Drug Description

Efavirenz, also known as EFV, is an HIV-1 specific, non-nucleoside reverse transcriptase inhibitor (NNRTI). [1]

References

[1] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

HIV/AIDS-Related Uses

Efavirenz was approved by the U.S. Food and Drug Administration (FDA) on September 17, 1998, for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. Efavirenz was approved under the FDA's accelerated review process, which allows approval based on analysis of surrogate markers or response, such as T-cell counts and HIV RNA viral levels, rather than clinical endpoints such as disease progression or survival. The safety and efficacy of efavirenz in children less than 3 years of age have not been established. [1]

Efavirenz should not be used as a single agent or add on as a sole agent to a failing regimen. Resistant virus emerges rapidly when efavirenz is administered as a monotherapy. The choice of new antiretroviral agents to be used in combination with efavirenz should take into consideration the potential for viral cross-resistance. [2]

References

[1] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[2] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

Dosing Information

Oral (capsule, tablet). [1]

Dosage Form

Capsules containing efavirenz 50 mg or 200 mg
Tablets (film-coated) containing efavirenz 600 mg. [2]

Adult Patients
The recommended dosage of efavirenz is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse reactions. Dosing at bedtime may improve the tolerability of nervous system symptoms. [3]

Efavirenz must be given in combination with other antiretroviral medications. [4]

If efavirenz is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz dose should be decreased to 300 mg once daily using the capsule formulation (one 200-mg and two 50-mg capsules or six 50-mg capsules). Efavirenz tablets should not be broken. [5]

If efavirenz is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of efavirenz to 800 mg once daily is recommended. [6]

Pediatric Patients
It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime. The recommended dose of efavirenz for pediatric patients 3 years of age or older weighing between 10 kg and 40 kg is shown below. The recommended dosage of efavirenz for pediatric patients weighing greater than 40 kg is 600 mg once daily. [7]

Pediatric Dose to be Given Once Daily [8]

Body Weight                                                                     Dose (mg)
10 to less than 15 kg  (22 to less than 33 lbs)            200
15 to less than 20 kg  (33 to less than 44 lbs)            250
20 to less than 25 kg  (44 to less than 55 lbs)            300
25 to less than 32.5 kg  (55 to less than 71.5 lbs)     350
32.5 to less than 40 kg  (71.5 to less than 88 lbs)     400
at least 40 kg  (at least 88 lbs)                                       600

Storage

Store efavirenz capsules and tablets at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [9]

References

[1] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[2] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[3] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[4] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[5] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[6] FDA Sustiva Prescribing Information, December 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021360s028lbl.pdf. Accessed 05/14/2012.

[7] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[8] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[9] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

Pharmacology

Efavirenz is a noncompetitive inhibitor of HIV-1 reverse transcriptase (RT). It has no inhibitory effect on HIV-2 RT or human cellular DNA polymerases alpha, beta, gamma, or delta. [1]

Peak efavirenz plasma concentrations of 1.6-9.1 μM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in peak plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. In HIV-1-infected patients at steady state, mean Cmax, mean trough plasma drug concentration (Cmin), and mean AUC were dose proportional following 200-mg, 400-mg, and 600-mg daily doses. Time-to-peak plasma concentrations were approximately 3to 5 hours and steady-state plasma concentrations were reached in 6 to10 days. In 35 patients receiving efavirenz 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 μM (mean ± SD), steady-state Cmin was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM(h). [2]

It is recommended that efavirenz be taken on an empty stomach. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse reactions. Administration of a single 600-mg dose of efavirenz capsules with a high-fat/highcaloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC∞ and a mean increase of 39% and 51% in efavirenz Cmax, respectively, relative to the exposures achieved when given under fasted conditions. Administration of a single 600-mg efavirenz tablet with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with a 28% increase in mean AUC∞ of efavirenz and a 79% increase in mean Cmax of efavirenz relative to the exposures achieved under fasted conditions. [3]

Efavirenz is highly bound (approximately 99.5% to 99.75%) to human plasma proteins, principally albumin. In HIV infected patients who received 200 mg to 600 mg of efavirenz once a day for at least 1 month, cerebrospinal fluid concentrations ranged from 0.26% to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately threefold higher than the nonprotein-bound (free) fraction of efavirenz in plasma. [4]

Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200 mg to 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22% to 42% lower) and a shorter terminal half-life of 40 to 55 hours (single dose half-life 52 to 76 hours). [5]

