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Efavirenz

Pronunciation: eh-FAV-ir-enz
Class: NNRTI

Trade Names

Sustiva
- Capsules, oral 50 mg
- Capsules, oral 200 mg
- Tablets, oral 600 mg

Pharmacology

Noncompetitive inhibition of HIV-1 reverse transcriptase.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

C max is 1.6 to 9.1 mcM. T max is 3 to 5 h. Steady state is reached in 6 to 10 days. Food significantly increases the AUC and C max . Should be taken on an empty stomach.

Distribution

Approximately 99.5% to 99.75% is protein bound, predominantly to albumin.

Metabolism

Metabolized in the liver by CYP-450 (primarily CYP3A4 and CYP2B6) to inactive metabolites.

Elimination

The half-life is 52 to 76 h (single dose) and 40 to 55 h (multiple doses). Approximately 14% to 34% is excreted in the urine (less than 1% as unchanged drug), and 16% to 61% is excreted in the feces.

Special Populations

Renal Function Impairment

Pharmacokinetics have not been studied. Because less than 1% is excreted unchanged in the urine, the impact of renal impairment should be minimal.

Hepatic Function Impairment

Pharmacokinetics have not been adequately studied.

Children

Pharmacokinetics in children were similar to adults.

Gender

Pharmacokinetics are similar between men and women.

Race

Pharmacokinetics are similar among the racial groups studied.

Indications and Usage

Treatment of HIV-1 infection in combination with other antiretroviral agents.

Contraindications

Concomitant use with bepridil, cisapride, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), midazolam, pimozide, St. John's wort ( Hypericum perforatum ), or triazolam; hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, toxic skin eruptions) to any component of the product.

Dosage and Administration

Adults

PO 600 mg at bedtime in combination with other antiretroviral agents.

Children 3 y of age and older 10 to less than 15 kg

PO 200 mg at bedtime in combination with other antiretroviral agents.

15 to less than 20 kg

PO 250 mg at bedtime in combination with other antiretroviral agents.

20 to less than 25 kg

PO 300 mg at bedtime in combination with other antiretroviral agents.

25 to less than 32.5 kg

PO 350 mg at bedtime in combination with other antiretroviral agents.

32.5 to less than 40 kg

PO 400 mg at bedtime in combination with other antiretroviral agents.

40 kg or more

PO 600 mg at bedtime in combination with other antiretroviral agents.

Coadministration With Voriconazole
Adults

PO When coadministered with voriconazole, increase the voriconazole maintenance dosage to 400 mg every 12 h and decrease the efavirenz dosage to 300 mg once daily, using the capsule formulation.

General Advice

  • Administer at bedtime to improve tolerance of CNS symptoms.
  • Tablets should be swallowed whole and not broken, crushed, or chewed.
  • Administer on an empty stomach, preferably at bedtime.
  • Must be given in combination with other antiretroviral agents (protease inhibitors and/or nucleoside analog reverse transcriptase inhibitors).

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Astemizole, bepridil, cisapride, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), midazolam, pimozide, triazolam

Efavirenz may elevate levels of these drugs, which may increase the risk of arrhythmias, hematologic abnormalities, or other potentially serious adverse reactions. Coadministration is contraindicated.

Atazanavir, calcium channel blockers (eg, diltiazem, felodipine, nicardipine, nifedipine, verapamil), clarithromycin, fosamprenavir, HMG-CoA reductase inhibitors (atorvastatin, pravastatin, simvastatin), indinavir, itraconazole, ketoconazole, lopinavir, methadone, posaconazole, rifabutin, rifampin, saquinavir, sertraline

Efavirenz may decrease plasma concentrations of these agents, which could reduce their efficacy. Monitor the clinical response of the patient and adjust the dose of these agents as needed. In some instances, alternative therapy should be considered. Saquinavir should not be used as the sole protease inhibitor in combination with efavirenz.

Cabazitaxel, ixabepilone

Plasma concentrations and clinical efficacy of these agents may be reduced. Avoid concurrent use.

Carbamazepine, phenobarbital, phenytoin

Plasma concentrations of the anticonvulsant and efavirenz may decrease. Periodically monitor anticonvulsant plasma levels and adjust the anticonvulsant dose as needed, or administer an alternative anticonvulsant.

Food

Efavirenz plasma concentrations may be elevated, increasing the risk of adverse reactions. Efavirenz should be taken on an empty stomach, preferably at bedtime.

Hormonal contraceptives

Efavirenz does not affect ethinyl estradiol concentrations, but progestin concentrations are markedly decreased. A reliable method of barrier contraception must be used in addition to hormonal contraception.

Immunosuppressants (eg, cyclosporine, sirolimus, tacrolimus)

Decreased exposure of immunosuppressants metabolized by CYP3A4 may be expected. Closely monitor immunosuppressant concentrations for at least 2 wk when starting or stopping efavirenz.

Maraviroc

Maraviroc plasma concentrations and clinical efficacy may be decreased. Maraviroc dosage adjustment may be required. Coadministration of maraviroc and efavirenz is contraindicated in patients with severe renal impairment (CrCl 30 mL/min).

Nevirapine

Efavirenz plasma concentrations and clinical efficacy may be reduced. However, the risk of adverse reactions may be increased. Coadministration is not recommended.

Ritonavir

Efavirenz may increase efavirenz plasma levels, which could increase adverse reactions (eg, dizziness, elevated liver enzymes, paresthesia). Clinical and laboratory (eg, liver enzymes) monitoring is indicated. Adjust therapy as needed.

St. John's wort

May reduce efavirenz plasma concentrations, which may decrease the clinical efficacy. Coadministration is contraindicated.

Voriconazole

Contraindicated at standard doses. Voriconazole doses should be increased while efavirenz doses should be decreased.

