creatinine clearance less than 50 mL/min) and in patients with end-stage renal disease requiring hemodialysis. Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been associated with tenofovir disoproxil fumarate 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, serum creatinine, serum phosphorous, urine glucose, and urine protein be assessed in all patients prior to treatment, and as clinically appropriate during treatment. 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.
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. Cases of osteomalacia associated with proximal renal tubulopathy have been reported in association with the use of tenofovir disoproxil fumarate. In a postmarketing 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. One study evaluating children with HIV aged 2 to 12 years found total body BMD gains in recipients of tenofovir to be lower than the gains observed in patients receiving either stavudine or zidovudine. Additionally, at treatment week 48, 1 tenofovir-treated patient experienced significant (more than 4%) BMD loss in the lumbar spine; significant BMD losses were not observed in the stavudine or zidovudine treatment groups. In another 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. In both studies, 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.
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. Efavirenz; lamivudine; tenofovir disoproxil fumarate can be restarted following interruptions due to rash; however, for those patients experiencing a life-threatening cutaneous reaction (Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions), readministration is contraindicated and an alternative treatment is recommended. Use of appropriate antihistamines or corticosteroids may be considered when the drug 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 an efavirenz-containing regimen in pediatric patients should be considered.
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 concentrations.
A majority of patients receiving efavirenz during clinical trials experienced CNS side effects, including dizziness, insomnia, impaired concentration, somnolence, abnormal dreams, and hallucinations. 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, 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. Promptly evaluate any patients who presents with signs or symptoms of a serious neurologic adverse reaction.
Serious psychiatric adverse events have been associated with efavirenz treatment. During clinical trials, adverse events reported by recipients of efavirenz-containing regimens included severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, paranoid reactions, catatonic reactions, and manic reactions. In addition, cases of death by suicide, delusions, psychosis-like behavior, and catatonia have been associated with postmarketing use of the drug. Patients who may be at increased risk include those with a history of mental illness (e.g., bipolar disorder, depression, mania, schizophrenia, or psychosis), alcoholism, or substance abuse. Instruct patients to seek immediate medical attention if signs of a psychiatric adverse event develop.
Fat redistribution and hyperlipidemia have been associated with use of combination antiretroviral therapy. More specifically, treatment with efavirenz-containing regimens has resulted in elevated concentrations of total cholesterol (hypercholesterolemia) and triglycerides (hypertriglyceridemia). Monitor cholesterol and triglyceride concentrations before and periodically during treatment with efavirenz; lamivudine; tenofovir disoproxil fumarate. If a patient develops hyperlipidemia during antiretroviral treatment, possible interventions include dietary modification, use of lipid lowering agents, or modification of the treatment regimen.
Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. The prevalence of transmitted drug resistance (TDR) in high-income countries ranges from 9% to 14% and varies by country. In most TDR surveys, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance and nucleoside reverse transcriptase inhibitor (NRTI) resistance are the most common mutation class types detected, followed by protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) resistance mutations, respectively. Resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. Lamivudine will not likely be effective in individuals who display antimicrobial resistance to emtricitabine, due to the similarities between the two drugs. Clinicians should not expect patients with the M184 mutation associated with emtricitabine to benefit from a lamivudine containing regimen. The M184 mutation confers high-level resistance, and lamivudine, like emtricitabine, selects for the M184 mutation. It is important that persons with detectable viral load who plan to switch therapy from emtricitabine to lamivudine have genotypic testing performed to determine whether the M184 mutation is present. A patient's treatment history is also extremely important; if emtricitabine has failed in the past, the 184 is archived, thus rendering lamivudine 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 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.
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-containing regimens 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.
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; lamivudine; 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 hepatits, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.
Patients with peripheral neuropathy can experience exacerbations during treatment with lamivudine-containing regimens.
Health care providers are advised of the potential for laboratory test interference during the use of efavirenz-containing regimens; specifically, interference with the urine cannabinoid test. False-positive urine cannabinoid test results have been reported with some screening assays in subjects who are receiving efavirenz. Confirmation of positive screening tests for cannabinoids by a more specific method is recommended.
HIV guidelines recommend consideration be given to avoiding use of efavirenz-containing regimens in patients with pre-existing psychiatric illnesses, HIV-associated dementia (HAD), prolongation of the QTc interval, or who are receiving methadone as narcotic replacement therapy.
NOTE: Data are insufficient to recommend use of efavirenz (400 mg formulation); lamivudine; tenofovir disoproxil fumarate (Symfi Lo) in patients receiving concurrent treatment with rifampin. HIV guidelines recommend use of efavirenz (600 mg formulation); lamivudine; tenofovir disoproxil fumarate (Symfi) in patients receiving concurrent treatment with rifampin.
NOTE: HIV guidelines recommend consideration be given to avoiding use of tenofovir disoproxil fumarate-containing regimens in patients with renal disease and osteoporosis.
Initiation of therapy for HIV treatment:
-For adults, initiation of treatment immediately (or as soon as possible) after HIV diagnosis is recommended in all patients to reduce the risk of disease progression and to prevent the transmission of HIV, including perinatal transmission and transmission to sexual partners. Starting antiretroviral therapy early is particularly important for patients with AIDS-defining conditions, those with acute or recent HIV infection, and individuals who are pregnant; delaying therapy in these subpopulations has been associated with high risks of morbidity, mortality, and HIV transmission.
-Prior to initiating treatment, obtain baseline plasma HIV RNA (viral load) and CD4 count; results do not need to be available before starting therapy.
-Antiretroviral drug-resistance testing:-Genotypic drug-resistance testing is recommended prior to initiation of therapy in all antiretroviral treatment-naive patients and prior to changing therapy for treatment failure.
--Standard genotypic drug-resistance testing in treatment-naive people should focus on testing for mutations in reverse transcriptase (RT) and protease (PR) genes.
-Testing for mutations in the integrase gene should also be performed if integrase strand transfer inhibitor (INSTI) resistance is a concern (e.g., people who acquire HIV after pre-exposure prophylaxis with long-acting cabotegravir).
-Phenotypic resistance testing may be used in conjunction with the genotypic test for patients with known or suspected complex drug-resistance mutation patterns.
-HIV-1 proviral DNA resistance testing is available for use in patients with HIV RNA concentrations below the limits of detection or with low-level viremia (i.e., less than 1,000 copies/mL), where genotypic testing is unlikely to be successful; however, the clinical utility of this assay has not been fully determined.
-It is not necessary to delay treatment until resistance test results are available; however, subsequent modifications to the treatment regimen should be made, if needed, once the test results are available.
-Pediatric guidelines are also available.
Place in therapy for HIV treatment:
-In certain clinical situations, efavirenz; lamivudine; tenofovir disoproxil fumarate is a preferred initial regimen for some non-pregnant adults and adolescents with HIV-1.
-Efavirenz; lamivudine; tenofovir disoproxil fumarate is an alternative HIV-1 treatment regimen for pregnant women who are unable to receive a preferred regimen. Due to the potential for central nervous system (CNS) related toxicities, screening for antenatal and postpartum depression is recommended.
-Pediatric guidelines are also available.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of human immunodeficiency virus (HIV) infection:
Oral dosage (Symfi Lo):
Adults weighing 35 kg or more: 1 tablet (efavirenz 400 mg; lamivudine 300 mg; tenofovir disoproxil fumarate 300 mg) PO on an empty stomach once daily at bedtime.
Children and Adolescents weighing 35 kg or more: 1 tablet (efavirenz 400 mg; lamivudine 300 mg; tenofovir disoproxil fumarate 300 mg) PO on an empty stomach once daily at bedtime.
Oral dosage (Symfi):
Adults weighing 40 kg or more: 1 tablet (efavirenz 600 mg; lamivudine 300 mg; tenofovir disoproxil fumarate 300 mg) PO on an empty stomach once daily at bedtime.
Children and Adolescents weighing 40 kg or more: 1 tablet (efavirenz 600 mg; lamivudine 300 mg; tenofovir disoproxil fumarate 300 mg) PO on an empty stomach once daily at bedtime.
Maximum Dosage Limits:
-Adults
Symfi Lo
weight 35 kg or more: efavirenz 400 mg/day PO; lamivudine 300 mg/day PO; tenofovir disoproxil fumarate 300 mg/day PO.
weight less than 35 kg: Use not recommended.
Symfi
weight 40 kg or more: efavirenz 600 mg/day PO; lamivudine 300 mg/day PO; tenofovir disoproxil fumarate 300 mg/day PO.
weight less than 40 kg: Use not recommended.
-Geriatric
Symfi Lo
weight 35 kg or more: efavirenz 400 mg/day PO; lamivudine 300 mg/day PO; tenofovir disoproxil fumarate 300 mg/day PO.
weight less than 35 kg: Use not recommended.
Symfi
weight 40 kg or more: efavirenz 600 mg/day PO; lamivudine 300 mg/day PO; tenofovir disoproxil fumarate 300 mg/day PO.
weight less than 40 kg: Use not recommended.
-Adolescents
Symfi Lo
weight 35 kg or more: efavirenz 400 mg/day PO; lamivudine 300 mg/day PO; tenofovir disoproxil fumarate 300 mg/day PO.
weight less than 35 kg: Use not recommended.
Symfi
weight 40 kg or more: efavirenz 600 mg/day PO; lamivudine 300 mg/day PO; tenofovir disoproxil fumarate 300 mg/day PO.
weight less than 40 kg: Use not recommended.
-Children
Symfi Lo
weight 35 kg or more: efavirenz 400 mg/day PO; lamivudine 300 mg/day PO; tenofovir disoproxil fumarate 300 mg/day PO.
weight less than 35 kg: Use not recommended.
Symfi
weight 40 kg or more: efavirenz 600 mg/day PO; lamivudine 300 mg/day PO; tenofovir disoproxil fumarate 300 mg/day PO.
weight less than 40 kg: Use not recommended.
-Infants
Use not recommended.
-Neonates
Use not recommended.
Patients with Hepatic Impairment Dosing
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 and C); data are insufficient to recommend use in these patients.
Patients with Renal Impairment Dosing
CrCl >= 50 mL/min: No dosage adjustment is needed.
CrCl < 50 mL/min: Not recommended.
Hemodialysis
Hemodialysis removes tenofovir from the blood, but is not expected to significantly remove efavirenz or lamivudine. Avoid use in patient with end-stage renal disease requiring hemodialysis.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Major) When possible, avoid concurrent use of dolutegravir with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and efavirenz is an inducer of CYP3A4.
Abemaciclib: (Major) Avoid coadministration of efavirenz with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Abemaciclib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Coadministration is predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 53%.
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; Aspirin: (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; Aspirin; Diphenhydramine: (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; Pyrilamine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Chlorpheniramine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Dextromethorphan: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Dextromethorphan; Doxylamine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; 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; 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. (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; 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; 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 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.
Adagrasib: (Major) Concomitant use of adagrasib and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Coadministration of tenofovir disoproxil fumarate with adagrasib 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 adagrasib is a P-gp inhibitor.
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 antiretrovirals (i.e., anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs)) 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). (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).
Aldesleukin, IL-2: (Major) Avoid concomitant use of tenofovir disoproxil and aldesleukin; coadministration may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required.
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.
Alogliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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) 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.
Amiloride: (Moderate) Drugs that are actively secreted via cationic tubular secretion, such as amiloride, should be co-administered with caution with lamivudine since they could increase lamivudine plasma concentrations, and therefore lamivudine associated adverse reactions, via potential competition for renal cationic secretion.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Drugs that are actively secreted via cationic tubular secretion, such as amiloride, should be co-administered with caution with lamivudine since they could increase lamivudine plasma concentrations, and therefore lamivudine associated adverse reactions, via potential competition for renal cationic secretion.
Aminoglycosides: (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) Concomitant use of amiodarone and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. (Moderate) Coadministration of tenofovir disoproxil fumarate with amiodarone 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 amiodarone is a P-gp inhibitor.
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. (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.
Amobarbital: (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.
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 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.
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.
Asciminib: (Moderate) Coadministration of tenofovir disoproxil fumarate with asciminib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and asciminib is a BCRP inhibitor.
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) 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. (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: (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.
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; 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.
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 darunavir 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) Avoid use of atogepant and efavirenz when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine 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) Concomitant use of atomoxetine 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.
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.
Atovaquone: (Major) Avoid concurrent administration of efavirenz and atovaquone; proguanil. Use of these drugs together results in a 75% decreased in atovaquone AUC and a 43% decrease in proguanil AUC. Consider use of an alternative malaria prophylaxis.
Atovaquone; Proguanil: (Major) Avoid concurrent administration of efavirenz and atovaquone; proguanil. Use of these drugs together results in a 75% decreased in atovaquone AUC and a 43% decrease in proguanil AUC. Consider use of an alternative malaria prophylaxis.