Efavirenz has a terminal half-life of 52 to76 hours after single doses and 40 to 55 hours after multiple doses. A one-month mass balance/excretion study was conducted using 400 mg per day with a 14C-labeled dose administered on Day 8. Approximately 14% to 34% of the radiolabel was recovered in the urine and 16% to 61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces. [6]

The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal. A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics. [7]

Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A. In vitro studies have shown that efavirenz inhibited CYP isozymes 2C9, 2C19, and 3A4 with Ki values (8.5 to 17 μM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (Ki values 82 to 160 μM) only at concentrations well above those achieved clinically. The inhibitory effect on CYP3A is expected to be similar between 200-mg, 400-mg, and 600-mg doses of efavirenz. Coadministration of efavirenz with drugs primarily metabolized by 2C9, 2C19, and 3A isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. [8]

Efavirenz is in FDA Pregnancy Category D. Efavirenz may cause fetal harm when administered during pregnancy, especially in the first trimester of pregnancy. If efavirenz is used during the first trimester of pregnancy or if pregnancy occurs while the patient is taking efavirenz, the patient should be appraised of the potential harm to the fetus. No adequate and well-controlled studies have been performed in pregnant women. In prospective reports, birth defects have occurred in 14 of 501 live births (first-trimester exposure) and 2 of 55 live births (second/third-trimester exposure). One of these reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been reported: however, this case included severe oblique facial clefts and amniotic banding, a known association with anopthalmia. Six retrospective reports identified findings consistent with neural tube defects, including meningomyelocele, in mothers exposed to efavirenz during the mother's first trimester. Although a causal relationship has not been established, similar defects have been observed in preclinical studies of efavirenz. [9]

Pregnancy should be avoided in women receiving efavirenz. Two methods of birth control, with a barrier method in combination with a nonbarrier method such as an oral or other hormonal contraceptive, should be used to avoid pregnancy in women taking efavirenz. Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of the drug is recommended. Before initiating therapy with efavirenz, women of childbearing potential should undergo pregnancy testing. It is recommended that efavirenz not be given to pregnant women except in situations in which there are no therapeutic alternatives. An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to efavirenz. Physicians may register patients online at http://www.APRegistry.com or by calling 1-800-258-4263. The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Although it is not known if efavirenz is secreted in human milk, efavirenz is secreted into the milk of lactating rats. Because of the potential for HIV transmission and the potential for serious adverse effects in nursing infants, mothers should be instructed not to breastfeed if they are receiving efavirenz. [10]

In cell culture, HIV-1 isolates with reduced susceptibility to EFV (>380-fold increase in EC90 value) emerged rapidly in the presence of drug. Genotypic characterization of these viruses identified single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in RT. [11]

Clinical isolates with reduced susceptibility in cell culture to EFV have been obtained. One or more RT substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 were observed in patients failing treatment with EFV in combination with IDV, or with ZDV plus LAM. The mutation K103N was the most frequently observed. Long-term resistance surveillance (average 52 weeks, range 4 to106 weeks) analyzed 28 matching baseline and virologic failure isolates. Sixty-one percent (17/28) of these failure isolates had decreased EFV susceptibility in cell culture with a median 88-fold change in EFV susceptibility (EC50 value) from reference. The most frequent NNRTI substitution to develop in these patient isolates was K103N (54%). Other NNRTI substitutions that developed included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%). [12]

Cross-resistance among NNRTIs has been observed. Clinical isolates previously characterized as EFV-resistant were also phenotypically resistant in cell culture to DLV and NVP compared to baseline. DLV- and/or NVP-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to EFV in cell culture. Greater than 90% of NRTI-resistant clinical isolates tested in cell culture retained susceptibility to EFV. [13]

References

[1] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[2] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[3] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[4] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[5] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[6] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[7] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[8] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[9] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[10] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[11] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[12] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[13] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

Adverse Events/Toxicity

Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1008 patients treated with regimens containing efavirenz for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among patients who received efavirenz or control regimens, respectively, were severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study 006, treatment with efavirenz was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the efavirenz and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz-treated and control-treated patients. One percent of efavirenz-treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of efavirenz cannot be determined from these reports. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits. [1]

