CLASSES

Non-Nucleoside Reverse Transcriptase Inhibitors/NNRTIs

DEA CLASS

Rx

DESCRIPTION

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

COMMON BRAND NAMES

Sustiva

HOW SUPPLIED

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

DOSAGE & INDICATIONS

†Indicates off-label use

MAXIMUM DOSAGE

600 mg/day PO.

600 mg/day PO.

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

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

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

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

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

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

ADMINISTRATION

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

STORAGE

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

CONTRAINDICATIONS / PRECAUTIONS

Unplanned antiretroviral therapy interruption may be necessary in 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., < 1—2 days) is necessary, in general it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of 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. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine range from < 1 week to > 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. 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 women during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. In treatment-naive women, consider initiation of HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations are greater than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations are greater than 500 copies/mL. Consider initiating treatment prior to receiving resistance test results. Avoid use of efavirenz during the first trimester (particular caution during first 8 weeks of pregnancy) and in females of child-bearing potential. Data from the Antiretroviral Pregnancy Registry indicates the prevalence of birth defects following first trimester exposure to efavirenz is 2.3% (20 of 852 births; 95% CI: 1.4, 3.6). A subsequent meta-analysis of 23 studies (including Antiretroviral Pregnancy Registry data) found first trimester exposure to efavirenz to be associated with 44 birth defects among 2,026 births (1.63%; 95% CI: 0.78, 2.48). Specifically, prospectively reported defects associated with efavirenz included one neural tube defect (sacral aplasia, myelomeningocele, hydrocephalus with fetal alcohol syndrome) and a separate single case of anophthalmia, which also included severe oblique facial clefts and amniotic banding. There have also been 6 retrospective reports of findings consistent with neural tube defects, including meningomyelocele, in which all mothers were exposed to efavirenz containing regimens in the first-trimester. Although the incidence of overall birth defects does not differ from the background rate among pregnant women in the US (2.7%), the low prevalence of neural tube defects among the general population means more exposure data are required to definitively rule out an associated between neural tube defects and efavirenz. Because of the potential for teratogenicity and the known failure rates of contraception in general, regimens that contain efavirenz should be avoided in women of child-bearing potential. Due to the long half-life of efavirenz, the manufacturer recommends the use of contraceptive measures for 12 weeks after discontinuation of efavirenz. If efavirenz must be used, patients should undergo pregnancy testing prior to initiation and be counseled on the risks to the fetus and the importance of prevention of pregnancy. In particular, treatment with efavirenz should be avoided during the first 8 weeks of pregnancy, which is the primary period of fetal organogenesis. Use after the second trimester of pregnancy can be considered if other alternatives are not available and if adequate contraception can be assured postpartum. Barrier contraception should always be used, and it should be noted that efavirenz, and other non-nucleoside reverse transcriptase inhibitors as well as protease inhibitors, may affect estrogen and norethindrone blood concentrations in women receiving oral contraceptives. If a woman becomes pregnant while taking this drug, and the fetus is thus exposed to efavirenz during the first trimester, thoroughly counsel the woman regarding the potential harm to the fetus. However, because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy and pregnancy is rarely recognized before 4 to 6 weeks of pregnancy, efavirenz can be continued in pregnant women receiving an efavirenz based regimen who presents for antenatal care in the first trimester if the regimen provided virologic suppression. Additionally, second trimester ultrasound to assess fetal anatomy may be prudent in women who received efavirenz during the first trimester. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit and at least every 3 months during pregnancy; consideration may be given to monitoring every 6 months in patients on HAART with consistently suppressed viral loads and a CD4 count well above the opportunistic infection threshold. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing) at baseline in all women with HIV RNA concentrations greater than 1,000 copies/mL; testing should also be considered for HIV RNA greater than 500 but less than 1,000 copies/mL. First trimester ultrasound is recommended to confirm gestational age and provide accurate estimation of gestational age at deliver. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in women receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. If a woman decides to discontinue therapy, a planned treatment interruption, taking into account the specific pharmacokinetic and administration parameters of each drug, should occur to avoid true or functional monotherapy and the development of resistance. It is strongly recommended that health care providers who are treating HIV-infected pregnant women and their neonates report cases of prenatal exposure to antiretroviral drugs to the Antiretroviral Pregnancy Registry; telephone 800-258-4263; fax 800-800-1052; the Antiretroviral Pregnancy Registry is also accessible via the Internet.

To reduce the risk of postnatal transmission, HIV-infected mothers within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy, including efavirenz. Efavirenz has been shown to pass into human breast milk. One study found efavirenz plasma concentrations in breast-fed infants (taken 3 to 4 hours after last dose) to be 13.1% of maternal plasma concentrations; the mean infant plasma concentrations were below those considered effective for HIV treatment in adults. Other antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.

Monitoring of liver enzymes prior to and during treatment with efavirenz is recommended for patients with underlying hepatic disease, including those with elevated transaminases, a known or suspected history of hepatitis, and patients receiving concurrent treatment with other hepatotoxic drugs. Further, give consideration to monitoring liver enzymes in all patients receiving efavirenz as there have been postmarketing reports of hepatic failure, including progression to transplant or death, in patients with no preexisting hepatic disease or other identifiable risk factors. In patients with persistent elevations of serum transaminases to greater than 5-times the upper limit of normal, the benefit of continued therapy with efavirenz must be weighed against the unknown risks of significant liver toxicity. Because of the significant hepatic metabolism of efavirenz and limited clinical experience in patients with hepatic disease, caution should be exercised in administering efavirenz to these patients. 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). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of emtricitabine; 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 higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still require treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

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

A majority of patients receiving efavirenz experience CNS side effects, described by some patients as 'feeling stoned'. Inform patients that these symptoms may occur and will likely spontaneously remit after a few months of therapy. Patients should avoid driving or operating machinery until they know how efavirenz may affect them. Some patients may have difficulty concentrating. In addition, ethanol or other psychoactive drugs may worsen these symptoms. Serious psychiatric adverse events, including severe depression, suicidal ideation, nonfatal suicide attempts, death by suicide, aggressive behavior, delusions and psychosis-like behavior, neurosis, paranoid reactions, catatonic reactions, and manic reactions, have been associated with efavirenz. Patients with a history of mental illness (e.g., bipolar disorder, depression, mania, or psychosis), alcoholism, or substance abuse may be at increased risk for CNS adverse events including psychiatric adverse events.

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

Testing for HIV antimicrobial resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform antimicrobial resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. In the US and Europe, current studies suggest that 6% to 16% of transmitted virus will be resistant to at least one antiretroviral drug, with 3% to 5% exhibiting reduced susceptibility to more than one class of drugs; therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. As with all other antiretroviral agents, antimicrobial resistance can develop when efavirenz is used either alone or in combination with other agents. Monotherapy with efavirenz is not recommended. Cross-resistance between reverse transcriptase inhibitors and protease inhibitors is unlikely because different enzyme targets are involved. In patients whom a planned discontinuation or interruption of efavirenz therapy is planned, there is an increased risk of NNRTI-resistant mutations. Pharmacokinetic data demonstrate the persistence of detectable drug levels for at least 21 days after discontinuation of efavirenz; simultaneously stopping all drugs in a regimen containing efavirenz may result in functional efavirenz monotherapy due to its long half-life. This is further complicated by evidence that certain genetic polymorphisms, more common among some ethnic groups (such as in African 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 between stopping efavirenz and other antiretroviral drugs is not known. An alternative strategy is to substitute the efavirenz with a PI prior to interruption of all antiretroviral drugs; if this strategy is used, the goal is to assure that the PI used also achieves complete viral suppression during this interval. Further research to determine the best approach to temporarily discontinuing efavirenz is needed.