Warfarin

Plasma concentrations may be increased or decreased. Monitor coagulation parameters and adjust the warfarin dose as needed.

Laboratory Test Interactions

False-positive urine assay screening test for cannabinoid may occur when the Microgenics Cedia DAU Multi-Level THC assay is used for screening.

Adverse Reactions

The following adverse reactions are for efavirenz in combination with other antiretrovirals:

CNS

Depression (19%); dizziness/light-headedness/fainting (16%); anxiety (13%); headache (11%); fatigue (8%); insomnia, nervousness (7%); impaired concentration (5%); abnormal dreams (3%); somnolence (2%); abnormal coordination, aggressive reactions, agitation, asthenia, ataxia, cerebellar coordination and balance disturbances, convulsions, delusions, emotional lability, hypoesthesia, mania, neuropathy, neurosis, paranoia, paresthesia, psychosis, suicide, tremor (postmarketing).

Dermatologic

Rash (46%); pruritus (9%); erythema multiforme, flushing, photoallergic dermatitis, Stevens-Johnson syndrome (postmarketing).

EENT

Abnormal vision, tinnitus (postmarketing).

GI

Diarrhea (39%); nausea/vomiting (12%); dyspepsia (4%); abdominal pain (3%); anorexia (2%); constipation, malabsorption (postmarketing).

Hepatic

Hepatic enzyme increase, hepatic failure, hepatitis (postmarketing).

Lab Tests

Elevated total cholesterol (54%); elevated ALT (20%); elevated AST (13%); elevated triglycerides (11%); decreased neutrophils (10%); elevated GGT (8%); increased amylase (6%); increased glucose (5%).

Musculoskeletal

Arthralgia, myalgia, myopathy (postmarketing).

Respiratory

Cough (16%); dyspnea (postmarketing).

Miscellaneous

Fever (21%); aches/discomfort (14%); pain (13%); allergic reactions, gynecomastia, redistribution of body fat (postmarketing).

Precautions

Monitor

Monitor cholesterol and triglycerides before initiating therapy and at periodic intervals during therapy. Monitor LFTs before and during treatment in patients with underlying hepatic disease, including hepatitis B and/or C, with marked transaminases elevations, and who are taking other medications associated with liver toxicity. Consider monitoring LFTs in patients without preexisting hepatic dysfunction or other risk factors.


Pregnancy

Category D (per manufacturer's prescribing information); Category C . Efavirenz may cause fetal harm when administered during the first trimester.

Lactation

Undetermined. HIV-infected mothers should not breast-feed their infants.

Children

Efavirenz has not been studied in children younger than 3 y of age.

Elderly

Use with caution because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

Hepatic Function

Use with caution.

Convulsions

Use with caution in patients with history of seizures. Convulsions have been reported.

CNS effects

CNS effects (eg, abnormal dreams, dizziness, hallucinations, impaired concentration, insomnia, somnolence) were reported in 53% of patients. Symptoms usually begin during the first or second day of therapy and generally resolve after the first 2 to 4 wk of therapy.

Dermatologic effects

Skin rash was reported in 26% of adults and 46% of children. Rashes are usually mild to moderate maculopapular skin eruptions that occur within the first 2 wk of therapy and resolve within 1 month.

Fat redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, may occur.

Hepatotoxicity

Hepatic failure has occurred in patients with no preexisting hepatic disease or other identifiable risk factors.

Immune reconstitution syndrome

May occur, necessitating further evaluation and treatment.

Lipids

Increases in total cholesterol and triglycerides have been reported.

Monotherapy

Resistant virus may emerge rapidly. Do not use efavirenz as a single agent to treat HIV-1.

Psychiatric effects

Serious adverse psychiatric experiences have been reported. Patients with a history of psychiatric disorders may be at greater risk. There have been occasional reports of death by suicide, delusions, and psychosis-like behavior.

Overdosage

Symptoms

Increased CNS symptoms, involuntary muscle contractions.

Patient Information

  • Instruct patient to take efavirenz at the same time each day as prescribed in combination with other antiviral drugs and not to skip doses, which could increase the viral load.
  • Inform patient not to alter the dose or discontinue therapy without consulting health care provider.
  • Inform patient that efavirenz may cause dizziness, impaired concentration, or drowsiness, and to avoid potentially hazardous tasks such as driving or operating machinery if they experience these symptoms.
  • Inform patient that dosing at bedtime improves the tolerability of CNS symptoms.
  • Alert patient to the potential for additive CNS effects when efavirenz is used concomitantly with alcohol or psychoactive drugs.
  • Caution patient or family that long-term effects and adverse reactions are not known. Therefore, report any problems to the primary health care provider.
  • Warn patient of the potential adverse reactions and drug/drug interactions.
  • Instruct patient to notify health care provider immediately if signs of rash or rash accompanied by fever, blistering, oral lesions, conjunctivitis, swelling, muscle or joint aches, general malaise, or infection such as a sore throat, fever, cough, or respiratory congestion occur.
  • Instruct patient to notify health care provider immediately if symptoms of serious psychiatric adverse reactions occur.
  • Inform patient of potential false-positive urine cannabinoid test results.
  • Inform patient that efavirenz has not been shown to reduce the risk of passing HIV to others through sexual contact or blood contamination. Encourage patients to practice abstinence or safe sex and to not share needles.
  • Advise women to use barrier contraception in combination with other methods of contraception (eg, oral or other hormonal contraceptives).
  • Advise women to continue to use contraception for 12 wk after stopping this medicine.
  • Caution mothers to discontinue breast-feeding while receiving efavirenz because there is potential for adverse reactions from the drug in breast-feeding infants and transmission of the HIV virus.

Copyright © 2009 Wolters Kluwer Health.

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