Efavirenz

Trade Names:
Sustiva
- Capsules 50 mg
- Capsules 200 mg
- Tablets 600 mg

Pharmacology

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Noncompetitive inhibition of HIV-1 reverse transcriptase.

Pharmacokinetics

Absorption

C _max is 1.6 to 9.1 mcM. T _max is 3 to 5 h. 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

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

Pharmacokinetics have not been adequately studied.

Pharmacokinetics similar between men and women.

Pharmacokinetics similar between racial groups studied.

Indications and Usage

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

Contraindications

Concomitant use with astemizole, bepridil, cisapride, ergot derivatives, midazolam, pimozide, St. John's wort, triazolam, or voriconazole (in standard doses); hypersensitivity to any component of the product.

Dosage and Administration

PO 600 mg/day in combination with other antiretroviral agents.

PO 200 mg/day in combination with other antiretroviral agents.

PO 250 mg/day in combination with other antiretroviral agents.

PO 300 mg/day in combination with other antiretroviral agents.

PO 350 mg/day in combination with other antiretroviral agents.

PO 400 mg/day in combination with other antiretroviral agents.

PO 600 mg/day in combination with other antiretroviral agents.

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.

Storage/Stability

Store at room temperature, between 59° and 86°F.

Drug Interactions

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

Efavirenz may decrease plasma concentrations of these agents, which could reduce their efficacy.

Plasma concentrations of the anticonvulsant may decrease.

May decrease plasma levels of efavirenz, which may reduce antiviral activity.

Efavirenz may increase plasma concentrations, which could increase activity or toxicity of these agents.

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

May increase efavirenz plasma levels, which could increase adverse reactions.

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

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

Plasma concentrations may be increased or decreased.

Laboratory Test Interactions

False-positive urine assay screening test for cannabinoid may occur.

Adverse Reactions

Cardiovascular

Flushing, palpitations (postmarketing).

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, exfoliative dermatitis, nail disorder, necrosis requiring surgery, photoallergic dermatitis, skin discoloration, Stevens-Johnson syndrome, toxic epidermal necrolysis (postmarketing).

EENT

Abnormal vision, tinnitus (postmarketing).

GI

Diarrhea (39%); vomiting (12%); nausea (10%); vomiting (6%); dyspepsia (4%); abdominal pain (3%); constipation, malabsorption (postmarketing).

Genitourinary

Gynecomastia (postmarketing).

Hepatic

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

Lab Tests

Elevated triglycerides (11%); decreased neutrophils (10%); elevated ALT, AST, and gamma-glutamyltransferase (8%); increased amylase (6%); increased glucose (5%).

Metabolic-Nutritional

Hypercholesterolemia, hypertriglyceridemia, redistribution of body fat (postmarketing).

Musculoskeletal

Arthralgia, myalgia, myopathy (postmarketing).

Respiratory

Cough (16%); dyspnea (postmarketing).

Miscellaneous

Fever (21%); aches/discomfort (14%); pain (13%); allergic reactions (postmarketing).

Precautions

Pregnancy

Category D .

Lactation

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

Elderly

Use with caution because of the greater frequency of decreased hepatic, renal, or cardiac function, and 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 symptoms

Reported in 53% of patients.

Fat redistribution

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

Hepatitis

Monitor liver enzymes in patients with known or suspected history of hepatitis B or C infection and in patients receiving medication associated with liver toxicity.

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.

Psychiatric symptoms

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.

Skin rash

Reported in 26% of adults and 46% of children.

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 experiencing 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.

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