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

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

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

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

ADVERSE REACTIONS

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

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

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

DRUG INTERACTIONS

Abacavir; Dolutegravir; Lamivudine: 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 patients or treatment-experienced but INSTI-naive patients who weigh at least 40 kg, the dose of dolutegravir should be increased to 50 mg PO twice daily when administered with efavirenz. For pediatric patients weighing 30 to 39 kg, increase the dose of dolutegravir to 35 mg PO twice daily if administered concurrently with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Predictions regarding this interaction can be made based on the drugs metabolic pathways. Efavirenz is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Acetaminophen: 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: 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; Butalbital: 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; Butalbital; Caffeine: 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; Butalbital; Caffeine; Codeine: 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: Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: 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: 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: Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: 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: 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: 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: 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: 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: 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: Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Dichloralphenazone; Isometheptene: 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: 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: 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: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz. 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: Oxycodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of oxycodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone. If coadministration of these agents is necessary, monitor patients at frequent intervals and consider dose adjustments if needed. Similarly, an interaction may occur if efavirenz; emtricitabine; tenofovir and oxycodone are coadministered. Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Pentazocine: Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
Acetaminophen; Propoxyphene: 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: 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; Tramadol: 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. 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.
Adefovir: 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).
Albuterol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Albuterol; Ipratropium: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Alfentanil: Efavirenz induces CYP3A4 and may decrease serum concentrations of other drugs metabolized by this enzyme, such as alfentanil.
Alfuzosin: Although data are limited, coadministration of efavirenz and alfuzosin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. A slight prolonging effect on the QT interval has also been observed during alfuzosin electrophysiology studies. Alfuzosin-induced QT prolongation appears to be less with 10 mg than with 40 mg. In addition, efavirenz may induce the CYP3A4 metabolism of alfuzosin, potentially reducing the efficacy of alfuzosin by decreasing its systemic exposure.
Aliskiren; Amlodipine: 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.
Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: 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.
Alprazolam: 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.
Ambrisentan: In vitro studies indicate ambrisentan is a substrate of CYP2C19, yet in vivo studies with omeprazole, a CYP2C19 inhibitor, did not demonstrate a clinically significant drug-drug interaction. Although data are lacking, significant CYP2C19 inhibitors, such as efavirenz, could potentially increase ambrisentan plasma concentrations via CYP2C19 inhibition. Monitor for increased toxicity as well as increased therapeutic effect during times of coadministration.
Amiodarone: If possible, avoid coadministration of efavirenz and amiodarone, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as amiodarone. It would be prudent to monitor for changes in amiodarone efficacy.
Amitriptyline: Although data are limited, coadministration of efavirenz and tricyclic antidepressants may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Amitriptyline; Chlordiazepoxide: Although data are limited, coadministration of efavirenz and tricyclic antidepressants may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). 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.
Amlodipine: 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.
Amlodipine; Atorvastatin: 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. 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.
Amlodipine; Benazepril: 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.
Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: 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.
Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: 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.
Amlodipine; Olmesartan: 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.
Amlodipine; Telmisartan: 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.
Amlodipine; Valsartan: 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.
Amoxicillin; Clarithromycin; Lansoprazole: 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.
Amoxicillin; Clarithromycin; Omeprazole: 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. Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C9 or CYP2C19.
Amprenavir: When amprenavir was coadministered with efavirenz, the systemic exposure AUC and Cmax of amprenavir were decreased by 36% and 43%, respectively. However, the clinical significance of this interaction has not been established.
Anagrelide: 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.
Apomorphine: Although data are limited, coadministration of efavirenz and apomorphine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Limited data indicate that QT prolongation is also possible with apomorphine; however, the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines. Doses 6 mg or less SC are associated with minimal increases in QTc; doses greater than 6 mg SC do not provide additional clinical benefit and are not recommended.
Aprepitant, Fosaprepitant: 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.
Arformoterol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval, such as efavirenz. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Aripiprazole: Although data are limited, coadministration of efavirenz and aripiprazole may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. QT prolongation has also 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 during use of a mild to moderate CYP3A4 inducer.
Arsenic Trioxide: 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: If possible, avoid coadministration of efavirenz and artemether; lumefantrine, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Artemether; lumefantrine is also associated with prolongation of the QT interval. Although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation and should be avoided. Consider ECG monitoring if efavirenz must be used with or after artemether; lumefantrine treatment. In addition, coadministration may decrease concentrations of artemether; lumefantrine and/or dihydroartemisinin (active metabolite of artemether). The antimalarial efficacy of artemether; lumefantrine may be decreased. In a drug interaction study, when artemether; lumefantrine was co-administered with efavirenz, the Cmax and AUC of artemether; lumefantrine decreased by 21% and 51%, respectively. If these drugs are co-administered, monitor for decreased antimalarial efficacy of artemether; lumefantrine.
Asenapine: 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; Carisoprodol: Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as efavirenz, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Aspirin, ASA; Carisoprodol; Codeine: Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as efavirenz, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Aspirin, ASA; Omeprazole: Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C9 or CYP2C19.
Aspirin, ASA; Oxycodone: Oxycodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of oxycodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone. If coadministration of these agents is necessary, monitor patients at frequent intervals and consider dose adjustments if needed. Similarly, an interaction may occur if efavirenz; emtricitabine; tenofovir and oxycodone are coadministered.
Atazanavir: Due to induction of the CYP3A4 isoenzyme by efavirenz, coadministration results in significantly decreased atazanavir AUC and Cmin. Do not coadminister these drugs to treatment-experienced patients. Coadministration is acceptable in treatment-naive patients weighing at least40 kg as a regimen of atazanavir 400 mg with ritonavir 100 mg given once daily with food and efavirenz 600 mg given once daily on an empty stomach.
Atazanavir; Cobicistat: 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. Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and daruanavir and atazanavir are CYP3A4 substrates.
Atomoxetine: Although data are limited, coadministration of efavirenz and atomoxetine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. QT prolongation has also occurred during therapeutic use of atomoxetine and following overdose.
Atorvastatin: Efavirenz has the potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with atorvastatin with caution.
Atorvastatin; Ezetimibe: 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: 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: 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.
Avanafil: 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.
Axitinib: 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 primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Efavirenz is a moderate CYP3A4 inducer. Efavirenz decreased the Cmax and AUC of another CYP3A4 substrate, simvastatin, by 72% and 68%, respectively. Coadministration with a strong CYP3A4/5 inducer, rifampin, significantly decreased the plasma exposure of axitinib in healthy volunteers. Efavirenz is also a CYP2C19 inhibitor in vitro, which theoretically could increase exposure to axitinib; however, the effects of efavirenz on CYP2C19 are not expected to overcome its effects on CYP3A4, as CYP3A4 is the major route of metabolism for axitinib.
Azithromycin: According to the manufacturer, clinically significant interactions are not expected with efavirenz and azithromycin. However, 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. There have also been case reports of QT prolongation and TdP with the use of azithromycin in postmarketing reports.
Barbiturates: 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: 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.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: Although data are limited, coadministration of efavirenz and metronidazole may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Potential QT prolongation has also been reported in limited case reports with metronidazole.
Bismuth Subsalicylate; Metronidazole; Tetracycline: Although data are limited, coadministration of efavirenz and metronidazole may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Potential QT prolongation has also been reported in limited case reports with metronidazole.
Boceprevir: Avoid concurrent administration of efavirenz and boceprevir, as use of these drugs together may result in hepatitis C treatment failures and efavirenz-related adverse events. When administered in combination, the mean plasma concentration (AUC) of boceprevir was deceased by 19%, and the mean AUC of efavirenz was increased by 20%. Predictions about the interaction can be made based on the metabolic pathways of efavirenz and boceprevir. Efavirenz is an inducer and substrate of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor and substrate of this isoenzyme.
Bortezomib: Agents that induce CYP3A4, such as efavirenz, may decrease the exposure to bortezomib and possibly decrease the efficacy of the drug; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of a potential interaction resulting from the concurrent administration of bortezomib with efavirenz is not known.
Bosentan: 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.
Bosutinib: Avoid concomitant use of bosutinib, a CYP3A4 substrate, with a moderate CYP3A4 inducer such as efavirenz, as a decrease in bosutinib plasma exposure may occur.
Brentuximab vedotin: 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: 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: Monitor for decreased efficacy of efavirenz if coadministration is necessary. Efavirenz is a CYP3A4 substrate; brigatinib induces CYP3A4. Drugs that induce CYP3A activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations.
Bromocriptine: Caution and close monitoring are advised if bromocriptine and efavirenz are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; efavirenz is a moderate inducer of CYP3A4.
Brompheniramine; Guaifenesin; Hydrocodone: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Brompheniramine; Hydrocodone; Pseudoephedrine: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Budesonide; Formoterol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval, such as efavirenz. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Bupivacaine; Lidocaine: 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).
Buprenorphine: 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: 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: 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: 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: 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.
Cabozantinib: Monitor for decreased efficacy of cabozantinib if concomitant use of cabozantinib and efavirenz is necessary. Cabozantinib is primarily metabolized by CYP3A4 and efavirenz is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), decreased cabozantinib (single dose) exposure by 77%. The manufacturer of cabozantinib recommends a dose increase when used with strong CYP3A4 inducers; however, recommendations are not available for concomitant use with a moderate inducer of CYP3A4.
Carbamazepine: Concomitant use of carbamazepine and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) is contraindicated. Carbamazepine substantially reduces the serum concentrations of NNRTIs, and thus coadministration may result in a loss of virologic response and possible resistance to the NNRTI. Carbamazepine induces the CYP3A4-mediated metabolism of NNRTIs, markedly decreasing the NNRTI concentration. In addition, efavirenz may induce the CYP metabolism of carbamazepine, resulting in decreased carbamazepine concentrations. A decrease in AUC was seen for both carbamazepine (27%) and efavirenz (36%) when coadministered.
Carbinoxamine; Hydrocodone; Phenylephrine: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Carbinoxamine; Hydrocodone; Pseudoephedrine: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Cariprazine: 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: Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as efavirenz, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