Avacopan: (Major) Avoid concomitant use of avacopan and efavirenz due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
Avanafil: (Moderate) Avanafil is a substrate of and primarily metabolized by CYP3A4. Efavirenz is an inducer of CYP3A4; coadministration may result in decreased avanafil concentrations. The concomitant use of avanafil and CYP inducers is not recommended.
Avapritinib: (Major) Avoid coadministration of avapritinib with efavirenz due to the risk of a decrease in the efficacy of avapritinib. Avapritinib is a CYP3A4 substrate and efavirenz is a strong CYP3A4 inducer. Coadministration with efavirenz is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Axitinib: (Major) Avoid coadministration of axitinib with efavirenz if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and efavirenz is a moderate CYP3A4 inducer.
Azithromycin: (Major) Avoid coadministration of azithromycin with efavirenz due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. QTc prolongation has been observed with the use of efavirenz.
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.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
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.
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. (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive.
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.
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.
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: (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. (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: (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. (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: (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. (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.
Butalbital; Aspirin; Caffeine; Codeine: (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. (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.
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. (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown.
Canagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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.
Capivasertib: (Major) Avoid coadministration of capivasertib with efavirenz due to decreased capivasertib exposure and risk of decreased efficacy. Capivasertib is a CYP3A substrate; efavirenz is a moderate CYP3A inducer. Coadministration is predicted to decrease the capivasertib overall exposure by 60%.
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.
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. (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) 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; 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; 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.
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) Tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic agent, such as cidofovir. If concurrent use is necessary, closely monitor for changes in renal function. Tenofovir is primarily excreted via the kidneys by a combination of glomerular filtration and active tubular secretion. Concurrent administration with a drug that reduces renal function or competes for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs; thus, increasing the risk of developing renal-related adverse events. Renal impairment, which may include acute renal failure and hypophosphatemia, has been reported with the use of tenofovir disoproxil fumarate.
Cilostazol: (Major) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as cilostazol.
Ciprofloxacin: (Moderate) Concomitant use of ciprofloxacin 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.
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: (Moderate) Concomitant use of clofazimine and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Clonazepam: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations, if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including (e.g., clonazepam). Monitor patients closely for excessive side effects.
Clorazepate: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations, if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including (e.g., clorazepate). Monitor patients closely for excessive side effects.
Clozapine: (Moderate) Consider alternatives to efavirenz when coadministering with clozapine as concurrent use may increase the risk of QT prolongation; decreased clozapine exposure may also occur. Monitor for loss of clozapine efficacy and consider increasing the clozapine dose if necessary. QTc prolongation has been observed with the use of efavirenz. Clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. In addition, efavirenz is an and inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
Cobicistat: (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with efavirenz due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro, and efavirenz is a moderate inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 73% when coadministered with a moderate CYP3A inducer.
Codeine: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with efavirenz can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If efavirenz is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Efavirenz is a moderate CYP3A4 inducer. (Moderate) Concomitant use of promethazine 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.
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) Concomitant use of promethazine 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.
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.
Danicopan: (Moderate) Coadministration of tenofovir disoproxil fumarate with danicopan 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 danicopan is a P-gp and BCRP inhibitor.
Dapagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Dapsone: (Moderate) Closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia if coadministration with efavirenz is necessary. Dapsone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis).
Daridorexant: (Major) Avoid concomitant use of daridorexant and efavirenz. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. During drug interaction studies, concomitant use of efavirenz decreased daridorexant overall exposure by over 50%. (Moderate) Coadministration of tenofovir disoproxil fumarate with daridorexant 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 daridorexant is a P-gp inhibitor.
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 darunavir and atazanavir are CYP3A4 substrates. (Moderate) Concurrent administration of darunavir with efavirenz results in decreased darunavir concentrations (13% reduction in AUC and 31% reduction in Cmin) and increased efavirenz concentration (21% increase in AUC and 17% increase in Cmin). No dosage adjustment recommendations are required for either medication. Use this combination with caution. (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) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine. (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates. (Moderate) Concurrent administration of darunavir with efavirenz results in decreased darunavir concentrations (13% reduction in AUC and 31% reduction in Cmin) and increased efavirenz concentration (21% increase in AUC and 17% increase in Cmin). No dosage adjustment recommendations are required for either medication. Use this combination with caution. (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.
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.
Dexamethasone: (Moderate) Monitor for a decrease in efavirenz efficacy during concurrent use of efavirenz and dexamethasone. If long term coadministration is required, consider using an alternative corticosteroid, such as prednisone or prednisolone. Concomitant use may decrease efavirenz exposure leading to potential loss of virologic control. Efavirenz is a CYP3A substrate and dexamethasone is a weak CYP3A inducer.
Dexmedetomidine: (Moderate) Concomitant use of dexmedetomidine 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.
Dextromethorphan; Bupropion: (Major) Concurrent use of efavirenz 600 mg/day and bupropion in healthy volunteers resulted in a reduction of the AUC and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged and the Cmax of hydroxybupropion was increased by 50%. Healthcare providers are advised to increase the dose of bupropion based on clinical response during concurrent use with efavirenz; however, the maximum recommended dose of bupropion should not be exceeded.
Dextromethorphan; Quinidine: (Major) Coadministration of efavirenz and quinidine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Quinidine administration is associated with QT prolongation and TdP. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as quinidine. (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.
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.
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.
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; 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.
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.
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 administered 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) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
Dolasetron: (Moderate) Consider alternatives to efavirenz when coadministering with dolasetron as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Dolutegravir: (Major) When possible, avoid concurrent use of dolutegravir with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and efavirenz is an inducer of CYP3A4.
Dolutegravir; Lamivudine: (Major) When possible, avoid concurrent use of dolutegravir with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and efavirenz is an inducer of CYP3A4.
Dolutegravir; Rilpivirine: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP). (Major) When possible, avoid concurrent use of dolutegravir with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and efavirenz is an inducer of CYP3A4.
Donepezil: (Moderate) Consider alternatives to efavirenz when coadministering with donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QTc prolongation has been observed with the use of efavirenz.
Donepezil; Memantine: (Moderate) Consider alternatives to efavirenz when coadministering with donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QTc prolongation has been observed with the use of efavirenz. (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
Doravirine: (Contraindicated) Concurrent treatment with efavirenz and doravirine is not recommended. Both medications are non-nucleoside reverse transcriptase inhibitors (NNRTIs), and using these drugs together would represent duplicate therapy. In addition, taking these drugs together results in decreased doravirine exposure. Doravirine is a CYP3A4 substrate; efavirenz is a CYP3A4 inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Contraindicated) Concurrent treatment with efavirenz and doravirine is not recommended. Both medications are non-nucleoside reverse transcriptase inhibitors (NNRTIs), and using these drugs together would represent duplicate therapy. In addition, taking these drugs together results in decreased doravirine exposure. Doravirine is a CYP3A4 substrate; efavirenz is a CYP3A4 inducer.
Doxercalciferol: (Moderate) Although these interactions have not been specifically studied, hepatic enzyme inducers such as efavirenz may affect the 25-hydroxylation of doxercalciferol and may necessitate dosage adjustments of doxercalciferol.
Doxorubicin Liposomal: (Major) Avoid coadministration of efavirenz with doxorubicin due to decreased doxorubicin plasma concentrations. Efavirenz is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
Doxorubicin: (Major) Avoid coadministration of efavirenz with doxorubicin due to decreased doxorubicin plasma concentrations. Efavirenz is a CYP3A4 inducer and doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with efavirenz is necessary, and monitor for changes in the efficacy or adverse effect profile of dronabinol (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate. Efavirenz is a moderate inhibitor of CYP2C9 in vitro, and a CYP3A4 inducer. Concomitant use may result in altered plasma concentrations of dronabinol.
Dronedarone: (Contraindicated) Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Efavirenz has also been associated with QT prolongation. Because of the potential for QT prolongation and TdP, use of efavirenz with dronedarone is contraindicated. (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.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Elacestrant: (Major) Avoid concurrent use of elacestrant and efavirenz due to the risk of decreased elacestrant exposure which may reduce its efficacy. Elacestrant is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Concomitant use reduced elacestrant overall exposure by 55% to 73%. (Moderate) Coadministration of tenofovir disoproxil fumarate with elacestrant may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is substrate of BCRP and P-gp; elacestrant is an inhibitor of BCRP and P-gp.
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; 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) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine. (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of elvitegravir with efavirenz or efavirenz; emtricitabine; tenofovir, as concurrent use is expected to decrease elvitegravir plasma concentrations. Efavirenz is a substrate and inducer of CYP3A4; elvitegravir is a CYP3A4 substrate. Use of these drugs together may result in loss of antiviral efficacy and potentially the development of viral resistance. (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine. (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates.
Empagliflozin; Linagliptin: (Moderate) Concomitant use of linagliptin with efavirenz may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; efavirenz is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
Empagliflozin; Linagliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems. (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. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Emtricitabine: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
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). (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
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). (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
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) Concomitant use of encorafenib and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease efavirenz exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to efavirenz and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. When efavirenz is coadministered with another strong CYP3A inducer, it is recommended to increase efavirenz from 600 mg to 800 mg (patients weighing 50 kg or more). Efavirenz is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. (Moderate) Coadministration of tenofovir disoproxil fumarate with encorafenib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and encorafenib is a BCRP inhibitor.
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, increase the dose of erdafitinib to 9 mg once daily. Erdafitinib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced erdafitinib overall exposure by 45%. (Moderate) Coadministration of tenofovir disoproxil fumarate with erdafitinib 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 erdafitinib is a P-gp inhibitor.
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. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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) Coadministration of tenofovir disoproxil fumarate with erythromycin 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 erythromycin is a P-gp inhibitor.
Escitalopram: (Moderate) Concomitant use of escitalopram 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.
Esomeprazole: (Minor) Although drug interaction studies have not been conducted, efavirenz may inhibit the metabolism of substrates for CYP2C9 or CYP2C19 such as esomeprazole. In vitro studies have shown that efavirenz inhibits CYP2C9 and CYP2C19 in the range of observed efavirenz plasma concentrations.
Estazolam: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including estazolam. Monitor patients closely for excessive side effects.
Estradiol: (Moderate) Estrogens are CYP3A4 substrates and efavirenz is a CYP3A4 inducer; concomitant use of efavirenz-containing products (including efavirenz; emtricitabine; tenofovir) may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., menopausal symptoms, breakthrough bleeding, reduced efficacy) if these drugs are used together.
Estradiol; Levonorgestrel: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations. (Moderate) Estrogens are CYP3A4 substrates and efavirenz is a CYP3A4 inducer; concomitant use of efavirenz-containing products (including efavirenz; emtricitabine; tenofovir) may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., menopausal symptoms, breakthrough bleeding, reduced efficacy) if these drugs are used together.
Estradiol; Norethindrone: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations. (Moderate) Estrogens are CYP3A4 substrates and efavirenz is a CYP3A4 inducer; concomitant use of efavirenz-containing products (including efavirenz; emtricitabine; tenofovir) may decrease the clinical efficacy of estrogens. Patients should be monitored for signs of decreased clinical effects of estrogens (e.g., menopausal symptoms, breakthrough bleeding, reduced efficacy) if these drugs are used together.
Estradiol; Norgestimate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Ethanol: (Major) Advise patients to avoid alcohol while taking efavirenz. It is possible that CNS symptoms such as dizziness, trouble sleeping, drowsiness, difficulty concentrating and/or abnormal dreams may be more severe if efavirenz is taken with alcohol.
Ethinyl Estradiol; 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. (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin, levonorgestrel, and etonogestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased by 80% and 83%, respectively. Etonogestrel AUC decreased by 63% to 82%. There have been postmarketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
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.
Ethotoin: (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.
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.
Etonogestrel: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin, levonorgestrel, and etonogestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased by 80% and 83%, respectively. Etonogestrel AUC decreased by 63% to 82%. There have been postmarketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
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. (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin, levonorgestrel, and etonogestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased by 80% and 83%, respectively. Etonogestrel AUC decreased by 63% to 82%. There have been postmarketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Etrasimod: (Moderate) Concomitant use of etrasimod 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. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
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.
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.
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.
Fexinidazole: (Major) Concomitant use of fexinidazole and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, monitor for decreased efavirenz efficacy if coadministration is necessary. Concurrent use may decrease the plasma concentrations of efavirenz leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Efavirenz is a CYP2B6 substrate and fexinidazole is a CYP2B6 inducer.
Finasteride; Tadalafil: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
Finerenone: (Major) Avoid concurrent use of finerenone and efavirenz due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Coadministration with efavirenz decreased overall exposure to finerenone by 80%.