Fifty-three percent (531/1008) of patients receiving efavirenz in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens. These symptoms included, but were not limited to, dizziness (28.1% of the 1008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). These symptoms were severe in 2.0% of patients, and 2.1% of patients discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2 weeks to 4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing efavirenz and from 3% to 5% in patients treated with a control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms. Dosing at bedtime may improve the tolerability of these nervous system symptoms. Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks, and 76 weeks for patients treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated patients were generally similar to those in the indinavir-containing control arm. Patients receiving efavirenz should be alerted to the potential for additive central nervous system effects when efavirenz is used concomitantly with alcohol or psychoactive drugs. Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery. [2]

In controlled clinical trials, 26% (266/1008) of patients treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of patients treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of patients treated with efavirenz. The incidence of Grade 4 rash (eg, erythema multiforme, Stevens-Johnson syndrome) in patients treated with efavirenz in all studies and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most patients continuing therapy with efavirenz, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in clinical trials was 1.7% (17/1008). Efavirenz can be reinitiated in patients interrupting therapy because of rash. Efavirenz should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. Rash was reported in 26 of 57 pediatric patients (46%) treated with efavirenz capsules. One pediatric patient experienced Grade 3 rash (confluent rash with fever), and two patients had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric patients was 8 days. Prophylaxis with appropriate antihistamines before initiating therapy with efavirenz in pediatric patients should be considered. [3]

Monitoring of liver enzymes before and during treatment is recommended for patients with underlying hepatic disease, including hepatitis B or C infection; patients with marked transaminase elevations; and patients treated with other medications associated with liver toxicity. A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with efavirenz needs to be weighed against the unknown risks of significant liver toxicity. [4]

Convulsions have been observed in patients being treated with efavirenz, generally in the presence of known medical history of seizures. Caution must be taken in any patient with a history of seizures. Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels. [5]

Treatment with efavirenz has resulted in increases in the concentration of total cholesterol and triglycerides. Cholesterol and triglyceride testing should be performed before initiating efavirenz therapy and at periodic intervals during therapy. [6]

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including efavirenz. During the first phase of combination antiretroviral treatment, patients may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis], which may require further evaluation and treatment. [7]

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. [8]

Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients. [9]

The most common (greater than 5%) efavirenz-associated adverse reactions of at least moderate severity are rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. [10]

Clinical adverse experiences observed in greater than 10% of 57 pediatric patients aged 3 to 16 years who received efavirenz capsules, nelfinavir, and one or more NRTIs in Study ACTG 382 were rash (46%), diarrhea/loose stools (39%), fever (21%), cough (16%), dizziness/lightheaded/fainting (16%), ache/pain/discomfort (14%), nausea/vomiting (12%), and headache (11%). The incidence of nervous system symptoms was 18% (10/57). One patient experienced Grade 3 rash, two patients had Grade 4 rash, and five patients (9%) discontinued because of rash. [11]

References

[1] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[2] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[3] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[4] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[5] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[6] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[7] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[8] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[9] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[10] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[11] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

Drug and Food Interactions

It is recommended that efavirenz be taken on an empty stomach. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse reactions. Administration of a single 600-mg dose of efavirenz capsules with a high-fat/highcaloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC∞ and a mean increase of 39% and 51% in efavirenz Cmax, respectively, relative to the exposures achieved when given under fasted conditions. Administration of a single 600-mg efavirenz tablet with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with a 28% increase in mean AUC∞ of efavirenz and a 79% increase in mean Cmax of efavirenz relative to the exposures achieved under fasted conditions. [1]

Coadministration of efavirenz can alter the concentrations of other drugs and other drugs may alter the concentrations of efavirenz. The potential for drug-drug interactions must be considered before and during therapy. [2]

For some drugs, competition for CYP3A by efavirenz could result in inhibition of their metabolism and create the potential for serious and/or life-threatening adverse reactions (eg, cardiac arrhythmias, prolonged sedation, or respiratory depression). [3]

• Antimigraine: ergot derivatives dihydroergotamine, ergonovine, ergotamine, acute ergot toxicity characterized by peripheral vasospasm and methylergonovine. Potential for serious and/or life-threatening reactions such as ischemia of the extremities and other tissues.
• Benzodiazepines: midazolam, triazolam. Potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
• Calcium channel blocker: bepridil. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
• GI motility agent: cisapride. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
• Neuroleptic: pimozide. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
• St. John’s wort (Hypericum perforatum). May lead to loss of virologic response and possible resistance to efavirenz or to the class of non-nucleoside reverse transcriptase inhibitors (NNRTI). [4]