Caspofungin: 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: 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: Although data are limited, coadministration of efavirenz and ceritinib may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Concentration-dependent QT prolongation has also been reported with ceritinib. In addition, efavirenz is a CYP3A4 substrate and inducer, while ceritinib is a CYP3A4 substrate and inhibitor. Coadministration may increase the systemic concentrations of efavirenz and decrease the concentrations of ceritinib.
Cevimeline: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as cevimeline.
Chlordiazepoxide: 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: 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: If possible, avoid coadministration of efavirenz and chloroquine, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). Chloroquine administration is associated with an increased risk of QT prolongation and TdP and the manufacturer recommends avoiding use with other drugs that prolong the QT interval when possible. QT prolongation has also been observed with use of efavirenz. In addition, efavirenz may induce the CYP3A4 metabolism of chloroquine, potentially reducing the efficacy of chloroquine by decreasing its systemic exposure.
Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Chlorpheniramine; Hydrocodone: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Chlorpheniramine; Hydrocodone; Phenylephrine: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Chlorpheniramine; Hydrocodone; Pseudoephedrine: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Chlorpromazine: If possible, avoid coadministration of efavirenz and chlorpromazine, as use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP.
Cilostazol: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as cilostazol.
Ciprofloxacin: Coadministration of efavirenz and ciprofloxacin may increase the risk for QT prolongation and torsades 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. Rare cases of QT prolongation and TdP have been reported with ciprofloxacin during post-marketing surveillance.
Cisapride: QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. QT prolongation has also been observed with efavirenz. Because of the potential for QT prolongation and TdP, use of efavirenz with cisapride is contraindicated.
Citalopram: 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: 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.
Clindamycin: Concomitant use of clindamycin and efavirenz may increase clindamycin clearance and result in loss of efficacy of clindamycin. Clindamycin is a CYP3A4 substrate; efavirenz is a moderate inducer of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
Clobazam: 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., clobazam). Monitor patients closely for excessive side effects.
Clomipramine: Although data are limited, coadministration of efavirenz and tricyclic antidepressants may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Clonazepam: 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: 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: If possible, avoid coadministration of efavirenz and clozapine, 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. Clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. In addition, efavirenz is a substrate and inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. According to the manufacturer, patients receiving clozapine in combination with a weak to moderate CYP3A4 inducer should be monitored for loss of effectiveness. Consideration should be given to increasing the clozapine dose if necessary.
Cobicistat: Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and daruanavir and atazanavir are CYP3A4 substrates.
Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: 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. Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and daruanavir and atazanavir are CYP3A4 substrates.
Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: 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. Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and daruanavir and atazanavir are CYP3A4 substrates.
Cobimetinib: 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; Phenylephrine; Promethazine: Although data are limited, coadministration of efavirenz and promethazine may increase the risk for QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
Codeine; Promethazine: Although data are limited, coadministration of efavirenz and promethazine may increase the risk for QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
Conivaptan: Conivaptan is a potent CYP3A4 inhibitor with potential to reduce the metabolism of efavirenz. In addition, efavirenz has potential to induce CYP3A4 isoenzymes, which could increase the metabolism of conivaptan, a sensitive CYP3A4 substrate. Although this potential interaction has not been studied, coadminister these drugs with caution.
Conjugated Estrogens: 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: 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: 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: Consider alternatives to therapy if coadministration of efavirenz with crizotinib is necessary, due to the risk of QT prolongation and torsade de pointes (TdP). If avoidance is not possible, monitor ECGs for QT prolongation and monitor electrolytes. Decreased plasma concentrations of crizotinib and increased concentrations of efavirenz may also occur; monitor for changes in efficacy and toxicity profiles. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if the QTc interval is prolonged 500 msec or more or greater than 60 msec change from baseline. QTc prolongation has been observed with the use of efavirenz; crizotinib has also been associated with QT prolongation. Additionally, crizotinib is primarily metabolized by CYP3A4/5 and efavirenz is a moderate CYP3A4 inducer. Coadministration of a crizotinib with a strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively; concomitant use with a moderate CYP3A4 inducer may also decrease crizotinib exposure. Finally, crizotinib is a moderate CYP3A4 inhibitor and efavirenz is a CYP3A4 substrate. Coadministration with crizotinib increased the AUC of another sensitive CYP3A4 substrate by 3.7-fold; exposure to efavirenz may also increase.
Cyclobenzaprine: Although data are limited, coadministration of efavirenz and cyclobenzaprine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Cyclobenzaprine is also associated with a possible risk of QT prolongation and TdP, particularly in the event of acute overdose. In addition, efavirenz may induce the CYP3A4 metabolism of cyclobenzaprine, potentially reducing the efficacy of cyclobenzaprine by decreasing its systemic exposure.
Cyclophosphamide: Use caution if cyclophosphamide is used concomitantly with efavirenz, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Efavirenz is a moderate CYP2B6 and 3A4 inducer, as well as a moderate in vitro inhibitor of CYP2C9 and 2C19; conversion of cyclophosphamide to its active or toxic metabolites may be affected. It is not yet clear what effects CYP2C9 or 2C19 inhibitors, or CYP450 inducers, have on the activation and/or toxicity of cyclophosphamide.
Cyclosporine: 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: The dose of daclatasvir, a CYP3A4 substrate, must be increased to 90 mg PO once daily when administered in combination with moderate CYP3A4 inducers, such as efavirenz. Taking these drugs together may decrease daclatasvir serum concentrations, potentially resulting in reduced antiviral efficacy and antimicrobial resistance.
Dapsone: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as dapsone.
Darifenacin: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as darifenacin.
Darunavir: Concurrent administration of darunavir with efavirenz results in decreased darunavir concentrations (13% reduction in AUC and 31% reduction in Cmin) and increased efavirenz concentration (21% increase in AUC and 17% increase in Cmin). No dosage adjustment recommendations are required for either medication. Use this combination with caution.
Darunavir; Cobicistat: Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and daruanavir and atazanavir are CYP3A4 substrates. Concurrent administration of darunavir with efavirenz results in decreased darunavir concentrations (13% reduction in AUC and 31% reduction in Cmin) and increased efavirenz concentration (21% increase in AUC and 17% increase in Cmin). No dosage adjustment recommendations are required for either medication. Use this combination with caution.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with efavirenz is contraindicated. The use of this drug combination was pooly tolerated by recipients and resulted in hepatic enzyme elevations. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with efavirenz is contraindicated. The use of this drug combination was pooly tolerated by recipients and resulted in hepatic enzyme elevations. Coadministration of ritonavir with efavirenz may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with both drugs. In addition, coadministration of ritonavir (500 mg every 12 hours) and efavirenz (600 mg once daily) has been associated with a higher frequency of other adverse reactions (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Giving these drugs together is expected to result in increased concentrations of both drugs.
Dasatinib: Although data are limited, coadministration of efavirenz and dasatinib may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. In vitro studies have shown that dasatinib also has the potential to prolong the QT interval. In addition, efavirenz may induce the CYP3A4 metabolism of dasatinib, potentially reducing the efficacy of dasatinib by decreasing its systemic exposure.
Daunorubicin: Although data are limited, coadministration of efavirenz and daunorubicin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Acute cardiotoxicity can occur during the administration of daunorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage.
Deflazacort: 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: Although data are limited, coadministration of efavirenz and degarelix may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs. Prescribers need to weigh the potential benefits and risks of degarelix use in patients with prolonged QT syndrome or in patients taking other drugs that may prolong the QT interval.
Delavirdine: The combined use of two NNRTIs has not been shown to be beneficial; thus, efavirenz and delavirdine should not be coadministered.
Desflurane: 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.
Desipramine: Although data are limited, coadministration of efavirenz and tricyclic antidepressants may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Deutetrabenazine: Avoid coadministration of deutetrabenazine with efavirenz. Clinically relevant QT prolongation may occur with deutetrabenazine. QTc prolongation has been observed with the use of efavirenz.
Dextromethorphan; Promethazine: Although data are limited, coadministration of efavirenz and promethazine may increase the risk for QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
Dextromethorphan; Quinidine: Coadministration of efavirenz and quinidine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Quinidine administration is associated with QT prolongation and TdP. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as quinidine.
Diazepam: In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including diazepam. In addition, efavirenz inhibits CYP2C9 in vitro; diazepam is also metabolized via this isoenzyme. Monitor patients closely for excessive side effects.
Diclofenac: 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: If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as efavirenz; if coadministration is required, do not exceed a total daily diclofenac dose of 100 mg. When used with a CYP2C9 inhibitor the systemic exposure to diclofenac (a CYP2C9 substrate) may increase, potentially resulting in adverse events.
Dienogest; Estradiol valerate: Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Diltiazem: Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
Diphenhydramine; Hydrocodone; Phenylephrine: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Disopyramide: 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: The pathway to disulfiram activation is mediated by CYP3A4/5 (major), CYP1A2, CYP2B6, and CYP2E1.Efavirenz is an in vivo inducer of CYP3A4 and CY2B6. Increased disulfiram activation may occur if these drugs are administred together.
Docetaxel: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as docetaxel.
Dofetilide: Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Efavirenz has also been associated with QT prolongation. Because of the potential for QT prolongation and TdP, use of efavirenz with dofetilide is contraindicated.
Dolasetron: Although data are limited, coadministration of efavirenz and dolasetron may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Dolasetron has been associated with a dose-dependant prolongation in the QT, PR, and QRS intervals on an electrocardiogram. In addition, efavirenz may induce the CYP3A4 metabolism of dolasetron; potentially reducing the efficacy of dolasetron by decreasing its systemic exposure.
Dolutegravir: 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 patients or treatment-experienced but INSTI-naive patients who weigh at least 40 kg, the dose of dolutegravir should be increased to 50 mg PO twice daily when administered with efavirenz. For pediatric patients weighing 30 to 39 kg, increase the dose of dolutegravir to 35 mg PO twice daily if administered concurrently with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Predictions regarding this interaction can be made based on the drugs metabolic pathways. Efavirenz is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Donepezil: Coadministration of efavirenz and donepezil 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. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates, such as donepezil. The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
Donepezil; Memantine: Coadministration of efavirenz and donepezil 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. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates, such as donepezil. The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
Doxepin: Although data are limited, coadministration of efavirenz and tricyclic antidepressants may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Doxercalciferol: 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: Avoid coadministration of efavirenz and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy and monitor the patient for QT prolongation and Torsades de pointes. 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. Also, QT prolongation has been observed with use of efavirenz, and acute cardiotoxicity can occur during the administration of doxorubicin, although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage.
Dronabinol, THC: 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: Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Efavirenz has also been associated with QT prolongation. Because of the potential for QT prolongation and TdP, use of efavirenz with dronedarone is contraindicated.
Droperidol: 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; Estradiol: 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: 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: 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.
Echinacea: Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, one study with etravirine did not show a significant effect of Echinacea on drug exposure. More study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
Elbasvir; Grazoprevir: 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: Concomitant use of eletriptan and efavirenz is not recommended. Eletriptan is metabolized by CYP3A4, and inhibition of CYP3A4 by efavirenz may result in elevated eletriptan concentrations and serious adverse events.