Fingolimod: (Moderate) Consider alternatives to efavirenz when coadministering with fingolimod as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Fingolimod initiation results in decreased heart rate and may prolong the QT interval.
Flecainide: (Major) Coadministration of efavirenz and flecainide may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or TdP; flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs that have the potential for QT prolongation may have an increased risk of developing proarrhythmias.
Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and CYP3A4 inducers, such as efavirenz is not recommended.
Fluconazole: (Moderate) Concomitant use of fluconazole 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.
Fluoxetine: (Moderate) Concomitant use of fluoxetine 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.
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.
Fluvastatin: (Moderate) Efavirenz inhibits CYP2C9, which is the isoenzyme primarily responsible for the metabolism of fluvastatin. Coadministration of fluvastatin with efavirenz may increase the risk of myopathy and rhabdomyolysis.
Fluvoxamine: (Moderate) Consider alternatives to efavirenz when coadministering with fluvoxamine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been reported with the use of efavirenz. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
Food: (Major) Advise patients to avoid cannabis use during efavirenz treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoid delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP2C9 substrates and efavirenz is a moderate CYP2C9 inhibitor.
Fosamprenavir: (Major) Appropriate doses of unboosted fosamprenavir when coadministered with efavirenz have not been established. When fosamprenavir plus ritonavir is administered once daily and given in combination with efavirenz, the dose of ritonavir must be increased by 100 mg/day (300 mg total). No change in the ritonavir dose is required when efavirenz is administered with fosamprenavir plus ritonavir twice daily. Systemic concentrations of fosamprenavir are reduced when administered concurrently with efavirenz. Fosamprenavir is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as efavirenz. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). QTc prolongation has also been observed with the use of efavirenz. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment. (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.
Fosphenytoin: (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.
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.
Fruquintinib: (Major) Avoid coadministration of fruquintinib with efavirenz if possible due to decreased fruquintinib exposure and risk of decreased efficacy. If concomitant use of fruquintinib and efavirenz is necessary, monitor for decreased efficacy. Fruquintinib is a CYP3A substrate; efavirenz is a strong CYP3A inducer. Coadministration is predicted to decrease fruquintinib exposure by 32%.
Futibatinib: (Moderate) Coadministration of tenofovir disoproxil fumarate with futibatinib 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 futibatinib is a P-gp and BCRP inhibitor.
Ganaxolone: (Major) Avoid concurrent use of ganaxolone and efavirenz due to the risk of decreased ganaxolone efficacy. If concomitant use is unavoidable, consider increasing ganaxolone dose without exceeding the maximum daily dose. Ganaxolone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
Ganciclovir: (Moderate) Concurrent use of nephrotoxic agents with ganciclovir should be done cautiously to avoid additive nephrotoxicity. Other nephrotoxic agents include tenofovir.
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) 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.
Glipizide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Glyburide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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.
Guanfacine: (Major) Efavirenz may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if efavirenz is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If efavirenz is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and efavirenz is a moderate CYP3A4 inducer.
Halogenated Anesthetics: (Major) Although data are limited, coadministration of efavirenz and halogenated anesthetics may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs can prolong the QT interval.
Haloperidol: (Moderate) Consider alternatives to efavirenz when coadministering with haloperidol as concurrent use may increase the risk of QT prolongation and reduce haloperidol efficacy. Efavirenz is a moderate CYP3A4 inducer that has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Haloperidol plasma concentration is significantly reduced when prolonged treatment (1 to 2 weeks) with enzyme-inducing drugs is added to therapy.
Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving efavirenz as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with efavirenz can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If efavirenz is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
Hydantoins: (Major) Complex interactions may occur when hydantoins (phenytoin, fosphenytoin, and possibly ethotoin) are administered to patients receiving treatment for HIV infection; if possible, a different anticonvulsant should be used. The combination regimens used to treat HIV often include substrates, inducers, and inhibitors of several CYP isoenzymes. If phenytoin is used in patients being treated for HIV, the patient must be closely monitored for antiviral efficacy and seizure control; appropriate dose adjustments for phenytoin or the antiretroviral medications are unknown. Efavirenz is a substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19. Phenytoin is a substrate and inducer of CYP3A4, CYP2C9, and CYP2C19. Use of these drugs in combination may decrease the serum concentrations of both phenytoin and efavirenz.
Hydrocodone: (Moderate) Concomitant use of hydrocodone with efavirenz can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If efavirenz is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
Hydrocodone; Ibuprofen: (Moderate) 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.
Hydroxychloroquine: (Major) Concomitant use of hydroxychloroquine and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Moderate) Concomitant use of hydroxyzine 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.
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.
Ibuprofen; Famotidine: (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.
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 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.
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.
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-2b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. 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 score greater than 6). (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) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. 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 score greater than 6). (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) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. 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 score greater than 6). (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) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. 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 score greater than 6). (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) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. 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 score greater than 6). (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) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. 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 score greater than 6). (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.
Iomeprol: (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 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.
Iopromide: (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.
Ioversol: (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.
Isavuconazonium: (Major) Coadministration of isavuconazonium with efavirenz is not recommended as there is a potential for elevated efavirenz concentrations and decreased concentrations of isavuconazonium. Decreased isavuconazonium concentrations may lead to a reduction of antifungal efficacy and the potential for treatment failure. Efavirenz is a substrate and inducer of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme.
Isoflurane: (Major) Although data are limited, coadministration of efavirenz and halogenated anesthetics may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs can prolong the QT interval.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) When efavirenz and rifampin are coadministered, decreased efavirenz concentrations are seen and decreased antiretroviral efficacy is expected. These drugs may be coadministered to patients weighing 50 kg or more if the efavirenz dose is increased to 800 mg PO daily. A small study evaluated this interaction by administering the drugs (both at 600 mg PO daily x 7 days) to 12 subjects, and found decreased mean efavirenz Cmax, AUC, and Cmin of 20%, 26%, and 32%. Of note, reduced efavirenz metabolism is seen in patients with genetic polymorphisms of cytochrome P450 2B6 (primarily in patients of African, Asian, and Hispanic descent). Increasing the dose in these patients can result in a significant increase in efavirenz toxicity; some patients may even require lower doses.
Isoniazid, INH; Rifampin: (Major) When efavirenz and rifampin are coadministered, decreased efavirenz concentrations are seen and decreased antiretroviral efficacy is expected. These drugs may be coadministered to patients weighing 50 kg or more if the efavirenz dose is increased to 800 mg PO daily. A small study evaluated this interaction by administering the drugs (both at 600 mg PO daily x 7 days) to 12 subjects, and found decreased mean efavirenz Cmax, AUC, and Cmin of 20%, 26%, and 32%. Of note, reduced efavirenz metabolism is seen in patients with genetic polymorphisms of cytochrome P450 2B6 (primarily in patients of African, Asian, and Hispanic descent). Increasing the dose in these patients can result in a significant increase in efavirenz toxicity; some patients may even require lower doses.
Isosulfan Blue: (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.
Isradipine: (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
Istradefylline: (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with istradefylline is necessary as concurrent use may increase tenofovir exposure. Tenofovir is a P-gp substrate and istradefylline is a P-gp inhibitor. (Moderate) Monitor for efavirenz-related adverse reactions if coadministration of istradefylline 40 mg daily is necessary. Efavirenz is a CYP3A4 substrate; istradefylline administered as 40 mg daily is a weak CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.
Itraconazole: (Major) Use of efavirenz is not recommended for 2 weeks before or during itraconazole therapy. Consider an alternative antifungal medication. Administering itraconazole with inducers of CYP3A4, such as efavirenz, may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy could be reduced. Efavirenz is also partially metabolized by CYP3A4; taking efavirenz with itraconazole (a potent CYP3A4 inhibitor) may increase exposure to efavirenz. In addition, both drugs are associated with QT prolongation; coadministration may increase this risk. (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 itraconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
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.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with efavirenz due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QTc prolongation has been observed with the use of efavirenz.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and efavirenz due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may decrease the exposure of ketoconazole, reducing its efficacy. Ketoconazole is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. (Moderate) Monitor for an increase in tenofovir-related adverse effects if coadministration with ketoconazole is necessary. Concurrent use may increase tenofovir exposure. Tenofovir disoproxil fumarate is a P-gp substrate and ketoconazole is a P-gp inhibitor.
Ketoprofen: (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.
Ketorolac: (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.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) The manufacturer of efavirenz recommends that alternatives to clarithromycin be considered when a macrolide antibiotic is required in patients receiving efavirenz. Coadministration of efavirenz and clarithromycin may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes TdP. QT prolongation has also been observed with use of efavirenz. In addition, concurrent use of efavirenz with clarithromycin 500 mg PO every 12 hours for seven days resulted in a significant decrease in the serum concentration of clarithromycin, but the clinical significance of this is not known. (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.
Lapatinib: (Moderate) Consider alternatives to efavirenz when coadministering with lapatinib as concurrent use may increase the risk of QT prolongation; increased efavirenz exposure is also possible. QTc prolongation has been observed with the use of efavirenz. Prolongation of the QTc interval has been observed with the use of efavirenz, a CYP3A4 substrate. Lapatinib is a weak CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with lapatinib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Increased plasma concentrations of tenofovir may occur.
Larotrectinib: (Major) Avoid concurrent use of larotrectinib and efavirenz due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If efavirenz is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of efavirenz. Larotrectinib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Coadministration with efavirenz is predicted to decrease larotrectinib exposure by 72%.
Lasmiditan: (Moderate) Coadministration of tenofovir disoproxil fumarate with lasmiditan 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 lasmiditan is a P-gp inhibitor.
Ledipasvir; Sofosbuvir: (Moderate) Closely monitor for tenofovir-associated adverse reactions if ledipasvir is administered with tenofovir disoproxil fumarate. In addition, because safety has not been established, avoid use of ledipasvir in combination with HIV regimens that contain tenofovir disoproxil fumarate and HIV protease inhibitors boosted with ritonavir. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate. If coadministration is deemed necessary, closely monitor for tenofovir adverse effects. Plasma concentrations of tenofovir may increase when administered with ledipasvir. Tenofovir is a substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); ledipasvir is an inhibitor of both P-gp and BCRP.
Lefamulin: (Major) Avoid coadministration of lefamulin with efavirenz as concurrent use may increase the risk of QT prolongation and decrease lefamulin exposure and efficacy. If coadministration cannot be avoided, monitor for decreased efficacy and ECG during treatment. Lefamulin is a CYP3A4 substrate that has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation.
Lemborexant: (Major) Avoid coadministration of lemborexant and efvirenz as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer.
Lenacapavir: (Major) Avoid concurrent use of lenacapavir and efavirenz due to the risk of decreased lenacapavir exposure which may result in loss of therapeutic effect and development of resistance. Lenacapavir is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Concomitant use with efavirenz reduced lenacapavir overall exposure by 56%.
Leniolisib: (Major) Avoid concomitant use of leniolisib and efavirenz. Concomitant use may decrease leniolisib exposure which may reduce its efficacy. Leniolisib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Concomitant use is predicted to reduce leniolisib overall exposure by 58%. (Moderate) Coadministration of tenofovir disoproxil fumarate with leniolisib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and leniolisib is a BCRP inhibitor.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with efavirenz due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Prolongation of the QTc interval has also been observed with the use of efavirenz.
Letermovir: (Major) Concurrent administration of letermovir and efavirenz is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Also, a clinically relevant increase in the plasma concentration of efavirenz may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Efavirenz is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor.
Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving efavirenz as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
Leuprolide; Norethindrone: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations. (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving efavirenz as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
Levamlodipine: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
Levofloxacin: (Moderate) Concomitant use of levofloxacin 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.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and efavirenz due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Additionally, concomitant use may decrease the exposure of ketoconazole, reducing its efficacy. Ketoconazole is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. (Moderate) Monitor for an increase in tenofovir-related adverse effects if coadministration with ketoconazole is necessary. Concurrent use may increase tenofovir exposure. Tenofovir disoproxil fumarate is a P-gp substrate and ketoconazole is a P-gp inhibitor.
Levonorgestrel: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Levonorgestrel; Ethinyl Estradiol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Lidocaine: (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and thus, may decrease serum concentrations of lidocaine. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range (e.g., systemic lidocaine).
Lidocaine; Epinephrine: (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and thus, may decrease serum concentrations of lidocaine. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range (e.g., systemic lidocaine).
Lidocaine; Prilocaine: (Moderate) Efavirenz induces cytochrome P450 (CYP) 3A4 and thus, may decrease serum concentrations of lidocaine. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range (e.g., systemic lidocaine).