Efavirenz has been shown in vivo to induce CYP3A. Other compounds that are substrates of CYP3A may have decreased plasma concentrations when coadministered with efavirenz. In vitro studies have demonstrated that efavirenz inhibits CYP2C9, 2C19, and 3A4 isozymes in the range of observed efavirenz plasma concentrations. Coadministration of efavirenz with drugs primarily metabolized by these isozymes may result in altered plasma concentrations of the coadministered drug. Therefore, appropriate dose adjustments may be necessary for these drugs. Drugs that induce CYP3A activity (eg, phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. [5]

Established and Other Potentially Significant Drug Interactions:

• Fosamprenavir calcium. Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with fosamprenavir plus ritonavir twice daily.
• Atazanavir. Treatment-naive patients: When coadministered with efavirenz, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and efavirenz 600 mg (once daily on an empty stomach, preferably at bedtime).Treatment-experienced patients: Coadministration of efavirenz and atazanavir is not recommended.
• Indinavir. The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. When indinavir at an increased dose (1000 mg every 8 hours) was given with efavirenz (600 mg once daily), the indinavir AUC and Cmin were decreased on average by 33-46% and 39-57%, respectively, compared to when indinavir (800 mg every 8 hours) was given alone.
• Lopinavir/ritonavir. Lopinavir/ritonavir tablets should not be administered once-daily in combination with efavirenz. In antiretroviral-naive patients, lopinavir/ritonavir tablets can be used twice daily in combination with efavirenz with no dose adjustment. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommended when used in combination with efavirenz.
• Ritonavir. When ritonavir 500 mg q12h was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when efavirenz is used in combination with ritonavir.
• Saquinavir. Should not be used as sole protease inhibitor in combination with efavirenz.
• Maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz.
• Warfarin. Plasma concentrations and effects potentially increased or decreased by efavirenz.
• Carbamazepine. There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used.
• Anticonvulsants (phenytoin, phenobarbital). Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
• Sertraline. Increases in sertraline dosage should be guided by clinical response.
• Voriconazole. Efavirenz and voriconazole must not be coadministered at standard doses. Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of efavirenz-associated side effects. When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg every 12 hours and efavirenz dose should be decreased to 300 mg once daily using the capsule formulation. Efavirenz  tablets should not be broken.
• Itraconazole. Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
• Ketoconazole. Drug interaction studies with efavirenz and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
• Posaconazole. Avoid concomitant use unless the benefit outweighs the risks.
• Clarithromycin. Plasma concentrations decreased by efavirenz; clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of efavirenz is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with efavirenz.
• Rifabutin. Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
• Rifampin. If efavirenz is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of efavirenz to 800 mg once daily is recommended.
• Diltiazem. Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem.
• Other Calcium Channel Blockers (eg, felodipine, nicardipine, nifedipine, verapamil). No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
• HMG-CoA reductase inhibitors (atorvastatin pravastatin simvastatin). Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
• Ethinyl estradiol/ Norgestimate, oral. A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
• Etonogestrel, implant. A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
• Immunosuppressants (cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A). Decreased exposure of the immunosuppressant may be expected due to CYP3A induction. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.
• Methadone. Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. [6] [7]

Based on the results of drug interaction studies, no dosage adjustment is recommended when efavirenz is given with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, lamivudine, lorazepam, nelfinavir, paroxetine, tenofovir disoproxil fumarate, and zidovudine. [8]

Specific drug interaction studies have not been performed with efavirenz and NRTIs other than lamivudine and zidovudine. Clinically significant interactions would not be expected since the NRTIs are metabolized via a different route than efavirenz and would be unlikely to compete for the same metabolic enzymes and elimination pathways. [9]

Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been observed in non-HIV-infected volunteers receiving efavirenz when the Microgenics CEDIA DAU Multi-Level THC assay was used for screening. Negative results were obtained when more specific confirmatory testing was performed with gas chromatography/mass spectrometry. Of the three assays analyzed (Microgenics CEDIA DAU Multi-Level THC assay, Cannabinoid Enzyme Immunoassay [Diagnostic Reagents, Inc], and AxSYM Cannabinoid Assay), only the Microgenics CEDIA DAU Multi-Level THC assay showed false-positive results. The other two assays provided true-negative results. The effects of efavirenz on cannabinoid screening tests other than these three are unknown. The manufacturers of cannabinoid assays should be contacted for additional information regarding the use of their assays with patients receiving efavirenz. [10]

References

[1] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[2] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[3] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[4] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[5] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[6] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[7] FDA Sustiva Prescribing Information, December 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021360s028lbl.pdf. Accessed 05/14/2012.