Eliglustat: Although data are limited, coadministration of efavirenz and eliglustat may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation if plasma concentrations are significantly increased. In addition, efavirenz may induce the CYP3A4 metabolism of eliglustat; potentially reducing the efficacy of eliglustat by decreasing its systemic exposure.
Elvitegravir: 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.
Empagliflozin; Linagliptin: Concomitant use of linagliptin with efavirenz may result in decreased serum concentrations of linagliptin. Linagliptin is a substrate of hepatic isoenzyme CYP3A4; efavirenz is a moderate inducer of CYP3A4. Caution and close monitoring for decreased efficacy of linagliptin are advised if these drugs are used together.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP).
Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP).
Enalapril; Felodipine: 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.
Enflurane: 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.
Enzalutamide: Avoid the concomitant use of enzalutamide, a CYP3A4 substrate, with a moderate CYP3A4 inducer such as efavirenz. Although this interaction has not been evaluated in vivo, use of enzalutamide in combination with a moderate CYP3A4 inducer may decrease plasma exposure of enzalutamide. Therefore, using an agent with no or minimal CYP3A4 induction potential is recommended.
Epirubicin: Although data are limited, coadministration of efavirenz and epirubicin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Acute cardiotoxicity can occur during the administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage.
Eplerenone: Efavirenz is a CYP3A4 inducer and may causes a decrease in eplerenone serum concentration. It is not known if the interaction is clinically significant.
Eribulin: 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: Avoid the coadministration of erlotinib with efavirenz if possible due to the risk of decreased erlotinib efficacy; if concomitant use is unavoidable, increase the dose of erlotinib by 50 mg increments at 2-week intervals, to a maximum of 450 mg. Efavirenz is a CYP3A4 inducer. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Efavirenz decreased the Cmax and AUC of another CYP3A4 substrate, simvastatin, by 72% and 68%, respectively. The erlotinib AUC was decreased by 58% to 80% when preceded by administration of rifampicin, a strong CYP3A4 inducer, for 7 to 11 days; coadministration with efavirenz may also decrease erlotinib exposure.
Erythromycin: 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. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Erythromycin is associated with QT prolongation and TdP. In addition, concurrent use may increase the systemic concentration of efavirenz and decrease the concentration of erythromycin. Efavirenz is a CYP3A4 substrate and inducer, while erythromycin is a CYP3A4 substrate and inhibitor.
Erythromycin; Sulfisoxazole: 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. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Erythromycin is associated with QT prolongation and TdP. In addition, concurrent use may increase the systemic concentration of efavirenz and decrease the concentration of erythromycin. Efavirenz is a CYP3A4 substrate and inducer, while erythromycin is a CYP3A4 substrate and inhibitor.
Escitalopram: Coadministration of efavirenz and escitalopram 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. Escitalopram has also been associated with a risk of QT prolongation and TdP. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as escitalopram.
Esomeprazole: 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.
Esomeprazole; Naproxen: 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: 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: 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: 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. 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: 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. 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: 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: 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 ethanol.
Ethinyl Estradiol: 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; Desogestrel: 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; Ethynodiol Diacetate: 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; Etonogestrel: Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Ethinyl Estradiol; Levonorgestrel: Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Ethinyl Estradiol; Norelgestromin: Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Ethinyl Estradiol; Norethindrone Acetate: Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Ethinyl Estradiol; Norethindrone: Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Ethinyl Estradiol; Norethindrone; Ferrous fumarate: 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; Norgestimate: 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: Patients should be advised to use a reliable method of barrier contraception in addition to oral contraceptives or non-oral combination contraceptives, including implantable etonogestrel, while using efavirenz. Efavirenz has no effect on ethinyl estradiol concentrations, but levels of progestins (norelgestromin and levonorgestrel) can be markedly decreased. Norelgestromin Cmax and AUC decreased by 46% and 64%, respectively. Levonorgestrel Cmax and AUC decreased bu 80% and 83%, respectively. There have been post-marketing reports of contraceptive failure with implantable etonogestrel in efavirenz-exposed patients. Decreased exposure of etonogestrel may be expected. There are no effects of ethinyl estradiol/norgestimate on efavirenz plasma concentrations.
Ethosuximide: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as ethosuximide.
Etoposide, VP-16: Monitor for clinical efficacy of etoposide if used concomitantly with efavirenz. Efavirenz is an inducer of CYP3A4; etoposide, VP-16 is a CYP3A4 substrate. Coadministration of etoposide with a strong CYP3A4 inducer (phenytoin) resulted in increased etoposide clearance and reduced efficacy, as did coadministration with a weak inducer of CYP3A4 and P-glycoprotein (P-gp) (valproic acid).
Etravirine: Concomitant use of etravirine with efavirenz may cause a significant decrease in etravirine plasma concentrations and, thus, a loss of therapeutic effect. Additionally, the combined use of two NNRTIs has not been shown to be beneficial; etravirine and other NNRTIs should not be coadministered.
Everolimus: Everolimus is a substrate and inhibitor of CYP3A4. Coadminister with CYP3A4 inducers, such as efavirenz, with caution. In addition, efavirenz is a substrate of CYP3A4. The significance of coadministering everolimus with a CYP3A4 substrate has not been established. Pharmacokinetic studies showed no significant impact of the coadministration of everolimus with the CYP3A4 and Pgp substrate atorvastatin.
Exemestane: Use caution if coadministration of exemestane with efavirenz is necessary, and monitor for a possible decrease in the efficacy of exemestane. Exemestane is a CYP3A4 substrate; efavirenz is a moderate CYP3A4 inducer. In a pharmacokinetic interaction study (n = 10) with a strong CYP3A4 inducer, rifampicin (600 mg daily for 14 days), the mean Cmax and AUC of exemestane (single dose) decreased by 41% and 54%, respectively. The manufacturer of exemestane recommends a dose increase when concomitant use with a strong CYP3A4 inducer is necessary; recommendations are not available for moderate CYP3A4 inducers.
Ezetimibe; Simvastatin: Efavirenz has potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with simvastatin with caution.
Ezogabine: Although data are limited, coadministration of efavirenz and ezogabine may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with QT prolongation.
Felodipine: Use caution and careful monitoring when coadministering efavirenz with calcium-channel blockers; efavirenz induces CYP3A4, potentially altering serum concentrations of drugs metabolized by this enzyme such as some calcium-channel blockers. When coadministered, efavirenz decreases the concentrations of diltiazem (decrease in Cmax by 60%, in AUC by 69%, and in Cmin by 63%) and its active metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem; dose adjustments should be made for diltiazem based on clinical response. No data are available regarding coadministration of efavirenz with other calcium channel blockers that are CYP3A4 substrates (e.g., felodipine, nicardipine, and verapamil); as with diltiazem, calcium-channel blocker doses should be adjusted based on clinical response.
Fentanyl: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as fentanyl. Fentanyl should be used with extreme caution if deemed appropriate for use in a patient taking efavirenz.
Fingolimod: Coadministration of efavirenz and fingolimod 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. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
Flecainide: 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: 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: According to the manufacturer, clinically significant interactions are not expected with efavirenz and fluconazole. However, use of these medications together may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with QT prolongation.
Fluoxetine: Coadministration of efavirenz and fluoxetine 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. Fluoxetine administration is associated with QT prolongation and TdP. In addition, concurrent use may increase the systemic concentration of efavirenz. Efavirenz is a CYP3A4 substrate, while fluoxetine is a mild CYP3A4 inhibitor.
Fluoxetine; Olanzapine: Although data are limited, coadministration of efavirenz and olanzapine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval. Coadministration of efavirenz and fluoxetine 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. Fluoxetine administration is associated with QT prolongation and TdP. In addition, concurrent use may increase the systemic concentration of efavirenz. Efavirenz is a CYP3A4 substrate, while fluoxetine is a mild CYP3A4 inhibitor.
Fluphenazine: Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as efavirenz.
Flurazepam: 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.
Fluticasone; Salmeterol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval, such as efavirenz. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Fluticasone; Vilanterol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval, such as efavirenz. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Fluvastatin: 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.
Food: The pharmacokinetic parameters of anti-retroviral medications (anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs), anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs), anti-retroviral nucleotide reverse transcriptase inhibitors, and anti-retroviral protease inhibitors) metabolized through the CYP isoenzyme system are slightly altered by smoked and oral marijuana. Despite this interaction, marijuana is not expected to adversely affect anti-retroviral efficacy. However, the incidence of marijuana associated adverse effects may change following coadministration with anti-retroviral drugs. Many anti-retrovirals are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with anti-retrovirals, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
Formoterol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval, such as efavirenz. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Formoterol; Mometasone: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval, such as efavirenz. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Fosamprenavir: Systemic concentrations of fosamprenavir are reduced when administered concurrently with efavirenz. Avoid administering these drugs concurrently, unless fosamprenavir is boosted with ritonavir. When fosamprenavir plus ritonavir is administered once daily and given in combination with efavirenz, the dose of ritonavir must be increased by 100 mg/day (300 mg total). No change in the ritonavir dose is required when efavirenz is administered with fosamprenavir plus ritonavir twice daily.
Foscarnet: 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.
Galantamine: Galantamine is a substrate for CYP3A4 and CYP2D6. Because efavirenz can act as an inducer of CYP3A4, patients receiving this combination should be monitored for loss of efficacy.
Gefitinib: Monitor for clinical response of gefitinib if used concomitantly with efavirenz. Gefitinib is metabolized significantly by CYP3A4 and efavirenz is a CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
Gemifloxacin: Although data are limited, coadministration of efavirenz and gemifloxacin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Gemifloxacin may also 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.
Glimepiride: Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like efavirenz. Monitor serum glucose concentrations if glimepiride is coadministered with efavirenz. Dosage adjustments may be necessary.
Glimepiride; Pioglitazone: Glimepiride is metabolized by CYP2C9. It is possible for serum concentrations of glimepiride to rise when coadministered with drugs that inhibit CYP2C9 like efavirenz. Monitor serum glucose concentrations if glimepiride is coadministered with efavirenz. Dosage adjustments may be necessary.
Glimepiride; Rosiglitazone: 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.
Glycopyrrolate; Formoterol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval, such as efavirenz. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Granisetron: Although data are limited, coadministration of efavirenz and granisetron may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Granisetron has also been associated with QT prolongation. In addition, efavirenz may induce the CYP3A4 metabolism of granisetron; potentially reducing the efficacy of granisetron by decreasing its systemic exposure.
Guaifenesin; Hydrocodone: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Guaifenesin; Hydrocodone; Pseudoephedrine: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Guanfacine: 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: 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: Coadministration of efavirenz and haloperidol 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. QT prolongation and 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. In addition, efavirenz is a substrate and inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of haloperidol. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and substrates or inhibitors of CYP3A4. Because this interaction may be unpredictable, it is advisable to closely monitor for adverse events or a decrease in efficacy when these medications are co-administered.
Halothane: 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.
Homatropine; Hydrocodone: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Hydantoins: 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.
Hydrochlorothiazide, HCTZ; Losartan: Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of drugs that are substrates for CYP2C9 or CYP2C19 including losartan.
Hydrocodone: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Hydrocodone; Ibuprofen: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Hydrocodone; Phenylephrine: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Hydrocodone; Potassium Guaiacolsulfonate: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Hydrocodone; Pseudoephedrine: Hydrocodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of hydrocodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. Monitor the patient for reduced efficacy of hydrocodone. A higher hydrocodone dose may be needed if used with efavirenz.
Hydroxychloroquine: Avoid coadministration of hydroxychloroquine and efavirenz. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. QTc prolongation has been observed with the use of efavirenz.
Hydroxyprogesterone: In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2B6 isoenzymes. The metabolism of drugs metabolized by CYP2B6, such as efavirenz may be increased during treatment with hydroxyprogesterone.