Linagliptin: (Moderate) Concomitant use of linagliptin with efavirenz may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; efavirenz is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
Linagliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems. (Moderate) Concomitant use of linagliptin with efavirenz may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; efavirenz is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
Lithium: (Moderate) Concomitant use of lithium 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.
Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with efavirenz due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. QTc prolongation has been observed with the use of efavirenz.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and efavirenz is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. (Moderate) Coadministration of tenofovir disoproxil fumarate with lonafarnib 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) substrate and lonafarnib is a P-gp inhibitor.
Loperamide: (Moderate) Concomitant use of loperamide and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Loperamide; Simethicone: (Moderate) Concomitant use of loperamide and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Lopinavir; Ritonavir: (Major) Concomitant use of lopinavir; ritonavir and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, increase the dose of lopinavir; ritonavir to 500/125 mg or 600/150 mg (tablets) or 520/130 mg (solution) twice daily in adults and pediatric patients weighing more than 45 kg if concomitant use is necessary; do not use once daily administration. For pediatric patients weighing less than 45 kg, use 300 mg/75 mg per m2/dose PO twice daily (solution) if concomitant use with efavirenz is necessary. Induction of CYP3A by efavirenz may decrease lopinavir concentrations, resulting in decreased efficacy. (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) 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. (Minor) There are varying results in reports of an interaction between tenofovir and lopinavir; ritonavir. In one report, the concurrent administration of tenofovir with lopinavir; ritonavir increased tenofovir Cmax 31%, AUC 34%, and Cmin 29%, with slight (15%) decreases in lopinavir Cmax and AUC; the alterations may be a food effect rather than a drug-drug interaction. In another report, lopinavir; ritonavir (400 mg; 100 mg PO twice daily for 14 days) increased the tenofovir (300 mg/day PO) Cmin 51% and AUC 32%, with no effect seen on lopinavir; ritonavir pharmacokinetics. While the clinical significance of this interaction is unknown, and is suspected to be insignificant, patients receiving lopinavir; ritonavir with tenofovir should be monitored for tenofovir-associated adverse events.
Lorlatinib: (Major) Avoid concomitant use of lorlatinib and efavirenz due to decreased plasma concentrations of both drugs, which may reduce efficacy and increase the potential for viral resistance. If concomitant use is necessary, increase the dose of lorlatinib to 125 mg PO once daily. Both lorlatinib and efavirenz are CYP3A4 substrates and moderate CYP3A4 inducers. Administration with another moderate CYP3A inducer decreased lorlatinib exposure by 23%.
Losartan: (Minor) Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of drugs that are substrates for CYP2C9 or CYP2C19 including losartan.
Losartan; Hydrochlorothiazide, HCTZ: (Minor) Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of drugs that are substrates for CYP2C9 or CYP2C19 including losartan.
Lovastatin: (Minor) Efavirenz has potential to induce CYP3A4 isoenzymes which may decrease the efficacy of lovastatin.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor can reduce the efficacy of efavirenz by decreasing its systemic exposure. If these agents must be used together, monitor efavirenz plasma concentrations; an efavirenz dosage adjustment may be required to obtain the desired therapeutic effect. Efavirenz is a substrate of CYP3A4 and CYP2B6. Lumacaftor is a strong CYP3A inducer, and in vitro data suggest that lumacaftor may also induce CYP2B6. When efavirenz is coadministered with rifampin, a strong CYP3A4 and CYP2B6 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients >= 50 kg). (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.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor can reduce the efficacy of efavirenz by decreasing its systemic exposure. If these agents must be used together, monitor efavirenz plasma concentrations; an efavirenz dosage adjustment may be required to obtain the desired therapeutic effect. Efavirenz is a substrate of CYP3A4 and CYP2B6. Lumacaftor is a strong CYP3A inducer, and in vitro data suggest that lumacaftor may also induce CYP2B6. When efavirenz is coadministered with rifampin, a strong CYP3A4 and CYP2B6 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients >= 50 kg).
Lumateperone: (Major) Avoid coadministration of lumateperone and efavirenz as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer.
Lurasidone: (Moderate) If lurasidone is used with efavirenz, it may be necessary to increase the lurasidone dose after chronic treatment (7 days or more) with efavirenz. Concurrent use may lead to a decrease in efficacy of lurasidone. Efavirenz is a moderate CYP3A inducer; lurasidone is a CYP3A substrate.
Macimorelin: (Major) Discontinue efavirenz and allow a sufficient washout period to pass before administering the macimorelin. Use of these drugs together can significantly decrease macimorelin plasma concentrations, and may result in a false positive test for growth hormone deficiency. No drug-drug interaction studies have been conducted; however, macimorelin is primarily metabolized by CYP3A4 and efavirenz is a CYP3A4 inducer. In addition, use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. QTc prolongation has been observed with the use of efavirenz.
Macitentan; Tadalafil: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
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.
Maprotiline: (Moderate) Consider alternatives to efavirenz when coadministering with maprotiline as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
Maraviroc: (Major) Coadministration of maraviroc, a CYP3A substrate, and efavirenz, a strong CYP3A inducer, without a concomitant strong CYP3A inhibitor, significantly decreases maraviroc concentrations, therefore, the adult maraviroc dose should be increased to 600 mg PO twice daily when coadministered with efavirenz without a concomitant strong CYP3A inhibitor. Coadministration of maraviroc and efavirenz is contraindicated in patients with CrCl less than 30 mL/min. For pediatric patients, concomitant use of maraviroc with a strong CYP3A inducer, without a strong CYP3A inhibitor, is not recommended. If the patient's medication regimen also contains a strong CYP3A inhibitor, the CYP3A inhibitor's actions are expected to exceed that of the inducer; overall, increased maraviroc concentrations are expected.
Maribavir: (Moderate) Coadministration of tenofovir disoproxil fumarate with maribavir 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 maribavir is a P-gp and BCRP inhibitor.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with efavirenz due to risk for reduced mavacamten efficacy. Concomitant use decreases mavacamten exposure. Mavacamten is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
Meclofenamate Sodium: (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.
Mefenamic Acid: (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.
Mefloquine: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as mefloquine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Moderate) Consider alternatives to efavirenz when coadministering with mefloquine. QTc prolongation has been observed with the use of efavirenz. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. In addition, efavirenz may induce the CYP3A4 metabolism of mefloquine; potentially reducing the efficacy of mefloquine. Concomitant administration may increase the risk of Plasmodium falciparum resistance during treatment of malaria.
Meloxicam: (Moderate) 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.
Memantine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Metformin; Repaglinide: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems. (Minor) Repaglinide is metabolized in the liver by cytochrome P450 isoenzyme CYP3A. Patients taking repaglinide concomitantly with a CYP3A inducer such as efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) should be monitored for reduced effectiveness of repaglinide and possible symptoms indicating hyperglycemia.
Metformin; Saxagliptin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Metformin; Sitagliptin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Methadone: (Major) Coadministration of efavirenz and methadone may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Methadone is considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In addition, efavirenz induces methadone metabolism via CYP3A4 and is associated with significant decreases in methadone concentrations. Clinical reports suggest that patients who are stabilized on methadone-maintenance therapy may experience opiate withdrawal symptoms when efavirenz is added to their HIV-regimen. Methadone-maintained patients should be monitored for evidence of withdrawal and the methadone dose should be adjusted accordingly.
Methenamine; Sodium 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.
Methohexital: (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.
Methotrexate: (Major) Avoid concomitant use of methotrexate with tenofovir disoproxil fumarate due to the risk of additive nephrotoxicity as well as an increased risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Tenofovir disoproxil fumarate and methotrexate are both nephrotoxic drugs; methotrexate is also renally eliminated. Coadministration of methotrexate with tenofovir disoproxil fumarate may result in decreased renal function as well as increased methotrexate plasma concentrations.
Metronidazole: (Moderate) Concomitant use of metronidazole and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and efavirenz as midostaurin exposure may be decreased, which may reduce its efficacy; concomitant use also increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Midostaurin is a CYP3A4 substrate and efavirenz is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively. (Moderate) Coadministration of tenofovir disoproxil fumarate with midostaurin may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and midostaurin is a BCRP inhibitor.
Mifepristone: (Major) Avoid use together when possible; consider alternatives to efavirenz. The use of these drugs together may increase the risk for QT prolongation or other efavirenz-induced side effects and may reduce mifepristone efficacy. Concurrent use will increase the systemic exposure of efavirenz and decrease mifepristone exposure. Efavirenz is a CYP2B6 substrate and CYP3A4 inducer, while mifepristone is a CYP3A4 substrate and CYP2B6 inhibitor. In addition, careful monitoring for mifepristone efficacy is necessary. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used. Also monitor for efavirenz-associated adverse reactions, such as nervous system or psychiatric symptoms, fast irregular heart rate, QT prolongation, hepatotoxicity, and rash. QT prolongation has been observed with use of efavirenz. Mifepristone, when given chronically for hormonal conditions such as Cushing's syndrome, has also been associated with dose-dependent prolongation of the QT interval.
Mirtazapine: (Moderate) Concomitant use of mirtazapine 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.
Mitapivat: (Major) Avoid coadministration of mitapivat with efavirenz if possible, due to decreased mitapivat efficacy. If concomitant use is necessary, up-titration of mitapivat may be required. Monitor hemoglobin and titrate the mitapivat dose based on response; do not exceed 100 mg PO twice daily. Mitapivat is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Efavirenz decreased mitapivat overall and peak exposure by approximately 60% and 30%, respectively, after mitapivat 5 or 20 mg twice daily. Efavirenz decreased mitapivat overall and peak exposure by 55% and 24%, respectively, after mitapivat 50 mg twice daily. (Moderate) Coadministration of tenofovir disoproxil fumarate with mitapivat 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 mitapivat is a P-gp inhibitor.
Mitotane: (Major) Use caution if mitotane and efavirenz are used concomitantly, as coadministration may significantly reduce plasma concentrations of efavirenz, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. When efavirenz is coadministered with rifampin, another strong CYP3A4 inducer, it is recommended to increase efavirenz from 600 mg/day to 800 mg/day (patients >= 50 kg). Mitotane is a strong CYP3A4 inducer and efavirenz is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of efavirenz.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and efavirenz. Concomitant use may decrease mobocertinib exposure resulting in decreased efficacy. Use may also increase the risk of QT prolongation and torsade de pointes (TdP). Mobocertinib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Use of a moderate CYP3A inducer is predicted to decrease the overall exposure of mobocertinib and its active metabolites by 58%.
Momelotinib: (Moderate) Coadministration of tenofovir disoproxil fumarate with momelotinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and momelotinib is a BCRP inhibitor.
Moxifloxacin: (Major) Coadministration of efavirenz and moxifloxacin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, torsade de pointes has been reported during post-marketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
Nabumetone: (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.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with efavirenz is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for reduced sirolimus efficacy if sirolimus is coadministered with efavirenz. Concomitant use may decrease sirolimus exposure. Sirolimus is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
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.
Naproxen; Esomeprazole: (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. (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.
Naproxen; 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.
Nefazodone: (Major) Nefazodone inhibits the CYP3A4 metabolism of efavirenz. Nefazodone has been used to treat depression in patients on antiretroviral medications concurrently. However, it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects.
Nelfinavir: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as nelfinavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Neratinib: (Major) Avoid concomitant use of efavirenz with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that efavirenz may decrease neratinib exposure by 52%. (Moderate) Coadministration of tenofovir disoproxil fumarate with neratinib 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) substrate and neratinib is a P-gp inhibitor.
Nevirapine: (Major) Coadministration of nevirapine and efavirenz is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. Concomitant use may also cause a decrease in plasma concentrations of efavirenz and, thus, a loss of therapeutic effect. The pharmacokinetics of nevirapine appear to be unaffected. Nevirapine is a CYP3A substrate and weak CYP3A inducer. Efavirenz is a CYP3A substrate and moderate CYP3A inducer.
Nicardipine: (Moderate) Use caution and careful monitoring when coadministering efavirenz with certain calcium-channel blockers. Efavirenz induces CYP3A4, potentially altering serum concentrations of calcium-channel blockers metabolized via CYP3A4. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments are made based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, lercanidipine, nicardipine, and verapamil); adjust based on clinical response.
NIFEdipine: (Moderate) Use caution and careful monitoring when coadministering efavirenz with certain calcium-channel blockers. Efavirenz induces CYP3A4, potentially altering serum concentrations of calcium-channel blockers metabolized via CYP3A4. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments are made based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, lercanidipine, nicardipine, and verapamil); adjust based on clinical response.
