No

Antiretroviral Agent, Reverse Transcriptase Inhibitor (Non-Nucleoside)

Treatment of HIV-1 infections in combination with at least two other antiretroviral agents. Also has some activity against hepatitis B virus and herpes viruses.

C

Teratogenic effects have been observed in Primates receiving efavirenz. Pregnancy should be avoided. Women of childbearing potential should undergo pregnancy testing prior to initiation of efavirenz. Barrier contraception should be used in combination with other (hormonal) methods of contraception.

Clinically significant hypersensitivity to any component of the formulation

Do not use as single-agent therapy; avoid pregnancy; women of childbearing potential should undergo pregnancy testing prior to initiation of therapy; do not administer with other agents metabolized by cytochrome P-450 isoenzyme 3A4 including astemizole, cisapride, midazolam, triazolam or ergot alkaloids (potential for life-threatening adverse effects); history of mental illness/drug abuse (predisposition to psychological reactions); may cause depression and/or other psychiatric symptoms including impaired concentration, dizziness or drowsiness (avoid potentially hazardous tasks such as driving or operating machinery if these effects are noted); discontinue if severe rash (involving blistering, desquamation, mucosal involvement or fever) develops. Caution in patients with known or suspected hepatitis B or C infection (monitoring of liver function is recommended); hepatic impairment. Persistent elevations of serum transaminases >5 times the upper limit of normal should prompt evaluation - benefit of continued therapy should be weighed against possible risk of hepatotoxicity. Children are more susceptible to development of rash - prophylactic antihistamines may be used.

2% to 10%:

Central nervous system: Dizziness (2% to 10%), inability to concentrate (0% to 9%), insomnia (0% to 7%), headache (5% to 6%) abnormal dreams (0% to 4%), somnolence (0% to 3%), depression (0% to 2%), anorexia (0% to 5%), nervousness (0% to 2%), fatigue (2% to 7%), hypoesthesia (1% to 2%)

Dermatologic: Rash (5% to 20%), pruritus (0% to 2%)

Gastrointestinal: Nausea (0% to 12%), vomiting (0% to 7%), diarrhea (2% to 12%), dyspepsia (0% to 4%), elevated transaminases (2% to 3%), abdominal pain (0% to 3%)

Miscellaneous: Increased sweating (0% to 2%)

<2%: Edema (peripheral), syncope, flushing, palpitations, tachycardia, fever, pain, malaise, ataxia, depression, seizures, hallucinations, psychosis, depersonalization, amnesia, anxiety, apathy, emotional lability, agitation, confusion, euphoria, impaired coordination, migraine, speech disorder, vertigo, alopecia, eczema, folliculitis, skin exfoliation, urticaria, increased cholesterol and triglycerides, hot flashes, pancreatitis, dry mouth, taste disturbance, flatulence, renal calculus, hematuria, hepatitis, thrombophlebitis, asthenia, neuralgia, paresthesia, peripheral neuropathy, tremor, arthralgia, myalgia, abnormal vision, diplopia, tinnitus, asthma, alcohol intolerance, allergic reaction, parosmia

Pediatric patients: Rash (40%), diarrhea (39%), fever (26%), cough (25%), nausea/vomiting (16%), central nervous system reactions (9%)

Increased central nervous system symptoms and involuntary muscle contractions have been reported in accidental overdose

Treatment is supportive, activated charcoal may enhance elimination; dialysis is unlikely to remove drug

Increased effect: CYP3A4, 2C9, 2C19 inhibitor; CYP3A4 inducer; coadministration with medications metabolized by these enzymes may lead to increased concentration-related effects. Astemizole, cisapride, midazolam, triazolam and ergot alkaloids may result in life-threatening toxicities. The AUC of nelfinavir is increased (20%); AUC of both ritonavir and efavirenz are increased by 20% during concurrent therapy. The AUC of ethinyl estradiol is increased 37% by efavirenz (clinical significance unknown). May increase effect of warfarin.