Hydroxyzine: Coadministration of efavirenz and hydroxyzine 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. Post-marketing data indicate that hydroxyzine causes both QT prolongation and TdP.
Ibrutinib: 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 using physiologically-based pharmacokinetic (PBPK) models suggest that moderate CYP3A4 inducers may decrease ibrutinib exposure up to 3-fold.
Ibuprofen; Oxycodone: Oxycodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of oxycodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone. If coadministration of these agents is necessary, monitor patients at frequent intervals and consider dose adjustments if needed. Similarly, an interaction may occur if efavirenz; emtricitabine; tenofovir and oxycodone are coadministered.
Ibutilide: 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.
Idarubicin: Although data are limited, coadministration of efavirenz and idarubicin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Acute cardiotoxicity can occur during the administration of idarubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage.
Idelalisib: 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: The concomitant use of ifosfamide, a substrate of CYP3A4 and CYP2B6, and efavirenz, a CYP3A4 inducer and substrate and a CYP2B6 inducer, may increase the metabolism of ifosfamide to its metabolites, 4-hydroxy-ifosfamide (active) and chloroacetaldehyde (inactive but neurotoxic/nephrotoxic). As a result of this interaction, the risk of ifosfamide toxicity is increased. If these agents are used together, monitor patients closely for ifosfamide adverse effects including nausea/vomiting, neurotoxicity, nephrotoxicity, hematuria, and infection. An ifosfamide dose reduction may be considered.
Iloperidone: 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.
Imatinib, STI-571: Due to the complex interaction that may occur between efavirenz and imatinib, STI-571, close monitoring of the antiviral and antineoplastic responses are recommended. Efavirenz is a CYP3A4 inducer and imatinib is a CYP3A4 inhibitor; both drugs are metabolized by this enzyme. Although no specific studies have been conducted, caution is recommended when administering these drugs together.
Imipramine: Although data are limited, coadministration of efavirenz and tricyclic antidepressants may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Indacaterol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval, such as efavirenz. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Indacaterol; Glycopyrrolate: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval, such as efavirenz. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Indinavir: 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.
Interferon Alfa-2a: The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Interferon Alfa-2b: The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Interferon Alfa-2b; Ribavirin: The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. The concomitant use of ribavirin and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Interferon Alfacon-1: The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Interferon Alfa-n3: The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Interferon Beta-1a: The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Interferon Beta-1b: The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Interferon Gamma-1b: The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Interferons: The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Irinotecan: Efavirenz is a moderate CYP3A4 inducer; irinotecan is a CYP3A4 substrate. Coadministration could potentially decrease irinotecan exposure, although coadministration of irinotecan with dexamethasone, a moderate CYP3A4 inducer, did not affect irinotecan pharmacokinetics. Monitor for efficacy of chemotherapy.
Isavuconazonium: 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: 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: 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: When efavirenz and rifampin are coadministered, decreased efavirenz concentrations are seen and decreased antiretroviral efficacy is expected. These drugs may be coadministered to patients weighing 50 kg or more if the efavirenz dose is increased to 800 mg PO daily. A small study evaluated this interaction by administering the drugs (both at 600 mg PO daily x 7 days) to 12 subjects, and found decreased mean efavirenz Cmax, AUC, and Cmin of 20%, 26%, and 32%. Of note, reduced efavirenz metabolism is seen in patients with genetic polymorphisms of cytochrome P450 2B6 (primarily in patients of African, Asian, and Hispanic descent). Increasing the dose in these patients can result in a significant increase in efavirenz toxicity; some patients may even require lower doses.
Isradipine: 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.
Itraconazole: Avoid concurrent administration of itraconazole and efavirenz or efavirenz-containing medications. 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. Use of an alternative antifungal medication should be considered. If these drugs must be used together, monitor for breakthrough fungal infections and adverse events.
Ivabradine: Avoid coadministration of ivabradine and efavirenz. Ivabradine is primarily metabolized by CYP3A4; efavirenz is an inducer of CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for treatment failure.
Ivacaftor: Use caution when administering ivacaftor and efavirenz concurrently; the clinical effect of this interaction is unknown. Ivacaftor is a CYP3A substrate, and efavirenz is a CYP3A inducer and may also act as an inhibitor. Co-administration may lead to altered ivacaftor exposure. Ivacaftor is also an inhibitor of CYP3A and efavirenz is partially metabolized by CYP3A. Co-administration may increase efavirenz exposure leading to increased or prolonged therapeutic effects and adverse events.
Ixabepilone: Ixabepilone is a CYP3A4 substrate and concomitant use with CYP3A4 inducers such as efavirenz may lead to reduced and subtherapeutic concentrations of ixabepilone. Caution should be utilized when CYP3A4 inducers or inhibitors are coadministered with ixabepilone; alternative therapies should be considered.
Ketoconazole: Avoid concurrent administration of ketoconazole and efavirenz or efavirenz-containing medications. Administering ketoconazole with inducers of CYP3A4, such as efavirenz, may decrease the bioavailability of ketoconazole to such an extent that efficacy may be reduced. Efavirenz is also partially metabolized by CYP3A4; taking efavirenz with ketoconazole (a potent CYP3A4 inhibitor) may increase exposure to efavirenz. In addition, both drugs are associated with QT prolongation; coadministration may increase this risk. Use of an alternative antifungal medication should be considered. If these drugs must be used together, monitor for breakthrough fungal infections and adverse events.
Lapatinib: Although data are limited, coadministration of efavirenz and lapatinib may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs can prolong the QT interval. Also, lapatinib is metabolized by CYP3A4 and CYP3A5 enzymes. Drugs that are inducers of CYP3A4 activity, such as efavirenz, will decrease the plasma concentrations of lapatinib. In patients receiving lapatinib and carbamazepine (100 mg twice daily for 3 days then 200 mg twice daily for 17 days), systemic exposure to lapatinib was decreased by approximately 72%. If concomitant treatment is necessary, consider a lapatinib dose escalation. If a strong CYP3A4 inducer is discontinued, reduce the lapatinib dose to the indicated dose.
Lenvatinib: Although data are limited, coadministration of efavirenz and lenvatinib may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. QT prolongation was also reported during clinical trials of lenvatinib. In addition, efavirenz may induce the CYP3A4 metabolism of lenvatinib; potentially reducing the efficacy of lenvatinib by decreasing its systemic exposure.
Lesinurad: Use lesinurad and efavirenz together with caution; efavirenz may increase the systemic exposure of lesinurad. Efavirenz is an inhibitor of CYP2C9 in vitro, and lesinurad is a CYP2C9 substrate.
Leuprolide: Although data are limited, coadministration of efavirenz and leuprolide may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Androgen deprivation therapy (e.g., leuprolide) also prolongs the QT interval.
Leuprolide; Norethindrone: Although data are limited, coadministration of efavirenz and leuprolide may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Androgen deprivation therapy (e.g., leuprolide) also prolongs the QT interval. 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.
Levalbuterol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Levobupivacaine: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as levobupivacaine.
Levofloxacin: Coadministration of efavirenz and levofloxacin 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. Levofloxacin has been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during post-marketing surveillance of levofloxacin.
Levomethadyl: Agents that induce hepatic cytochrome P450 (CYP) 3A4, such as efavirenz, may reduce serum levels of levomethadyl leading to symptoms of withdrawal in stabilized patients.
Levonorgestrel: 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: 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: 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: 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: Although data are limited, coadministration of efavirenz and lithium may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs have been associated with QT prolongation.
Long-acting beta-agonists: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval, such as efavirenz. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Loperamide: Coadministration of efavirenz and loperamide 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. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. In addition, the plasma concentration and efficacy of loperamide may be reduced when administered concurrently with efavirenz. Loperamide is metabolized by the hepatic enzymes CYP3A4 and CYP2B6; efavirenz is an inducer of both enzymes.
Loperamide; Simethicone: Coadministration of efavirenz and loperamide 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. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. In addition, the plasma concentration and efficacy of loperamide may be reduced when administered concurrently with efavirenz. Loperamide is metabolized by the hepatic enzymes CYP3A4 and CYP2B6; efavirenz is an inducer of both enzymes.
Lopinavir; Ritonavir: Although data are limited, coadministration of efavirenz and lopinavir; ritonavir may increase the risk for QT prolongation and torsade de pointes (TdP). Both drugs are associated with QT prolongation. In addition, induction of CYP3A by efavirenz may decrease lopinavir plasma concentrations. If coadministered, the dose of lopinavir; ritonavir must be increased and given twice daily; do not use once daily administration. Consult dosing information for recommended adjustments. Coadministration of ritonavir with efavirenz may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with both drugs. In addition, coadministration of ritonavir (500 mg every 12 hours) and efavirenz (600 mg once daily) has been associated with a higher frequency of other adverse reactions (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Giving these drugs together is expected to result in increased concentrations of both drugs.
Losartan: Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of drugs that are substrates for CYP2C9 or CYP2C19 including losartan.
Lovastatin: Efavirenz has potential to induce CYP3A4 isoenzymes which may decrease the efficacy of lovastatin.
Lovastatin; Niacin: Efavirenz has potential to induce CYP3A4 isoenzymes which may decrease the efficacy of lovastatin.
Lumacaftor; Ivacaftor: 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).
Lumacaftor; Ivacaftor: Use caution when administering ivacaftor and efavirenz concurrently; the clinical effect of this interaction is unknown. Ivacaftor is a CYP3A substrate, and efavirenz is a CYP3A inducer and may also act as an inhibitor. Co-administration may lead to altered ivacaftor exposure. Ivacaftor is also an inhibitor of CYP3A and efavirenz is partially metabolized by CYP3A. Co-administration may increase efavirenz exposure leading to increased or prolonged therapeutic effects and adverse events.
Lurasidone: Because lurasidone is primarily metabolized by CYP3A4, decreased plasma concentrations of lurasidone may occur when the drug is co-administered with inducers of CYP3A4. Concurrent use of lurasidone and CYP3A4 inducers, such as efavirenz or combination products containing efavirez (e.g. efavirenz; emtricitabine; tenofovir), may lead to a decrease in efficacy of lurasidone. If lurasidone is used with a moderate CYP3A4 inducer, it may be necessary to increase the lurasidone dose after chronic treatment (7 days or more).
Maprotiline: Coadministration of efavirenz and maprotiline 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. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, efavirenz may induce the CYP3A4 metabolism of maprotiline, potentially reducing the efficacy of maprotiline by decreasing its systemic exposure.
Maraviroc: 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.
Mefloquine: 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. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval, such as efavirenz. 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.
Meperidine; Promethazine: Although data are limited, coadministration of efavirenz and promethazine may increase the risk for QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
Mestranol; Norethindrone: 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.
Metaproterenol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Metformin; Repaglinide: Repaglinide is metabolized in the liver by cytochrome P450 isoenzyme CYP3A4. Patients taking repaglinide concomitantly with a CYP3A4 inducer such as efavirenz or efavirenz-containing products (e.g. efavirenz; emtricitabine; tenofovir) should be monitored for reduced effectiveness of repaglinide and possible symptoms indicating hyperglycemia.
Methadone: Coadministration of efavirenz and methadone may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Methadone is considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (more than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In addition, efavirenz induces methadone metabolism via CYP3A4 and is associated with significant decreases in methadone concentrations. Clinical reports suggest that patients who are stabilized on methadone-maintenance therapy may experience opiate withdrawal symptoms when efavirenz is added to their HIV-regimen. Methadone-maintained patients should be monitored for evidence of withdrawal and the methadone dose should be adjusted accordingly.
Metronidazole: Although data are limited, coadministration of efavirenz and metronidazole may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Potential QT prolongation has also been reported in limited case reports with metronidazole.
Midostaurin: The concomitant use of midostaurin and efavirenz may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin.
Mifepristone, RU-486: Although data are limited, coadministration of efavirenz and mifepristone, RU-486 may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Mifepristone has also been associated with dose-dependent prolongation of the QT interval. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used. In addition, concurrent use may increase the systemic concentration of efavirenz and decrease the concentration of mifepristone. Efavirenz is a CYP3A4 substrate and inducer, while mifepristone is a CYP3A4 substrate and inhibitor. Caution is warranted when mifepristone is used in the treatment of Cushing's syndrome and coadministered with these agents.
Mitotane: 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.