Nilotinib: (Major) Coadministration of nilotinib and a drug that prolongs the QT interval, such as efavirenz, is not advised; nilotinib prolongs the QT interval. If concurrent administration is unavoidable, the manufacturer of nilotinib recommends interruption of nilotinib treatment. If nilotinib must be continued, closely monitor the patient for QT interval prolongation. In addition, concomitant use of nilotinib, a substrate and an inhibitor of CYP3A4, and efavirenz, a substrate and inducer of CYP3A4, may result in decreased nilotinib plasma concentrations and/or increased efavirenz concentrations. Selecting an alternate agent with less potential for CYP3A4 induction should be considered. Closely monitor patients if these drugs are used together; increasing the nilotinib dosage will most likely not account for the loss of exposure based on the nonlinear pharmacokinetics of nilotinib.
Nimodipine: (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
Nirmatrelvir; Ritonavir: (Moderate) 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) Monitor for a diminished response to nirmatrelvir if concomitant use of efavirenz is necessary. Concomitant use of nirmatrelvir and efavirenz may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. (Moderate) Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Concurrent use is is expected to result in increased concentrations of both drugs.
Nirogacestat: (Major) Avoid concomitant use of nirogacestat and efavirenz. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Concomitant use is predicted to reduce nirogacestat overall exposure by 67%.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with efavirenz due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and efavirenz is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
Non-Ionic Contrast Media: (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.
Non-oral combination contraceptives: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin, levonorgestrel, and etonogestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased by 80% and 83%, respectively. Etonogestrel AUC decreased by 63% to 82%. There have been postmarketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Nonsteroidal antiinflammatory drugs: (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.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Norethindrone: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Norethindrone; Ethinyl Estradiol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Norgestimate; Ethinyl Estradiol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Norgestrel: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Ofloxacin: (Moderate) Concomitant use of ofloxacin 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.
Olanzapine: (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Moderate) Concomitant use of fluoxetine 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. (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Olanzapine; Samidorphan: (Moderate) Consider alternatives to efavirenz when coadministering with efavirenz as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Olaparib: (Major) Avoid coadministration of olaparib with efavirenz due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and efavirenz is a moderate CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with efavirenz is predicted to decrease the olaparib Cmax by 31% and the AUC by 60%.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
Olutasidenib: (Major) Avoid concurrent use of olutasidenib and efavirenz due to the risk of decreased olutasidenib exposure which may reduce its efficacy. Olutasidenib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
Omaveloxolone: (Major) Avoid concurrent use of omaveloxolone and efavirenz. Concurrent use may decrease omaveloxolone exposure which may reduce its efficacy. Omaveloxolone is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
Omeprazole: (Minor) Efavirenz inhibits and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C19.
Omeprazole; Amoxicillin; Rifabutin: (Major) Due to decreased exposure of rifabutin, the FDA-approved labeling recommends that the daily dose of rifabutin be increased by 50% when coadministered with efavirenz. For patients being treated for tuberculosis, guidelines recommend a daily dose of 450 to 600 mg. For rifabutin regimens given two or three times per week, consider doubling the rifabutin dose. Rifabutin is a substrate of CYP3A4; efavirenz is a moderate CYP3A4 inducer. (Minor) Efavirenz inhibits and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C19.
Omeprazole; Sodium Bicarbonate: (Minor) Efavirenz inhibits and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C19.
Ondansetron: (Major) Coadministration of efavirenz and ondansetron may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Ondansetron has been associated with QT prolongation and post-marketing reports of TdP. Risk for QT prolongation increases with increased dosage, and a 32 mg IV dose must no longer be used for prevention of chemotherapy induced emesis. If these drugs must be coadministered, ECG monitoring is recommended. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as ondansetron.
Oral Contraceptives: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Oritavancin: (Major) Efavirenz is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of efavirenz may be reduced if these drugs are administered concurrently.
Orlistat: (Major) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with tenofovir, PMPA. Loss of virological control has been reported in HIV-infected patients taking orlistat with tenofovir disoproxil fumarate and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued. (Major) Monitor HIV RNA concentrations frequently during concurrent use of orlistat and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Discontinue orlistat if an increased HIV viral load is confirmed. Loss of virological control has been reported in persons with HIV infection taking orlistat with antiretrovirals, including NNRTIs. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the antiretroviral agent. (Moderate) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs). Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with efavirenz as concurrent use may increase the risk of QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation. QTc prolongation has been observed with the use of efavirenz.
Osimertinib: (Major) Avoid coadministration of efavirenz with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QTc prolongation has been observed with the use of efavirenz. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may result in increased tenofovir absorption. Tenofovir disoproxil is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
Oteseconazole: (Moderate) Coadministration of tenofovir disoproxil fumarate with oteseconazole may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Oxaliplatin: (Major) Avoid coadministration of oxaliplatin with tenofovir disoproxil fumarate due to the risk of increased oxaliplatin-related adverse reactions. Tenofovir disoproxil fumarate is known to be potentially nephrotoxic; because platinum-containing drugs like oxaliplatin are eliminated primarily through the kidney, oxaliplatin clearance may be decreased by coadministration with nephrotoxic agents. (Major) Consider alternatives to efavirenz when treatment with oxaliplatin is necessary. QTc prolongation has been observed with the use of efavirenz. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Oxaprozin: (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.
Oxybutynin: (Moderate) Oxybutynin is metabolized by CYP3A. Drugs that induce CYP3A, such as efavirenz, may cause decreased serum concentrations of oxybutynin. The clinical significance of such interactions is not known; however patients receiving oxybutynin with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) concomitantly should be monitored for efficacy.
Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with efavirenz is necessary; consider increasing the dose of oxycodone as needed. If efavirenz is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking efavirenz due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. QTc prolongation has been observed with the use of efavirenz.
Paclitaxel: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as paclitaxel.
Pacritinib: (Major) Avoid concurrent use of pacritinib with efavirenz due to the risk of decreased pacritinib exposure which may impair efficacy. Concomitant use may also increase the risk of QT/QTc prolongation and torsade de pointes (TdP). Pacritinib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. (Moderate) Concomitant use of tenofovir disoproxil fumarate with pacritinib 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; pacritinib is a P-gp and BCRP inhibitor.
Palbociclib: (Moderate) Monitor for an increase in efavirenz-related adverse reactions if coadministration with palbociclib is necessary. Palbociclib is a weak time-dependent inhibitor of CYP3A while efavirenz is a CYP3A4 substrate.
Palovarotene: (Major) Avoid concomitant use of palovarotene and efavirenz. Concurrent use may decrease palovarotene exposure which may reduce its efficacy. Palovarotene is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
Pamidronate: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as pamidronate. 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.
Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval, such as efavirenz, is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or greater during therapy; permanently discontinue if QT prolongation does not resolve. In addition, efavirenz may induce the CYP3A4 metabolism of panobinostat, potentially reducing the efficacy of panobinostat by decreasing its systemic exposure.
Paricalcitol: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as paricalcitol.
Paromomycin: (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.
Pasireotide: (Moderate) Consider alternatives to efavirenz when coadministering with pasireotide as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval, such as efavirenz, is not advised; pazopanib has been reported to prolong the QT interval. If pazopanib and the other drug must be continued, closely monitor the patient for QT interval prolongation. In addition, concurrent use may increase the systemic concentration of efavirenz and decrease the concentration of pazopanib. Efavirenz is a CYP3A4 substrate and inducer, while pazopanib is a CYP3A4 substrate and mild inhibitor.
Peginterferon Alfa-2a: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. 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 score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Peginterferon Alfa-2b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. 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 score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Peginterferon beta-1a: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. 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 score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and efavirenz due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease pemigatinib exposure by more than 50%.
Pentamidine: (Major) Although data are limited, coadministration of efavirenz and pentamidine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs.
Pentobarbital: (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.
Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with efavirenz due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of efavirenz occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Efavirenz is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
Perindopril; Amlodipine: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
Perphenazine: (Minor) Consider alternatives to efavirenz when coadministering with perphenazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Perphenazine is associated with a possible risk for QT prolongation.
Perphenazine; Amitriptyline: (Minor) Consider alternatives to efavirenz when coadministering with perphenazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Perphenazine is associated with a possible risk for QT prolongation.
Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with efavirenz. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
Phenobarbital: (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.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (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.
Phenytoin: (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.
Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as efavirenz. In addition, pimavanserin is primarily metabolized by CYP3A4 and CYP3A5 and the manufacturer recommends avoiding concomitant use of pimavanserin with moderate CYP3A4 inducers, such as efavirenz. Moderate inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Efavirenz has also been associated with QT prolongation. Because of the potential for QT prolongation and TdP, use of efavirenz with pimozide is contraindicated.
Pioglitazone; Glimepiride: (Moderate) Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like efavirenz. Monitor serum glucose concentrations if glimepiride is coadministered with efavirenz. Dosage adjustments may be necessary.
Pioglitazone; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Piroxicam: (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) Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of piroxicam, a substrate for CYP2C9.
Pirtobrutinib: (Major) Avoid concurrent use of pirtobrutinib and efavirenz due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. If concomitant use is necessary, an empiric pirtobrutinib dosage increase is required. If the current dosage is 200 mg once daily, increase the dose to 300 mg; if the current dosage is 50 mg or 100 mg once daily, increase the dose by 50 mg. Pirtobrutinib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Concomitant use reduced pirtobrutinib overall exposure by 49%. (Moderate) Coadministration of tenofovir disoproxil fumarate with pirtobrutinib 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 pirtobrutinib is a P-gp and BCRP inhibitor.
Pitolisant: (Major) Avoid coadministration of pitolisant with efavirenz as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. QTc prolongation has been observed with the use of efavirenz.
Plazomicin: (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.
Polymyxin B: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as polymyxin B. 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.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking efavirenz due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. QTc prolongation has been observed with the use of efavirenz.
Posaconazole: (Contraindicated) The concurrent use of posaconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as efavirenz, is contraindicated. Posaconazole has been associated with QT prolongation and torsade de pointes. In addition, concomitant use may increase the risk for breakthrough fungal infection. Efavirenz is believed to interact with posaconazole by inducing UDP glucuronidation. When posaconazole was administered with efavirenz, the mean reductions in Cmax were 45% and the mean reductions in AUC were 50% for posaconazole. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as posaconazole. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Pralsetinib: (Major) Avoid concurrent use of efavirenz and pralsetinib due to the risk of decreased pralsetinib exposure which may reduce its efficacy. If concomitant use is necessary, increase the current dose of pralsetinib (400 mg to 600 mg; 300 mg to 500 mg; 200 mg to 300 mg) starting on day 7 of coadministration. Pralsetinib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Coadministration decreased pralsetinib overall exposure by 45%.
Praziquantel: (Major) Avoid concomitant use of praziquantel and efavirenz. Concurrent use may decrease praziquantel exposure which may reduce its efficacy. If concomitant use is necessary, monitor for reduced response to praziquantel. Praziquantel is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. When praziquantel was administered after 13 days of treatment with efavirenz, the mean praziquantel AUC was 77% lower than when praziquantel was given alone.
Pretomanid: (Major) Avoid coadministration of pretomanid with efavirenz as concurrent use decreased pretomanid exposure by 66% which may lead to decreased efficacy; concurrent use may also increase the risk for hepatotoxicity. Pretomanid is a CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications. (Moderate) Coadministration of tenofovir disoproxil fumarate with pretomanid 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 pretomanid is a P-gp and BCRP inhibitor.
Primaquine: (Moderate) Consider alternatives to efavirenz when coadministering with primaquine. QT prolongation has been observed with use of both efavirenz and primaquine.
Primidone: (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.
Probenecid: (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, such as probenecid; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
Probenecid; Colchicine: (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, such as probenecid; patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
Procainamide: (Major) Coadministration of efavirenz and procainamide may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Procainamide is associated with a well-established risk of QT prolongation and TdP. (Moderate) Cationic drugs that are eliminated by renal tubular secretion such as procainamide may compete with lamivudine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of the response to lamivudine and/or procainamide is recommended to individualize dosage. In selected individuals, procainamide serum concentration monitoring may be appropriate.
Prochlorperazine: (Minor) Consider alternatives to efavirenz when coadministering with prochlorperazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Prochlorperazine is associated with a possible risk for QT prolongation.
Promethazine: (Moderate) Concomitant use of promethazine 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.
Promethazine; Dextromethorphan: (Moderate) Concomitant use of promethazine 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.
Promethazine; Phenylephrine: (Moderate) Concomitant use of promethazine 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.
Propafenone: (Major) Although data are limited, coadministration of efavirenz and propafenone may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Propafenone is a Class IC antiarrhythmic which increases the QT interval, but largely due to prolongation of the QRS interval. In addition, efavirenz is an inducer of CYP3A4; propafenone concentrations may be decreased with coadministration. (Moderate) Coadministration of tenofovir disoproxil fumarate with propafenone 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 propafenone is a P-gp inhibitor.