Decreased effect: Other inducers of this enzyme (including phenobarbital, rifampin and rifabutin) may decrease serum concentrations of efavirenz. Concentrations of indinavir may be reduced; dosage increase to 1000 mg 3 times/day is recommended. Concentrations of saquinavir may be decreased (use as sole protease inhibitor is not recommended). Plasma concentrations of clarithromycin are decreased (clinical significance unknown). May decrease effect of warfarin.

Store below 25°C (77°F)

As a non-nucleoside reverse transcriptase inhibitor, efavirenz has activity against HIV-1 by binding to reverse transcriptase. It consequently blocks the RNA-dependent and DNA-dependent DNA polymerase activities including HIV-1 replication. It does not require intracellular phosphorylation for antiviral activity.

Absorption: Increased 50% by fatty meals

Distribution: Highly protein bound (>99%) primarily to albumin; CSF concentrations exceed free fraction in serum

Metabolism: Hepatic

Half-life: Single dose: 52-76 hours; after multiple doses: 40-55 hours

Time to peak concentration: 3-8 hours

Elimination: 14% to 34% in urine (as metabolites) and 16% to 41% in feces (primarily as efavirenz)

Oral: Dosing at bedtime is recommended to limit central nervous system effects; should not be used as single-agent therapy

10 kg to <15 kg: 200 mg once daily

15 kg to <20 kg: 250 mg once daily

20 kg to <25 kg: 300 mg once daily

25 kg to <32.5 kg: 350 mg once daily

32.5 kg to <40 kg: 400 mg once daily

greater than or equal to 40 kg: 600 mg once daily

Adults: 600 mg once daily

Dosing adjustment in renal impairment: None recommended

Dosing comments in hepatic impairment: Limited clinical experience, use with caution

May be taken with or without food. Avoid high-fat meals when taking this medication. High-fat meals increase the absorption of efavirenz.

Serum transaminases (discontinuation of treatment should be considered for persistent elevations greater than five times the upper limit of normal), cholesterol, triglycerides, signs and symptoms of infection

False positive test for cannabinoids have been reported when the CEDIA DAU Multilevel THC assay is used. False positive results with other assays for cannabinoids have not been observed

May cause difficulty in concentration, insomnia, abnormal dreams, sedation, depression, nervousness, and fatigue. May rarely cause hallucinations, psychosis, anxiety, euphoria, emotional lability, agitation.

Should not be administered with other drugs known to be metabolized by the CYP3A4 system (midazolam, triazolam, ergot alkaloids) as combination may lead to life-threatening adverse effects

No information available to require special precautions

Dry mouth and taste disturbance in <2% of patients

Efavirenz is not a cure for HIV, nor will it reduce transmission of HIV. Take as directed (usually at bedtime to reduce CNS effects), with or without food. Do not alter dose or discontinue without consulting prescriber. Avoid high fat meals when taking this medication. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake). Avoid excessive alcohol (severe reaction), prescription, and OTC sedatives unless consulting prescriber. You may experience dry mouth, taste disturbances, nausea, or vomiting (small frequent meals or sucking hard candy may help - consult prescriber if nausea or vomiting persists); diarrhea (buttermilk, boiled milk, or yogurt may help); or dizziness, anxiety, tremor, impaired coordination (use caution when driving or engaging in tasks requiring alertness until response to drug is known); Report CNS changes (acute headache, abnormal dreams, sleepiness or fatigue, seizures, hallucinations, amnesia, emotional lability, confusion); sense of fullness or ringing in ears; vision changes or double vision; muscle pain, weakness, tremors, numbness, spasticity, or change in gait; skin rash or irritation; chest pain or palpitations; or other unusual effects related to this medication. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant. Do not breast-feed.

Capsule: 50 mg, 100 mg, 200 mg

Adkins JC and Noble S, "Efavirenz," Drugs, 1998, 56(6):1055-64.

Panel on Clinical Practices for Treatment of HIV Infection, "Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents," December 1, 1998, http://www.hivatis.org/trtgdlns.html.

"Three New Drugs for HIV Infection," Med Lett Drugs Ther, 1998, 40(1041):114-6.

Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection," April 15, 1999, http://www.hivatis.org.