Moxifloxacin: 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.
Nefazodone: 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.
Nevirapine: Avoid concurrent use of efavirenz with nevirapine as the combination has been associated with increased adverse reactions without improved efficacy. Coadministration may result in decreased efavirenz AUC (22%), Cmin (36%), and Cmax (17%). The pharmacokinetics of nevirapine appear to be unaffected. The clinical implications of this interaction are not known.
Niacin; Simvastatin: Efavirenz has potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with simvastatin with caution.
Nicardipine: 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: 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: 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: 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.
Nintedanib: Efavirenz is a CYP3A4 inducer and nintedanib is a minor substrate of CYP3A4. Coadministration of nintedanib with CYP3A4 inducers such as efavirenz should be avoided as these drugs may decrease exposure to nintedanib and compromise its efficacy.
Nisoldipine: 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.
Non-oral combination contraceptives: 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: 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: 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.
Nortriptyline: Although data are limited, coadministration of efavirenz and tricyclic antidepressants may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Octreotide: Administer octreotide cautiously in patients receiving drugs that prolong the QT interval. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therap. Since bradycardia is a risk factor for development of TdP , the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval, such as efavirenz. In addition, concurrent use may increase the systemic concentration of efavirenz. Efavirenz is a CYP3A4 substrate, while octreotideis a CYP3A4 inhibitor.
Ofloxacin: Ccoadministration of efavirenz and ofloxacin 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 ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
Olanzapine: Although data are limited, coadministration of efavirenz and olanzapine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with 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: Avoid the coadministration of olaparib with efavirenz if possible; if concomitant use is necessary, be aware of a potential for decreased efficacy of both olaparib and efavirenz. Olaparib is a CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. Simulations have suggested that efavirenz may decrease the AUC of olaparib by 50% to 60% and the Cmax by 20% to 30%. Efavirenz is a substrate of CYP2B6 and 3A4, while olaparib is a CYP2B6 inducer in vitro. According to the manufacturer of efavirenz, medications that induce CYP2B6 activity would be expected to increase the clearance of efavirenz.
Olodaterol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval, such as efavirenz. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Ombitasvir; Paritaprevir; Ritonavir: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with efavirenz is contraindicated. The use of this drug combination was pooly tolerated by recipients and resulted in hepatic enzyme elevations. Coadministration of ritonavir with efavirenz may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with both drugs. In addition, coadministration of ritonavir (500 mg every 12 hours) and efavirenz (600 mg once daily) has been associated with a higher frequency of other adverse reactions (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Giving these drugs together is expected to result in increased concentrations of both drugs.
Omeprazole: Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C9 or CYP2C19.
Omeprazole; Sodium Bicarbonate: Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of omeprazole since it is a substrate for CYP2C9 or CYP2C19.
Ondansetron: 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: 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: 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: 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 non-nucleoside reverse transcriptase inhibitors (NNRTIs). 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.
Osimertinib: Consider alternatives to efavirenz when coadministering with a drug with a risk of torsade de pointes (TdP) such as osimertinib. If concomitant use is necessary, periodically monitor ECGs and electrolytes. Concentration-dependent QTc prolongation has been suggested at the recommended dosing of osimertinib in a pharmacokinetic/pharmacodynamic analysis. QTc prolongation has been observed with the use of efavirenz. Concomitant use may increase the risk of QT prolongation.
Oxaliplatin: Coadministration of efavirenz and oxaliplatin 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. QT prolongation and ventricular arrhythmias including fatal TdP have been reported with oxaliplatin use in post-marketing experience.
Oxybutynin: Oxybutynin is metabolized by CYP3A4. Drugs that induce CYP3A4, such as efavirenz, may cause decreased serum concentrations of oxybutynin. The clinical significance of such interactions is not known; however patients receiving oxybutynin with efavirenz or efavirenz-containing products (e.g. efavirenz; emtricitabine; tenofovir) concomitantly should be monitored for efficacy.
Oxycodone: Oxycodone is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, may cause increased clearance of oxycodone, which could result in lack of efficacy or the development of an abstinence syndrome in a patient who had developed physical dependence to oxycodone. If coadministration of these agents is necessary, monitor patients at frequent intervals and consider dose adjustments if needed. Similarly, an interaction may occur if efavirenz; emtricitabine; tenofovir and oxycodone are coadministered.
Paclitaxel: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as paclitaxel.
Palbociclib: Use caution and monitor patients for decreased palbociclib efficacy if efavirenz is used concomitantly with palbociclib. Palbociclib is a primary substrate of CYP3A and efavirenz is a moderate CYP3A inducer. In a drug interaction study, coadministration of multiple daily doses of a moderate CYP3A inducer, modafinil, decreased the plasma exposure of a single dose of palbociclib in healthy patients by 32% and the Cmax by 11% (n = 14).
Paliperidone: Paliperidone has been associated with QT prolongation. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as efavirenz. However, if coadministration is considered necessary by the practitioner, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. In addition, efavirenz may induce the CYP3A4 metabolism of paliperidone, potentially reducing the efficacy of paliperidone by decreasing its systemic exposure.
Panobinostat: 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: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as paricalcitol.
Pasireotide: Although data are limited, coadministration of efavirenz and pasireotide may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs.
Pazopanib: 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: The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Peginterferon Alfa-2b: The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Peginterferon beta-1a: The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Pentamidine: Although data are limited, coadministration of efavirenz and pentamidine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs
Perampanel: Efavirenz may induce or inhibit CYP3A4. As perampanel is a substrate of CYP3A4, use caution during concurrent use. Patients should be closely monitored, and dose adjustments should occur in response to adverse effects or a subtherapeutic response to perampanel.
Perindopril; Amlodipine: 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.
Perphenazine: Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as efavirenz.
Perphenazine; Amitriptyline: Although data are limited, coadministration of efavirenz and tricyclic antidepressants may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as efavirenz.
Phenylephrine; Promethazine: Although data are limited, coadministration of efavirenz and promethazine may increase the risk for QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
Pimavanserin: 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, efavirenz may induce the CYP3A4 metabolism of pimavanserin; potentially reducing the efficacy of pimavanserin by decreasing its systemic exposure.
Pimozide: 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.
Pirbuterol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Piroxicam: Efavirenz inhibits CYP2C9 and CYP2C19 and may inhibit the metabolism of piroxicam, a substrate for CYP2C9.
Posaconazole: The concurrent use of posaconazole with drugs that are associated with QT prolongation and are also CYP3A4 substrates, such as efavirenz, is contraindicated. Posaconazole has been associated with QT prolongation and torsade de pointes. In addition, concomitant use may increase the risk for breakthrough fungal infection. Efavirenz is believed to interact with posaconazole by inducing UDP glucuronidation. When posaconazole was administered with efavirenz, the mean reductions in Cmax were 45% and the mean reductions in AUC were 50% for posaconazole.
Praziquantel: In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Therefore, use of praziquantel with efavirenz, a CYP3A4 inducer, should be done with caution as concomitant use may produce therapeutically ineffective concentrations of praziquantel.
Primaquine: Although data are limited, coadministration of efavirenz and primaquine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs.
Procainamide: Coadministration of efavirenz and procainamide may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Procainamide is associated with a well-established risk of QT prolongation and TdP.
Prochlorperazine: Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as efavirenz.
Promethazine: Although data are limited, coadministration of efavirenz and promethazine may increase the risk for QT prolongation and torsade de pointes (TdP). Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. QT prolongation has also been observed with use of efavirenz.
Propafenone: 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.
Protriptyline: Although data are limited, coadministration of efavirenz and tricyclic antidepressants may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Quazepam: 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 prazepam. Monitor patients closely for excessive side effects.
Quetiapine: 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: Coadministration of efavirenz and quinidine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Quinidine administration is associated with QT prolongation and TdP. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as quinidine.
Quinine: Quinine has been associated with QT prolongation and rare cases of torsade de pointes (TdP). Avoid concurrent use of quinine with other drugs that may cause QT prolongation and TdP, such as efavirenz. In addition, concurrent use may alter the systemic concentration of efavirenz and decrease the concentration of quinine. Efavirenz is a CYP3A4 substrate and inducer, while quinine is a CYP3A4 substrate, inducer, and inhibitor.
Ranolazine: Ranolazine is metabolized mainly by CYP3A and is contraindicated in patients receiving drugs known to be CYP3A inducers. Efavirenz induces CYP3A4. Although not specifically mentioned by the manufacturer, coadministration of ranolazine with a CYP3A enzyme inducer such as efavirenz may result in decreased ranolazine plasma concentrations and decreased efficacy. Additionally, both efavirenz and ranolazine have been associated with QT prolongation.
Red Yeast Rice: 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.
Regadenoson: Although data are limited, coadministration of efavirenz and regadenoson may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs.
Repaglinide: Repaglinide is metabolized in the liver by cytochrome P450 isoenzyme CYP3A4. Patients taking repaglinide concomitantly with a CYP3A4 inducer such as efavirenz or efavirenz-containing products (e.g. efavirenz; emtricitabine; tenofovir) should be monitored for reduced effectiveness of repaglinide and possible symptoms indicating hyperglycemia.
Ribavirin: The concomitant use of ribavirin and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Ribociclib: 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 and the systemic exposure of ribociclib may be decreased resulting in decreased efficacy. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; QTc prolongation has also been observed with the use of efavirenz. Concomitant use may increase the risk for QT prolongation. Ribociclib is extensively metabolized by CYP3A4 and efavirenz is a moderate CYP3A4 inducer. Additionally, ribociclib is a moderate CYP3A4 inhibitor and efavirenz is a CYP3A4 substrate.
Ribociclib; Letrozole: 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 and the systemic exposure of ribociclib may be decreased resulting in decreased efficacy. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner; QTc prolongation has also been observed with the use of efavirenz. Concomitant use may increase the risk for QT prolongation. Ribociclib is extensively metabolized by CYP3A4 and efavirenz is a moderate CYP3A4 inducer. Additionally, ribociclib is a moderate CYP3A4 inhibitor and efavirenz is a CYP3A4 substrate.
Rifabutin: While interactions may be present, certain non-nucleoside reverse transcriptase inhibitors (NNRTIs) may be given in combination with rifabutin to adult patients under specific circumstances. When used in combination with efavirenz, the daily dose of rifabutin should be increased by 50%. For rifabutin regimens given two or three times per week, consider doubling the rifabutin dose.
Rifampin: 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: Rifapentine is a CYP3A4 inducer; efavirenz is a substrate of this enzyme. Avoid coadministration, as concurrent use may result in decreased efavirenz plasma concentrations and loss of antiretroviral activity. Additionally, HIV patients treated with rifapentine have a higher rate of TB relapse than those treated with other rifamycin-based regimens; an alternative agent is recommended.
Rilpivirine: 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).
Risperidone: 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: Coadministration of ritonavir with efavirenz may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with both drugs. In addition, coadministration of ritonavir (500 mg every 12 hours) and efavirenz (600 mg once daily) has been associated with a higher frequency of other adverse reactions (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Giving these drugs together is expected to result in increased concentrations of both drugs.
Rivaroxaban: 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: Coadminister efavirenz or efavirenz-containing products (e.g. efavirenz; emtricitabine; tenofovir) and roflumilast cautiously as this may lead to reduced systemic exposure to roflumilast. Efavirenz induces CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Romidepsin: Romidepsin has been reported to prolong the QT interval. If romidepsin must be coadministered with another drug that prolongs the QT interval, such as efavirenz, appropriate cardiovascular monitoring precautions (i.e., electrolytes and ECGs at baseline and periodically during treatment) should be considered. In addition, romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like efavirenz, may decrease systemic concentrations of romidepsin.
Ruxolitinib: 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.
Salmeterol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval, such as efavirenz. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Saquinavir: 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.