Quetiapine: (Major) Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. According to the manufacturer, use of quetiapine should be avoided in combination with drugs known to increase the QT interval, such as efavirenz. In addition, efavirenz may induce the CYP3A4 metabolism of quetiapine, and thus, decrease the serum concentration of quetiapine.
Quinidine: (Major) Coadministration of efavirenz and quinidine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Quinidine administration is associated with QT prolongation and TdP. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as quinidine. (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.
Quinine: (Major) Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Avoid concurrent use of quinine with other drugs that may cause QT prolongation and TdP, such as efavirenz. In addition, concurrent use may alter the systemic concentration of efavirenz and decrease the concentration of quinine. Efavirenz is a CYP3A4 substrate and inducer, while quinine is a CYP3A4 substrate, inducer, and inhibitor.
Quizartinib: (Major) Avoid concomitant use of efavirenz with quizartinib due to the risk of decreased quizartinib exposure which may reduce its efficacy. Concomitant use may also increase the risk of QT/QTc prolongation and torsade de pointes (TdP). Quizartinib is a CYP3A substrate, efavirenz is a moderate CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration decreased the overall exposure of quizartinib by 90%.
Ranolazine: (Contraindicated) Do not use ranolazine in combination with CYP3A inducers like efavirenz as ranolazine exposure and therapeutic response may be decreased; additive effects on the QT interval are also possible. Efavirenz is a moderate CYP3A4 inducer that has been associated with QTc prolongation. Ranolazine is a CYP3A substrate that is associated with dose- and plasma concentration-related increases in the QTc interval. Although the effect of moderate inducers is not reported by the ranolazine manufacturer, coadministration with a strong CYP3A inducer decreased the ranolazine plasma concentrations by 95%. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ranolazine. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Red Yeast Rice: (Moderate) Since certain red yeast rice products (i.e., pre-2005 Cholestin formulations) contain lovastatin, clinicians should use red yeast rice cautiously in combination with drugs known to interact with lovastatin. CYP3A4 inducers, such as efavirenz, can theoretically reduce the effectiveness of HMG-CoA reductase activity via induction of CYP3A4 metabolism.
Regorafenib: (Moderate) Use caution if coadministration of regorafenib with tenofovir, PMPA is necessary, and monitor for an increase in tenofovir-related adverse reactions. Tenofovir is a BCRP substrate and regorafenib is a BCRP inhibitor. Regorafenib-mediated BCRP inhibition may increase exposure to tenofovir.
Relugolix: (Moderate) Consider alternatives to efavirenz when coadministering with relugolix. QTc prolongation has been observed with the use of efavirenz. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Relugolix; Estradiol; Norethindrone acetate: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations. (Moderate) Consider alternatives to efavirenz when coadministering with relugolix. QTc prolongation has been observed with the use of efavirenz. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
Repaglinide: (Minor) Repaglinide is metabolized in the liver by cytochrome P450 isoenzyme CYP3A. Patients taking repaglinide concomitantly with a CYP3A inducer such as efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) should be monitored for reduced effectiveness of repaglinide and possible symptoms indicating hyperglycemia.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with efavirenz due to decreased repotrectinib exposure and risk of decreased efficacy. Repotrectinib is a CYP3A substrate; efavirenz is a moderate CYP3A inducer.
Ribavirin: (Moderate) The concomitant use of ribavirin and antiretroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. (Moderate) Use lamivudine 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. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
Ribociclib: (Major) Avoid coadministration of ribociclib with efavirenz due to an increased risk for QT prolongation. Additionally, the systemic exposure of efavirenz may be increased resulting in an increase in treatment-related adverse reactions. Efavirenz is a CYP3A4 substrate that has been associated with QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Concomitant use may increase the risk for QT prolongation.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with efavirenz due to an increased risk for QT prolongation. Additionally, the systemic exposure of efavirenz may be increased resulting in an increase in treatment-related adverse reactions. Efavirenz is a CYP3A4 substrate that has been associated with QT prolongation. Ribociclib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Concomitant use may increase the risk for QT prolongation.
Rifabutin: (Major) Due to decreased exposure of rifabutin, the FDA-approved labeling recommends that the daily dose of rifabutin be increased by 50% when coadministered with efavirenz. For patients being treated for tuberculosis, guidelines recommend a daily dose of 450 to 600 mg. For rifabutin regimens given two or three times per week, consider doubling the rifabutin dose. Rifabutin is a substrate of CYP3A4; efavirenz is a moderate CYP3A4 inducer.
Rifampin: (Major) When efavirenz and rifampin are coadministered, decreased efavirenz concentrations are seen and decreased antiretroviral efficacy is expected. These drugs may be coadministered to patients weighing 50 kg or more if the efavirenz dose is increased to 800 mg PO daily. A small study evaluated this interaction by administering the drugs (both at 600 mg PO daily x 7 days) to 12 subjects, and found decreased mean efavirenz Cmax, AUC, and Cmin of 20%, 26%, and 32%. Of note, reduced efavirenz metabolism is seen in patients with genetic polymorphisms of cytochrome P450 2B6 (primarily in patients of African, Asian, and Hispanic descent). Increasing the dose in these patients can result in a significant increase in efavirenz toxicity; some patients may even require lower doses.
Rifapentine: (Moderate) Monitor for decreased efficacy of efavirenz if coadministered with rifapentine. Concurrent use may decrease the plasma concentrations of efavirenz leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Efavirenz is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer.
Rilpivirine: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP).
Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and efavirenz. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
Rimegepant: (Major) Avoid coadministration of rimegepant with efavirenz; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
Ripretinib: (Major) Avoid coadministration of ripretinib with efavirenz. If concomitant use is unavoidable, increase the frequency of ripretinib dosing from 150 mg once daily to 150 mg twice daily; monitor for clinical response and tolerability. Resume once daily dosing of ripretinib 14 days after discontinuation of efavirenz. Coadministration is predicted to decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A and efavirenz is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Risperidone: (Major) Coadministration of efavirenz and risperidone may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Risperidone has been associated with a possible risk for QT prolongation and/or TdP. Reports of QT prolongation and TdP during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting. If coadministration is chosen, and the patient has known risk factors for cardiac disease or arrhythmia, then the patient should be closely monitored clinically. In addition, efavirenz may induce the CYP3A4 metabolism of risperidone, potentially reducing the efficacy of risperidone by decreasing its systemic exposure.
Ritonavir: (Moderate) 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) Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Concurrent use is is expected to result in increased concentrations of both drugs.
Rivaroxaban: (Minor) Coadministration of rivaroxaban and efavirenz may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Efavirenz is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
Roflumilast: (Moderate) Coadminister efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Efavirenz induces CYP3A and roflumilast is a CYP3A substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Rolapitant: (Moderate) Use caution if tenofovir, PMPA and rolapitant are used concurrently, and monitor for tenofovir-related adverse effects. Tenofovir is a substrate of the Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp), where an increase in exposure may significantly increase adverse effects; rolapitant is a BCRP and P-gp inhibitor. The Cmax and AUC of another BCRP substrate, sulfasalazine, were increased by 140% and 130%, respectively, on day 1 with rolapitant, and by 17% and 32%, respectively, on day 8 after rolapitant administration. When rolapitant was administered with digoxin, a P-gp substrate, the day 1 Cmax and AUC were increased by 70% and 30%, respectively; the Cmax and AUC on day 8 were not studied.
Romidepsin: (Moderate) Consider alternatives to efavirenz and monitoring electrolytes and ECGs at baseline and periodically during treatment if administered with romidepsin as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. QTc prolongation has been observed with the use of efavirenz.
Ropeginterferon alfa-2b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. 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 score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are CYP3A4 inducers such as efavirenz, a dose adjustment is not necessary, but closely monitor patients and titrate the ruxolitinib dose based on safety and efficacy. The Cmax and AUC of a single 50 mg dose of ruxolitinib was decreased by 32% and 61%, respectively, after rifampin 600 mg once daily was administered for 10 days. The relative exposure to ruxolitinib's active metabolites increased by about 100%, which may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition.
Salicylates: (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.
Salsalate: (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.
Saquinavir: (Major) Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as torsades de pointes (TdP). Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval, such as efavirenz. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Also, appropriate dosing recommendations for concomitant efavirenz and saquinavir, coadministered with or without ritonavir, have not been established. The concurrent administration of saquinavir soft gel capsule and efavirenz has resulted in decrease in saquinavir AUC and Cmax by 62% and 50%, respectively. A case report of 2 patients who had efavirenz (600 mg once daily) added to their ritonavir/saquinavir-SGC regimen (400/600 mg twice daily), showed modest increases in saquinavir AUC after the addition of efavirenz. The AUC of ritonavir increased in one patient and decreased in the other. Increasing the dose of saquinavir to 800 mg every 12 hours decreased the AUC of ritonavir and increased the AUC of efavirenz in both patients after 14 days. However, the increased dose of saquinavir produced a less than proportional increase in the saquinavir AUC. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as saquinavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Secobarbital: (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.
Segesterone Acetate; Ethinyl Estradiol: (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations. (Major) Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin, levonorgestrel, and etonogestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased by 80% and 83%, respectively. Etonogestrel AUC decreased by 63% to 82%. There have been postmarketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and efavirenz due to the risk of decreased selpercatinib exposure which may reduce its efficacy; additive QT prolongation may also occur. Selpercatinib is a CYP3A4 substrate that is associated with concentration-dependent QT prolongation; efavirenz is a moderate CYP3A4 inducer that is associated with QTc prolongation. Coadministration with efavirenz is predicted to decrease selpercatinib exposure by 40% to 70%. (Moderate) Coadministration of tenofovir disoproxil fumarate with selpercatinib 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 selpercatinib is a P-gp inhibitor.
Selumetinib: (Major) Avoid coadministration of selumetinib and efavirenz due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with efavirenz is predicted to decrease selumetinib exposure by 38%.
Sertraline: (Moderate) Concomitant use of sertraline 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. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Although data are limited, coadministration of efavirenz and halogenated anesthetics may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs can prolong the QT interval.
Sildenafil: (Moderate) Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as sildenafil.
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.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving efavirenz due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Efavirenz has also been associated with prolongation of the QT interval. Additionally, concomitant use of siponimod and efavirenz is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, efavirenz decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of efavirenz. Concomitant use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Coadministration of tenofovir disoproxil fumarate with taurursodiol 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 taurursodiol is a P-gp and BCRP inhibitor.
Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of velpatasvir with efavirenz, as concurrent administration significantly decreases velpatasvir plasma concentrations and may result in loss of antiviral efficacy. In a drug interaction study, use of these drugs together resulted in an approximate 50% reduction in velpatasvir exposure. Velpatasvir is substrate of P-glycoprotein (P-gp) and to a lesser extent CYP3A; efavirenz induces P-gp and CYP3A. (Moderate) Monitor patients for tenofovir-associated adverse reactions, such as renal toxicity, in patients receiving regimens containing tenofovir disoproxil fumarate and velpatasvir due to potential increases in tenofovir serum concentrations. When administered concurrently with velpatasvir, the peak concentration (Cmax), systemic exposure (AUC), and the trough concentration (Cmin) of tenofovir increased by 44%, 40%, and 84%, respectively. Tenofovir is a substrate of the breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) transporters, while velpatasvir inhibits both BCRP and P-gp. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of velpatasvir with efavirenz, as concurrent administration significantly decreases velpatasvir plasma concentrations and may result in loss of antiviral efficacy. In a drug interaction study, use of these drugs together resulted in an approximate 50% reduction in velpatasvir exposure. Velpatasvir is substrate of P-glycoprotein (P-gp) and to a lesser extent CYP3A; efavirenz induces P-gp and CYP3A. (Major) Avoid coadministration of voxilaprevir with moderate to potent inducers of CYP3A4, such as efavirenz. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy. Voxilaprevir is metabolized by CYP3A4. (Major) Avoid concurrent administration of voxilaprevir with tenofovir disoproxil fumarate. Taking these medications together may increase tenofovir plasma concentrations, potentially increasing the risk for adverse events. Tenofovir disoproxil fumarate is a substrate for the drug transporter Breast Cancer Resistance Protein (BCRP). Voxilaprevir is a BCRP inhibitor. (Moderate) Monitor patients for tenofovir-associated adverse reactions, such as renal toxicity, in patients receiving regimens containing tenofovir disoproxil fumarate and velpatasvir due to potential increases in tenofovir serum concentrations. When administered concurrently with velpatasvir, the peak concentration (Cmax), systemic exposure (AUC), and the trough concentration (Cmin) of tenofovir increased by 44%, 40%, and 84%, respectively. Tenofovir is a substrate of the breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) transporters, while velpatasvir inhibits both BCRP and P-gp. Consider use of tenofovir alafenamide in place of tenofovir disoproxil fumarate.