[8] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[9] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[10] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

Contraindications

Efavirenz is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of its components. [1]

For some drugs, competition for CYP3A by efavirenz could result in inhibition of their metabolism and create the potential for serious and/or life-threatening adverse reactions (eg, cardiac arrhythmias, prolonged sedation, or respiratory depression). [2]

Drugs That Are Contraindicated or Not Recommended for Use With Efavirenz:

• Antimigraine: ergot derivatives dihydroergotamine, ergonovine, ergotamine, acute ergot toxicity characterized by peripheral vasospasm and methylergonovine. Potential for serious and/or life-threatening reactions such as ischemia of the extremities and other tissues.
• Benzodiazepines: midazolam, triazolam. Potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
• Calcium channel blocker: bepridil. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
• GI motility agent: cisapride. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
• Neuroleptic: pimozide. Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
• St. John’s wort (Hypericum perforatum). May lead to loss of virologic response and possible resistance to efavirenz or to the class of non-nucleoside reverse transcriptase inhibitors (NNRTI). [3]

References

[1] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[2] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[3] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

Clinical Trials

Click here to search ClinicalTrials.gov for trials that use Efavirenz.

Chemistry

CAS Name

2H-3,1-Benzoxazin-2-one, 6-chloro-4-(cyclopropylethynyl)-1,4- dihydro-4-(trifluoromethyl)-, (4S)- [1]

CAS Number

154598-52-4 [2]

Molecular Formula

C14-H9-Cl-F3-N-O2

Elemental Composition

C53.27%, H2.87%, Cl11.23%, F18.05%, N4.44%, O10.14%

Molecular Weight

315.68

Physical Description

White to slightly pink crystalline powder. [3]

Solubility

Practically insoluble in water (less than 10 mcg/ml). [4]

References

[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/14/08.

[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/14/08.

[3] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

[4] FDA Sustiva Prescribing Information, November 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020972s036lbl.pdf. Accessed 07/31/2011

Further Reading

Sustiva Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Arendt G, de Nocker D, von Giesen HJ, Nolting T. Neuropsychiatric side effects of efavirenz therapy. Expert Opin Drug Saf. 2007 Mar;6(2):147-54.
Kuritzkes DR, Ribaudo HJ, Squires KE, Koletar SL, Santana J, Riddler SA, Reichman R, Shikuma C, Meyer WA 3rd, Klingman KL, Gulick RM; ACTG A5166s Protocol Team. Plasma HIV-1 RNA Dynamics in Antiretroviral-Naive Subjects Receiving either Triple-Nucleoside or Efavirenz-Containing Regimens: ACTG A5166s. J Infect Dis. 2007 Apr 15;195(8):1169-76. Epub 2007 Mar 6.
Landovitz RJ, Angel JB, Hoffmann C, Horst H, Opravil M, Long J, Greaves W, Fätkenheuer G. Phase II study of vicriviroc versus efavirenz (both with zidovudine/lamivudine) in treatment-naive subjects with HIV-1 infection. J Infect Dis. 2008 Oct 15;198(8):1113-22.
Nachega JB, Hislop M, Dowdy DW, Gallant JE, Chaisson RE, Regensberg L, Maartens G. Efavirenz versus nevirapine-based initial treatment of HIV infection: clinical and virological outcomes in Southern African adults. AIDS. 2008 Oct 18;22(16):2117-25.
ter Heine R, Scherpbier HJ, Crommentuyn KM, Bekker V, Beijnen JH, Kuijpers TW, Huitema AD. A pharmacokinetic and pharmacogenetic study of efavirenz in children: dosing guidelines can result in subtherapeutic concentrations. Antivir Ther. 2008;13(6):779-87.
Wintergerst U, Hoffmann F, Jansson A, Notheis G, Huss K, Kurowski M, Burger D. Antiviral efficacy, tolerability and pharmacokinetics of efavirenz in an unselected cohort of HIV-infected children. J Antimicrob Chemother. 2008 Jun;61(6):1336-9. Epub 2008 Mar 13.

Manufacturer Information

Efavirenz

Bristol - Myers Squibb Co
PO Box 4500
Princeton, NJ 08543-4500
Phone: 800-321-1335

Sustiva

Bristol - Myers Squibb Co
PO Box 4500
Princeton, NJ 08543-4500
Phone: 800-321-1335