Sertraline: Coadministration of efavirenz and sertraline 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. There have been post-marketing reports of QT prolongation and TdP during treatment with sertraline. Also, sertraline is a substrate of CYP2C9, CYP2C19, and CYP3A4; efavirenz is an inducer of CYP3A4 and inhibitor of CYP2C9 and CYP2C19. Coadministration results in decreased sertraline Cmax (29%), AUC (39%), and Cmin (46%). Changes in sertraline dose may be required, and should be based on clinical response.
Sevoflurane: 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.
Short-acting beta-agonists: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Sibutramine: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as sibutramine.
Sildenafil: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as sildenafil.
Simeprevir: Avoid concurrent use of simeprevir and efavirenz. Induction of CYP3A4 by efavirenz significantly reduces the plasma concentrations of simeprevir, potentially resulting in treatment failure. Concurrent treatment for 14 days has resulted in decreased Cmax, AUC, and Cmin of simeprevir by 51% (90% CI: 46% to 56%), 71% (90% CI: 67% to 74%), and 91% (90% CI: 88% to 92%), respectively.
Simvastatin: Efavirenz has potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with simvastatin with caution.
Simvastatin; Sitagliptin: 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.
Sirolimus: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates that have a narrow therapeutic range, such as sirolimus. Monitoring of serum sirolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz.
Sofosbuvir; Velpatasvir: Avoid coadministration of velpatasvir with inducers of CYP3A4 and CYP2B6, such as efavirenz. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 and CYP2B6 substrate.
Solifenacin: Coadministration of efavirenz and solifenacin 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. Solifenacin has been associated wtih 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.
Somatropin, rh-GH: When somatropin, an inducer of CYP3A4, and anti-retroviral non-nucleoside reverse transcriptase inhibitors, a CYP3A4 substrate, are coadminsitered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), did not have decreased antiretroviral effectiveness, as indicated by no change in the concentration of circulating CD4 counts or viral load.
Sonidegib: Avoid the concomitant use of sonidegib and efavirenz; sonidegib exposure may be significantly decreased and its efficacy reduced. Increased efavirenz levels may also occur if these agents are taken together. Sonidegib is a CYP3A4 substrate and a CYP2B6 inhibitor in vitro and efavirenz is a CYP3A4 inducer and CYP2B6 substrate. Physiologic-based pharmacokinetics (PBPK) simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 56% in cancer patients who received 14 days of sonidegib 200 mg/day with a moderate CYP3A inducer (i.e., efavirenz). Additionally, the PBPK model predicts that the sonidegib geometric mean steady-state AUC (0-24 hours) would decrease by 69% in cancer patients who received sonidegib 200 mg/day with a moderate CYP3A inducer (i.e., efavirenz) for 4 months.
Sorafenib: Sorafenib has been associated with QT prolongation. ECG monitoring is recommended if sorafenib and another drug that prolongs the QT interval, such as efavirenz, must be coadministered; closely monitor the patient for QT interval prolongation. Also, sorafenib is a CYP3A4 substrate, and concomitant use with a CYP3A4 inducer may lead to reduced sorafenib concentrations. Monitor paitents for reduced efficacy of sorafenib.
Sotalol: Coadministration of efavirenz and sotalol 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. Sotalol administration is associated with QT prolongation and TdP. Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
Sufentanil: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as sufentanil.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: Coadministration of efavirenz and sulfamethoxazole; trimethoprim 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. QT prolongation resulting in ventricular tachycardia and TdP has been reported during post-marketing use of sulfamethoxazole; trimethoprim.
Sunitinib: Although data are limited, coadministration of efavirenz and sunitinib may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs. In addition, concurrent administration of sunitinib with inducers of CYP3A4, such as efavirenz, results in decreased concentrations of sunitinib and its primary active metabolite, respectively. Whenever possible selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If an alternative therapy is not available, monitor patients closely for changes in sunitinib efficacy; a dosage adjustment of sunitinib may be required.
Suvorexant: Suvorexant is primarily metabolized by CYP3A, and decreased systemic exposure of suvorexant may occur during concurrent use with strong CYP3A inducers such as efavirenz. Patients should be monitored for a reduction in efficacy if this combination is necessary.
Tacrolimus: Although data are limited, coadministration of efavirenz and tacrolimus may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs. Also, efavirenz induces CYP3A4 and may decrease serum concentrations of tacrolimus. Monitoring of serum tacrolimus concentrations for at least 2 weeks is recommended when starting or stopping treatment with efavirenz.
Tadalafil: Tadalafil is metabolized predominantly by CYP3A4. Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme.
Tamoxifen: Caution is advised with the concomitant use of tamoxifen and efavirenz due to an increased risk of QT prolongation; reduced tamoxifen efficacy is also possible. Monitor for evidence of QT prolongation and altered tamoxifen efficacy if coadministration is needed. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. QTc prolongation has been observed with the use of efavirenz. Concomitant use of efavirenz and tamoxifen may decrease concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Efavirenz is a CYP3A4 inducer, as well as a CYP2C9 and CYP2C19 inhibitor. Efavirenz may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP2C9 and CYP2C19; plasma concentrations of tamoxifen and its active metabolites have also been reduced when coadministered with other CYP3A4 inducers.
Tasimelteon: 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.
Telaprevir: The HIV guidelines recommend increasing the telaprevir dose to 1125 mg every 8 hours when coadministered with efavirenz. Close clinical monitoring is advised during coadministration due to the potential for HIV and hepatitis C treatment failures. If dose adjustments are made, re-adjust the dose upon completion of concurrent treatment. Predictions about the interaction can be made based on each drugs metabolic pathways. Efavirenz is an inducer and substrate of the hepatic isoenzyme CYP3A4; telaprevir is an inhibitor and substrate of this isoenzyme. When used in combination, the mean plasma concentrations (AUC) of telaprevir and efavirenz were deceased by 26% and 7%, respectively.
Telavancin: Although data are limited, coadministration of efavirenz and telavancin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs.
Telithromycin: Coadministration of efavirenz and telithromycin 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. Telithromycin is associated with QT prolongation and TdP. In addiiton, concentrations of efavirenz may be increased and the concentrations of telithromycin may be decreased with coadministration. Efavirenz is a CYP3A4 substrate and inducer, while telithromycin is a CYP3A4 substrate and a strong CYP3A4 inhibitor.
Telotristat Ethyl: Use caution if coadministration of telotristat ethyl and efavirenz is necessary, as the systemic exposure of efavirenz may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of efavirenz; consider increasing the dose of efavirenz if necessary. Efavirenz is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
Temsirolimus: Use caution if coadministration of temsirolimus with efavirenz is necessary, due to the risk of decreased efficacy of temsirolimus. Temsirolimus is a CYP3A4 substrate and efavirenz is a moderate inducer of CYP3A4. The manufacturer of temsirolimus recommends a dose increase if coadministered with a strong CYP3A4 inducer, but recommendations are not available for concomitant use of moderate CYP3A4 inducers. Coadministration of temsirolimus with rifampin, a strong CYP3A4/5 inducer, had no significant effect on the AUC or Cmax of temsirolimus, but decreased the sirolimus AUC and Cmax by 56% and 65%, respectively.
Terbinafine: 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.
Terbutaline: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Beta-agonists may also be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Tetrabenazine: Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc, such as efavirenz.
Thioridazine: 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: 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.
Tiotropium; Olodaterol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval, such as efavirenz. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Tizanidine: Although data are limited, coadministration of efavirenz and tizanidine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs.
Tofacitinib: Efavirenz is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Tolbutamide: Efavirenz inhibits CYP2C9 and CYP2C19. Efavirenz may inhibit the metabolism of tolbutamide since it is a substrate for CYP2C9 or CYP2C19.
Tolterodine: Although data are limited, coadministration of efavirenz and tolterodine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with 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.
Tolvaptan: Tolvaptan is metabolized by CYP3A4. Efavirenz is an inducer of CYP3A4. Coadministration of CYP3A4 inducers, such as efavirenz, with tolvaptan may result in a reduced plasma concentration and subsequent reduced effectiveness of tolvaptan therapy. The concomitant use of tolvaptan and CYP3A4 inducers should be avoided. If coadministration is unavoidable, an increase in the tolvaptan dose may be necessary and patients should be monitored for decreased effectiveness of tolvaptan.
Toremifene: Although data are limited, coadministration of efavirenz and toremifene may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz.Toremifene has also been shown to prolong the QTc interval in a dose- and concentration-related manner. In addition, efavirenz (a CYP3A4 inducer) may increase the rate of toremifene metabolism.
Trabectedin: Use caution if coadministration of trabectedin and efavirenz is necessary, due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Coadministration with rifampin (600 mg daily for 6 days), a strong CYP3A inducer, decreased the systemic exposure of a single dose of trabectedin by 31% and the Cmax by 21% compared to a single dose of trabectedin given alone. The manufacturer of trabectedin recommends avoidance of coadministration with strong CYP3A inducers; there are no recommendations for concomitant use of moderate or weak CYP3A inducers.
Tramadol: 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.
Trandolapril; Verapamil: 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: 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.
Tricyclic antidepressants: Although data are limited, coadministration of efavirenz and tricyclic antidepressants may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Trifluoperazine: Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation, such as efavirenz.
Trimetrexate: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as trimetrexate.
Trimipramine: Although data are limited, coadministration of efavirenz and tricyclic antidepressants may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Tricyclic antidepressants share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
Ulipristal: Ulipristal is a substrate of CYP3A4 and efavirenz is a CYP3A4 inhibitor and inducer. Concomitant use may increase or decrease the plasma concentration of ulipristal resulting in an increased risk for adverse events or decrease in efficacy.
Umeclidinium; Vilanterol: Although data are limited, coadministration of efavirenz and beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval, such as efavirenz. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
Vandetanib: Avoid the concomitant use of vandetanib with drugs known to prolong the QT interval, such as efavirenz. If coadministration is necessary, an ECG is needed initially, as well as more frequent monitoring of the QT interval. If QTcF is more than 500 ms, interrupt vandetanib dosing until the QTcF is less than 450 ms; then, vandetanib may be resumed at a reduced dose. Vandetanib can prolong the QT interval in a concentration-dependent manner. Torsade de pointes (TdP) and sudden death have been reported in patients receiving vandetanib. In addition, because efavirenz is a CYP3A4 inducer, there is an unpredictable effect on vandetanib efficacy and toxicity. In a crossover study (n = 12), coadministration of vandetanib with a strong CYP3A4 inducer decreased the mean AUC of vandetanib by 40% (90% CI, 56% to 63%); a clinically meaningful change in the mean vandetanib Cmax was not observed. However, the AUC and Cmax of active metabolite, N-desmethyl-vandetanib, increased by 266% and 414%, respectively.
Vardenafil: Although data are limited, coadministration of efavirenz and vardenafil may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Vardenafil is also associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as vardenafil.
Vemurafenib: Vemurafenib has been associated with QT prolongation. ECG monitoring is recommended if vemurafenib and another QT prolonging drug, such as efavirenz, must be coadministered; closely monitor the patient for QT interval prolongation. In addition, concomitant use may result in decreased vemurafenib and efavirenz concentrations. Both drugs are substrates and inducers of CYP3A4.
Venetoclax: 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: Coadministration of efavirenz and venlafaxine 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. Venlafaxine administration is associated with a possible risk of QT prolongation; TdP has reported with post-marketing use. In addition, efavirenz may induce the CYP3A4 metabolism of venlafaxine; potentially reducing the efficacy of venlafaxine by decreasing its systemic exposure.
Verapamil: 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.
Vilazodone: Because CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone, decreased plasma concentrations of vilazodone may theoretically occur when the drug is co-administered with inducers of CYP3A4 such as efavirenz. Patients should be monitored for adverse effects or loss of efficacy while receiving topiramate and efavirenz.
Vinblastine: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as vinca alkaloids.
Vinca alkaloids: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as vinca alkaloids.
Vincristine Liposomal: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as vinca alkaloids.
Vincristine: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as vinca alkaloids.
Vinorelbine: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as vinca alkaloids.
Vorapaxar: 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: 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: Although data are limited, coadministration of efavirenz and vorinostat may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of both drugs.
Warfarin: Agents that inhibit CYP isoenzymes 3A4, 1A2, or 2C9, such as efavirenz, may decrease the metabolism of warfarin leading to increased anticoagulation effects. Monitor INR and adjust warfarin dosage as necessary.
Ziprasidone: Ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine. Given the potential for QT prolongation, ziprasidone is contraindicated for use with drugs that are known to cause QT prolongation with potential for torsades de pointes including efavirenz.
Zolpidem: 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: Efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme, such as zonisamide.