Solifenacin: (Moderate) Consider alternatives to efavirenz when coadministering with solifenacin as concurrent use may increase the risk of QT prolongation; decreased solifenacin exposure is also possible. QTc prolongation has been observed with the use of efavirenz. Solifenacin has been associated with dose-dependent prolongation of the QT interval and TdP has been reported with post-marketing use, although causality was not determined. In addition, efavirenz may induce the CYP3A4 metabolism of solifenacin; potentially reducing the efficacy of solifenacin by decreasing its systemic exposure.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and efavirenz; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and efavirenz is a CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
Sorafenib: (Major) Avoid coadministration of sorafenib with efavirenz due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. QTc prolongation has also been observed with the use of efavirenz. (Moderate) Monitor for an increase in tenofovir-related adverse reactions if coadministration with sorafenib is necessary. Tenofovir is a P-glycoprotein (P-gp) substrate and sorafenib inhibits P-gp in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
Sorbitol: (Major) Avoid coadministration of lamivudine oral solution and sorbitol if possible due to sorbitol dose-dependent reduction in lamivudine exposure. An all-tablet regimen should be used when possible to avoid a potential interaction with sorbitol. Consider more frequent monitoring of viral load when treating with lamivudine oral solution. In a drug interaction study in 16 healthy adult patients, coadministration of a single 300 mg dose of lamivudine oral solution with sorbitol 3.2 g, 10.2 g, or 13.4 g resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC24 and 28%, 52%, and 55% in the Cmax of lamivudine.
Sotalol: (Major) Concomitant use of sotalol and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sotorasib: (Moderate) Coadministration of tenofovir disoproxil fumarate with sotorasib 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 sotorasib is a P-gp and BCRP inhibitor.
Sparsentan: (Moderate) Coadministration of tenofovir disoproxil fumarate with sparsentan 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 sparsentan is a P-gp and BCRP inhibitor.
St. John's Wort, Hypericum perforatum: (Contraindicated) Concurrent use of St. John's Wort, Hypericum perforatum and efavirenz is contraindicated. When coadministered, there is a potential for treatment failure and the development of efavirenz or NNRTI resistance. St. John's Wort is a strong inducer of CYP3A4, which is partially responsible for the metabolism of efavirenz. Coadministration may result in decreased efavirenz serum concentrations, which could cause impaired virologic response.
Stiripentol: (Moderate) Consider a dose adjustment of efavirenz when coadministered with stiripentol. Coadministration may alter plasma concentrations of efavirenz resulting in an increased risk of adverse reactions and/or decreased efficacy. Efavirenz is a CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
Streptomycin: (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.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if efavirenz must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with efavirenz is necessary; consider increasing the dose of sufentanil injection as needed. If efavirenz is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Sulindac: (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.
Sumatriptan; 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.
Sunitinib: (Major) Consider alternatives to efavirenz when coadministering with sunitinib. QTc prolongation has been observed with the use of efavirenz. Sunitinib can also prolong the QT interval.
Tacrolimus: (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, including tacrolimus. (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with efavirenz. Monitoring of serum tacrolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz. Tacrolimus is a CYP3A4 substrate that may prolong the QT interval and cause torsade de pointes (TdP). Efavirenz induces CYP3A4; QTc prolongation has been observed with the use of efavirenz.
Tadalafil: (Moderate) Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
Tafamidis: (Moderate) Caution is advised with the coadministration of tafamidis 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 dose adjustment may be needed with coadministration. Tenofovir disoproxil fumarate is a substrate of breast cancer resistance protein (BCRP) and tafamidis is a BCRP inhibitor.
Tamoxifen: (Moderate) Concomitant use of tamoxifen 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.
Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and efavirenz. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors may increase exposure to tasimelteon with the potential for adverse reactions. Because efavirenz may inhibit or induce CYP3A4, the clinical outcome of this combination is unknown.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with efavirenz as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
Tedizolid: (Moderate) Coadministration of tenofovir disoproxil fumarate with tedizolid may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and tedizolid is a BCRP inhibitor.
Telavancin: (Moderate) Consider alternatives to efavirenz when coadministering with telavancin. QTc prolongation has been observed with the use of efavirenz. Telavancin has been associated with QT prolongation.
Telmisartan; Amlodipine: (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
Temsirolimus: (Moderate) Monitor for an increase in tenofovir disoproxil fumarate-related adverse reactions if coadministration with temsirolimus is necessary. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of tenofovir disoproxil fumarate.
Tepotinib: (Moderate) Coadministration of tenofovir disoproxil fumarate with tepotinib 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 tepotinib is a P-gp inhibitor.
Terbinafine: (Moderate) Caution is advised when administering terbinafine with efavirenz. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C9, CYP2C19, and CYP3A4; efavirenz is inhibitor of CYP2C9 and CYP2C19, and an inhibitor/inducer of CYP3A4. Monitor patients for adverse reactions and breakthrough fungal infections if these drugs are coadministered.
Tetrabenazine: (Major) Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc, such as efavirenz.
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.
Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Thioridazine is considered contraindicated for use along with agents that may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Efavirenz has also been associated with QT prolongation. Because of the potential for QT prolongation and TdP, use of efavirenz with thioridazine is contraindicated.
Ticagrelor: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ticagrelor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Moderate) If possible, avoid use of ticagrelor with efavirenz or efavirenz-containing products (i.e., efavirenz; emtricitabine; tenofovir); coadministration may result in decreased efficacy of ticagrelor, and potentially increased adverse events of efavirenz. Ticagrelor is a substrate and weak inhibitor of CYP3A4/5. Efavirenz has been shown to induce CYP3A in vivo and is partially metabolized by CYP3A4.
Tipranavir: (Moderate) Concurrent administration of tipranavir and ritonavir with tenofovir, results in decreased tipranavir concentrations. The clinical significance of this interaction has not been established, and no recommendations for tenofovir dosage adjustments are available.
Tobramycin: (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.
Tolmetin: (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.
Tolterodine: (Moderate) Consider alternatives to efavirenz when coadministering with tolterodine due to increased risk for QT prolongation. QTc prolongation has been observed with the use of efavirenz. Tolterodine has also been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as tolterodine.
Toremifene: (Major) Avoid coadministration of efavirenz with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Prolongation of the QTc interval has also been observed with the use of efavirenz.
Tramadol: (Moderate) The (+) enantiomer of tramadol preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. Efavirenz is an inducer of CYP3A4 and CYP2B6. Coadministration may affect the metabolism of tramadol leading to altered tramadol exposure. Decreased serum tramadol concentrations and reduced efficacy may occur. In addition, both medications have been associated with the development of seizures; caution is advised.
Tramadol; Acetaminophen: (Moderate) The (+) enantiomer of tramadol preferentially undergoes N-demethylation, which is mediated by CYP3A4 and CYP2B6. Efavirenz is an inducer of CYP3A4 and CYP2B6. Coadministration may affect the metabolism of tramadol leading to altered tramadol exposure. Decreased serum tramadol concentrations and reduced efficacy may occur. In addition, both medications have been associated with the development of seizures; caution is advised. (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Trandolapril; Verapamil: (Moderate) Coadministration of tenofovir disoproxil fumarate with verapamil 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 verapamil is a P-gp inhibitor. (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
Trazodone: (Major) Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval, such as efavirenz. In addition, efavirenz may induce the CYP3A4 metabolism of trazodone; potentially reducing the efficacy of trazodone by decreasing its systemic exposure.
Triclabendazole: (Moderate) Concomitant use of triclabendazole and efavirenz may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
Trifluoperazine: (Minor) Consider alternatives to efavirenz when coadministering with trifluoperazine as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Trifluoperazine is associated with a possible risk for QT prolongation.
Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving efavirenz as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QTc interval has also been observed with the use of efavirenz.
Trospium: (Moderate) Trospium is eliminated by active tubular secretion and has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion including lamivudine. In theory, coadministration of trospium with lamivudine may increase the serum concentrations of trospium or lamivudine due to competition for the drug elimination pathway. (Minor) Both trospium and tenofovir are eliminated by active renal tubular secretion; coadministration has the potential to increase serum concentrations of trospium or tenofovir due to competition for the drug elimination pathway. Careful patient monitoring and dosage adjustment of trospium and/or tenofovir, PMPA is recommended.
Tucatinib: (Moderate) Coadministration of tenofovir disoproxil fumarate with tucatinib 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) substrate and tucatinib is a P-gp inhibitor.
Ubrogepant: (Major) Increase the initial and second dose of ubrogepant to 100 mg if coadministered with efavirenz as concurrent use may decrease ubrogepant exposure and reduce its efficacy. Ubrogepant is a CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer.
Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and efavirenz is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
Valacyclovir: (Moderate) Monitor for changes in serum creatinine and phosphorus if tenofovir disoproxil fumarate is administered in combination with nephrotoxic agents, such as valacyclovir. 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.
Valganciclovir: (Minor) Since tenofovir is primarily eliminated by the kidneys, concurrent administration of tenofovir disoproxil with valganciclovir may increase serum concentrations of tenofovir via competition for renal tubular secretion.
Valoctocogene Roxaparvovec: (Major) Avoid concomitant use of efavirenz and valoctocogene roxaparvovec. Concomitant use may cause elevations in hepatic function tests and decrease factor VIII activity.
Vancomycin: (Moderate) Tenofovir should be avoided with concurrent or recent use of a nephrotoxic agent, such as vancomycin. Patients receiving these drugs together should be carefully monitored for changes in serum creatinine and phosphorus. Renal impairment, which may include hypophosphatemia, has been reported with the use of tenofovir; a majority of cases occurring in patients who have underlying systemic or renal disease or who are concurrently taking nephrotoxic agents.
Vandetanib: (Major) Avoid coadministration of vandetanib with efavirenz due to an increased risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Prolongation of the QTc interval has also been observed with the use of efavirenz.
Vardenafil: (Moderate) Concomitant use of vardenafil 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.
Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. ECG monitoring is recommended if vemurafenib and another QT prolonging drug, such as efavirenz, must be coadministered; closely monitor the patient for QT interval prolongation. In addition, concomitant use may result in decreased vemurafenib and efavirenz concentrations. Both drugs are substrates and inducers of CYP3A4. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as vemurafenib. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
Venetoclax: (Major) Avoid the concomitant use of venetoclax and efavirenz; venetoclax levels may be decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Consider alternative agents. In a drug interaction study (n = 11), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer. Use of venetoclax with a moderate CYP3A4 inducer has not been evaluated.
Venlafaxine: (Moderate) Concomitant use of venlafaxine 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.
Verapamil: (Moderate) Coadministration of tenofovir disoproxil fumarate with verapamil 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 verapamil is a P-gp inhibitor. (Moderate) Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
Voclosporin: (Major) Avoid coadministration of voclosporin with efavirenz. Coadministration may decrease voclosporin exposure resulting in decreased efficacy. Concomitant use may also increase the risk of QT prolongation. Voclosporin is a sensitive CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease voclosporin exposure by 70%. (Moderate) Coadministration of tenofovir disoproxil fumarate and voclosporin may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Concomitant use may also may result in additive nephrotoxicity. Monitor for renal toxicity if concomitant use is required. Tenofovir disoproxil fumarate is a P-gp substrate and voclosporin is a P-gp inhibitor.
Vonoprazan: (Major) Avoid concomitant use of vonoprazan and efavirenz due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of vonoprazan and efavirenz due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of vonoprazan and efavirenz due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) The manufacturer of efavirenz recommends that alternatives to clarithromycin be considered when a macrolide antibiotic is required in patients receiving efavirenz. Coadministration of efavirenz and clarithromycin may increase the risk for QT prolongation and torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and torsades de pointes TdP. QT prolongation has also been observed with use of efavirenz. In addition, concurrent use of efavirenz with clarithromycin 500 mg PO every 12 hours for seven days resulted in a significant decrease in the serum concentration of clarithromycin, but the clinical significance of this is not known. (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.
Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and efavirenz. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with efavirenz, a CYP3A inducer.
Voriconazole: (Major) Coadministration of standard doses of voriconazole and efavirenz (400 mg PO daily or higher) is contraindicated. If efavirenz and voriconazole must be coadministered, dosage adjustments of both drugs are required. During coadministration, increase the voriconazole maintenance dose to 400 mg PO every 12 hours and decrease the efavirenz dose to 300 mg PO once daily, using the capsule formulation; efavirenz tablets should not be broken. When coadministered, efavirenz (400 mg PO daily) significantly decreased the steady state Cmax and AUC of voriconazole by 61% and 77%, respectively and voriconazole significantly increased the steady state Cmax and AUC of efavirenz by 38% and 44%, respectively. If administered at standard doses, this would pose the risk of voriconazole therapeutic failure and increased efavirenz-related toxicities. In addition, concurrent use may increase the risk for QT prolongation. Voriconazole has been associated with QT prolongation and rare cases of torsade de pointes. QT prolongation has also been observed during use of efavirenz.
Vorinostat: (Moderate) Consider alternatives to efavirenz when coadministering with vorinostat as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. Vorinostat therapy is associated with a risk of QT prolongation.
Voxelotor: (Major) Avoid coadministration of voxelotor and efavirenz as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. If coadministration is unavoidable, increase voxelotor dosage to 2,000 mg PO once daily in patients 12 years and older. In patients 4 to 11 years old, weight-based dosage adjustments are recommended; consult product labeling for specific recommendations. Voxelotor is a substrate of CYP3A; efavirenz is a moderate CYP3A inducer. Coadministration of voxelotor with a moderate CYP3A inducer is predicted to decrease voxelotor exposure by up to 24%.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with efavirenz is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Efavirenz is a moderate CYP2C9 inhibitor and warfarin is a CYP2C9 substrate. Additionally, efavirenz is a moderate CYP3A4 inducer and warfarin is a CYP3A4 substrate.
Zanubrutinib: (Major) Avoid concurrent use of zanubrutinib and efavirenz due to the risk of decreased zanubrutinib exposure which may reduce its efficacy. If concomitant use is necessary, increase the zanubrutinib dose to 320 mg twice daily and monitor response. Resume the previous dose of zanubrutinib if efavirenz is discontinued. Zanubrutinib is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Concomitant use with efavirenz is predicted to decrease zanubrutinib exposure by 60%. Concomitant use with another moderate CYP3A inducer decreased zanubrutinib exposure by 44%.
Ziprasidone: (Major) Concomitant use of ziprasidone and efavirenz should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. QTc prolongation has been observed with the use of efavirenz. Consider alternatives to efavirenz when coadministering with a drug with a known risk of TdP.
Zoledronic Acid: (Moderate) Tenofovir-containing products should be avoided with concurrent or recent use of a nephrotoxic agent, such as zoledronic acid. 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.
Zolpidem: (Moderate) It is advisable to closely monitor for reductions in zolpidem efficacy during co-administration of moderate CYP3A4 inducers, such as efavirenz. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of significant decreases in systemic exposure and pharmacodynamic effects of zolpidem during co-administration of rifampin, a potent CYP3A4 inducer.
Zonisamide: (Minor) Caution is advised when administering tenofovir disoproxil fumarate concurrently with zonisamide, as coadministration may result in elevated tenofovir plasma concentrations. Inhibitors of the drug transporter P-glycoprotein (P-gp), such as zonisamide, may increase absorption of tenofovir, a P-gp substrate. If these medications are administered together, monitor for tenofovir-associated adverse reactions.
Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRT), lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI), and tenofovir disoproxil fumarate is a nucleotide reverse transcriptase inhibitor (although sometimes classified with the NRTIs). Combination therapy targets different points in the life cycle of HIV, reducing viral capacity to mutate to drug-resistant strains.
Efavirenz: As an NNRTI of HIV-1, efavirenz binds directly to a site on reverse transcriptase that is near, but distinct from, where NRTIs bind. This binding causes disruption of the enzyme's active site, thereby blocking RNA-dependent and DNA-dependent DNA polymerase activities. Activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. Efavirenz is not active against HIV-2 reverse transcriptase.
Resistance to efavirenz has been identified in clinical isolates with one or more of the following reverse transcriptase substitutions: A98, L100, K101, K103, V106, V108, Y188, G190, P225, F227, and M230. The amino acid substitutions most frequently observed in patients failing treatment with efavirenz is K103. Cross-resistance has been observed among NNRTIs. Clinical isolates identified as efavirenz-resistance are also phenotypically resistant in cell culture to delavirdine and nevirapine.
Avoid the use of efavirenz-containing medications in patients with HIV-2, as HIV-2 is intrinsically resistant to NNRTIs. To identify the HIV strain, The Centers for Disease Control and Prevention guidelines for HIV diagnostic testing recommend initial HIV testing using an HIV-1/HIV-2 antigen/antibody combination immunoassay and subsequent testing using an HIV-1/HIV-2 antibody differentiation immunoassay.
Lamivudine: Lamivudine inhibits viral reverse transcriptase in both HIV-1 and HBV. When used in combination with efavirenz and tenofovir, it is used specifically for its activity against HIV. Lamivudine is a synthetic nucleoside analog of cytosine and is phosphorylated by cellular enzymes to its active 5'-triphosphate metabolite, lamivudine triphosphate. Lamivudine triphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA, resulting in chain termination.
HIV-1 resistance to lamivudine is predominately due to methionine to valine or isoleucine (M184V/I) substitution in reverse transcriptase. Cross-resistance is expected with abacavir, didanosine, and emtricitabine.
Tenofovir disoproxil fumarate: Tenofovir inhibits viral reverse transcriptase in both HIV-1 and HBV. Tenofovir disoproxil fumarate (tenofovir DF) is an acyclic nucleoside phosphonate (nucleotide) diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir. Tenofovir is then taken up by cells and undergoes phosphorylation to form tenofovir diphosphate (PMPApp). Tenofovir diphosphate competes with the natural substrate deoxyadenosine 5'-triphosphate (dATP) for incorporation into the DNA. Once incorporated, tenofovir diphosphate, which lacks a 3' hydroxyl group, causes premature DNA chain termination.
HIV-1 isolates that express a K65R amino acid substitutions in reverse transcriptase show a 2- to 4-fold reduction in the susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in reduced susceptibility. The K70E substitution selected clinically by tenofovir results in reduced susceptibility to abacavir, didanosine, emtricitabine, and lamivudine. HIV-1 isolates with the K65R substitution also show reduced susceptibility to lamivudine and emtricitabine.
Efavirenz; lamivudine; tenofovir is administered orally.
Efavirenz: Efavirenz is highly protein bound (99.5% to 99.7%), predominantly to albumin. The major metabolic pathways are via CYP3A and CYP2B6 to hydroxylated metabolites, with subsequent glucuronidation. Efavirenz has a terminal half-life of 52 to 76 hours after a single dose and 40 to 55 hours after multiple doses. Approximately 14% to 34% of radiolabeled efavirenz dose is excreted in the urine (mostly metabolites) and 16% to 61% is eliminated in the feces (mostly parent drug).
Lamivudine: Lamivudine is extensively distributed, and exhibits low plasma protein binding (less than 36%). Metabolism is a minor elimination route, with approximately 5% of the dose being excreted in the urine as the trans-sulfoxide metabolite within 12 hours post-dose. The majority of the dose (70%) is eliminated unchanged in the urine by active organic cationic secretion. The observed mean elimination half-life ranges from 5 to 7 hours.
Tenofovir disoproxil fumarate: Protein binding of tenofovir is negligible (less than 0.7%) and binding is independent of concentration over the range of 0.01 to 25 mcg/mL. Intracellularly, tenofovir undergoes phosphorylation to its active metabolite, tenofovir diphosphate (PMPApp). Tenofovir and tenofovir diphosphate have a prolonged intracellular half-life (15 to 50 hours). In vitro studies indicate that neither tenofovir disoproxil fumarate nor tenofovir are substrates of cytochrome P450 enzymes. Approximately 70% to 80% of the dose is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active renal tubular secretion; there may be competition for elimination with other compounds that are also renally eliminated. The terminal elimination half-life is approximately 17 hours.
Affected cytochrome P450 isoenzymes and transporters: CYP3A, CYP2B6, CYP2C9, CYP2C19, P-gp, BRCP
In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A and CYP2B6. In addition, efavirenz inhibits CYP2C9, CYP2C19, and CYP3A4 in vitro. Efavirenz is metabolized via CYP3A and CYP2B6. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. Administration with inhibitors of these transporters may result in increased absorption of tenofovir.
-Route-Specific Pharmacokinetics
Oral Route
Administration of efavirenz; lamivudine; tenofovir disoproxil fumarate has not been evaluated with food.
-Efavirenz: Peak plasma concentrations are achieved 3 to 5 hours after administration of a single dose with steady-state plasma concentrations reached in 6 to 10 days.
-Lamivudine: Following oral administration, lamivudine is rapidly absorbed with an absolute bioavailability of approximately 86%. Drug exposure (AUC) and the maximum plasma concentration (Cmax) increase in proportion to the dose over a range from 0.25 to 10 mg/kg.
-Tenofovir disoproxil fumarate: The bioavailability in a fasting state is 25%; when given with either a high fat or light meal, tenofovir AUC and Cmax increase by 35% and 15%, respectively.
-Special Populations
Hepatic Impairment
-Efavirenz: Significant effects on efavirenz pharmacokinetics were not observed in patients with mild hepatic impairment (Child-Pugh Class A); data were insufficient to determine if moderate and severe hepatic impairment (Child-Pugh B and C) impact efavirenz pharmacokinetics.
-Lamivudine: Lamivudine pharmacokinetic parameters are not altered by diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated hepatic disease.
-Tenofovir disoproxil fumarate: No substantial pharmacokinetic changes have been noted following tenofovir disoproxil fumarate administration in patients with moderate to severe hepatic impairment (Child-Pugh B and C).
Renal Impairment
-Efavirenz: Efavirenz pharmacokinetic parameters have not been studied in patients with renal impairment.
-Lamivudine: The pharmacokinetic parameters of lamivudine are altered in patients with renal impairment. A single dose study involving patients with varying degrees of renal dysfunction, found patients with moderate and severe renal impairment had significant increases in lamivudine exposure (AUC) and maximum plasma concentration (Cmax) when compared to patients with normal renal function.
-Tenofovir disoproxil fumarate: The pharmacokinetic parameters of tenofovir disoproxil fumarate are altered in patients with renal impairment. A single dose study involving patients with varying degrees of renal dysfunction, found patients with CrCl less than 50 mL/min or with end-stage renal disease requiring dialysis had increases in tenofovir exposure (AUC) and maximum plasma concentration (Cmax) when compared to patients with normal renal function.
Ethnic Differences
Published literature have reported higher plasma concentrations in patients of African and Asian descent, as well as Latino patients, compared to White patients. Studies evaluating these racial differences attribute the elevated concentrations to single nucleotide polymorphisms (SNP) in CYP2B6, the enzyme primarily responsible for efavirenz metabolism. Patients with the SNP experience reduced CYP2B6 activity resulting in impaired efavirenz metabolism and elevated plasma concentrations. In a study evaluating the pharmacokinetics of efavirenz in 58 health subjects with CYP2B6 polymorphisms, the mean Cmax was found to be 2.25-fold higher in subjects with the CYP2B6 *6/*6 genotype than in those with the CYP2B6 *1/*1 genotype.
Other
Pregnancy
-Efavirenz: Pregnancy does not significantly alter systemic concentrations (AUC) of efavirenz; however, the efavirenz geographic mean trough concentration (Cmin) is 24% lower during the 3rd trimester as compared to postpartum (1.6 versus 2.05 mcg/mL; p = 0.01). Despite these lower values, the Cmin for most women (88%) still exceeds the minimum target concentration associated with virologic efficacy (1 mcg/mL). No dosage adjustments are necessary. There is moderate placental transfer to the fetus.
-Lamivudine: Although population pharmacokinetic modeling suggests the oral clearance of lamivudine is increased by 22% during pregnancy, limited data from 2 studies involving 36 pregnant women (16 at 36 weeks, 20 at 38 weeks gestation) found the pharmacokinetic parameters of lamivudine to be similar to those observed in non-pregnant and postpartum adults. No change in dose is indicated. Also, placental transfer of lamivudine results in amniotic fluid drug concentrations that are 3.9 (1.2 to 12.8)-fold greater than maternal serum concentrations.
-Tenofovir: Pregnancy alters the pharmacokinetic parameters of tenofovir. In one study, a 30% increase in the clearance of tenofovir was observed in 34 HIV-infected pregnant women. In addition, the drug exposure (AUC), peak (Cmax), and trough (Cmin) obtained during the 3rd trimester were 23% (p < 0.001), 19% (p = 0.001) and 21% (p = 0.003) lower, respectively, than those obtained postpartum. Despite these reductions, most women maintain a therapeutic AUC of at least 2 mg x hr/L throughout pregnancy; thus, dosage adjustments are not required. Changes in the pharmacokinetics of tenofovir are theorized to be a result of increased renal clearance, expanded plasma volume, and reduced gastrointestinal absorption. Tenofovir has a high placental transfer to the fetus.