PREGNANCY AND LACTATION

Antiretroviral therapy should be provided to all women during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. In treatment-naive women, consider initiation of HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations are greater than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations are greater than 500 copies/mL. Consider initiating treatment prior to receiving resistance test results. Avoid use of efavirenz during the first trimester (particular caution during first 8 weeks of pregnancy) and in females of child-bearing potential. Data from the Antiretroviral Pregnancy Registry indicates the prevalence of birth defects following first trimester exposure to efavirenz is 2.3% (20 of 852 births; 95% CI: 1.4, 3.6). A subsequent meta-analysis of 23 studies (including Antiretroviral Pregnancy Registry data) found first trimester exposure to efavirenz to be associated with 44 birth defects among 2,026 births (1.63%; 95% CI: 0.78, 2.48). Specifically, prospectively reported defects associated with efavirenz included one neural tube defect (sacral aplasia, myelomeningocele, hydrocephalus with fetal alcohol syndrome) and a separate single case of anophthalmia, which also included severe oblique facial clefts and amniotic banding. There have also been 6 retrospective reports of findings consistent with neural tube defects, including meningomyelocele, in which all mothers were exposed to efavirenz containing regimens in the first-trimester. Although the incidence of overall birth defects does not differ from the background rate among pregnant women in the US (2.7%), the low prevalence of neural tube defects among the general population means more exposure data are required to definitively rule out an associated between neural tube defects and efavirenz. Because of the potential for teratogenicity and the known failure rates of contraception in general, regimens that contain efavirenz should be avoided in women of child-bearing potential. Due to the long half-life of efavirenz, the manufacturer recommends the use of contraceptive measures for 12 weeks after discontinuation of efavirenz. If efavirenz must be used, patients should undergo pregnancy testing prior to initiation and be counseled on the risks to the fetus and the importance of prevention of pregnancy. In particular, treatment with efavirenz should be avoided during the first 8 weeks of pregnancy, which is the primary period of fetal organogenesis. Use after the second trimester of pregnancy can be considered if other alternatives are not available and if adequate contraception can be assured postpartum. Barrier contraception should always be used, and it should be noted that efavirenz, and other non-nucleoside reverse transcriptase inhibitors as well as protease inhibitors, may affect estrogen and norethindrone blood concentrations in women receiving oral contraceptives. If a woman becomes pregnant while taking this drug, and the fetus is thus exposed to efavirenz during the first trimester, thoroughly counsel the woman regarding the potential harm to the fetus. However, because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy and pregnancy is rarely recognized before 4 to 6 weeks of pregnancy, efavirenz can be continued in pregnant women receiving an efavirenz based regimen who presents for antenatal care in the first trimester if the regimen provided virologic suppression. Additionally, second trimester ultrasound to assess fetal anatomy may be prudent in women who received efavirenz during the first trimester. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit and at least every 3 months during pregnancy; consideration may be given to monitoring every 6 months in patients on HAART with consistently suppressed viral loads and a CD4 count well above the opportunistic infection threshold. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing) at baseline in all women with HIV RNA concentrations greater than 1,000 copies/mL; testing should also be considered for HIV RNA greater than 500 but less than 1,000 copies/mL. First trimester ultrasound is recommended to confirm gestational age and provide accurate estimation of gestational age at deliver. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in women receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. If a woman decides to discontinue therapy, a planned treatment interruption, taking into account the specific pharmacokinetic and administration parameters of each drug, should occur to avoid true or functional monotherapy and the development of resistance. It is strongly recommended that health care providers who are treating HIV-infected pregnant women and their neonates report cases of prenatal exposure to antiretroviral drugs to the Antiretroviral Pregnancy Registry; telephone 800-258-4263; fax 800-800-1052; the Antiretroviral Pregnancy Registry is also accessible via the Internet.

To reduce the risk of postnatal transmission, HIV-infected mothers within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy, including efavirenz. Efavirenz has been shown to pass into human breast milk. One study found efavirenz plasma concentrations in breast-fed infants (taken 3 to 4 hours after last dose) to be 13.1% of maternal plasma concentrations; the mean infant plasma concentrations were below those considered effective for HIV treatment in adults. Other antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.

MECHANISM OF ACTION

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. It binds directly to a site on reverse transcriptase that is near but distinct from where nucleoside reverse transcriptase inhibitors (NRTIs) bind. This binding causes disruption of the enzyme's active site thereby blocking RNA-dependent and DNA-dependent DNA polymerase activities. Unlike NRTIs, efavirenz does not compete with template or nucleoside triphosphates nor does it require phosphorylation to be active. HIV-2 reverse transcriptase is not inhibited by efavirenz. The 90—95% inhibitory concentrations range from 1.7 to 25 nM.
 
In efavirenz resistant patients, mutations in reverse transcriptase occurred most frequently (>= 90%) at amino acid position 103 (lysine to asparagine). Other reverse transcriptase mutations occurring at one or more amino acid positions 98, 100, 101, 106, 108, 188, 190, and 255 are also associated with resistance to efavirenz. A mean loss in susceptibility (IC90) to efavirenz of 47-fold was observed in some clinical isolates. Cross-resistance to NNRTIs has been observed in vitro. HIV-1 strains previously characterized as efavirenz-resistant were also phenotypically resistant to nevirapine and delavirdine in vitro. However, clinically derived ZDV-resistant HIV-1 isolates tested in vitro retained susceptibility to efavirenz.
 
Avoid use of efavirenz in patients infected with HIV-2, as HIV-2 is intrinsically resistant to NNRTIs. To identify the HIV strain, The 2014 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.

PHARMACOKINETICS

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