Efavirenz (efavirenz)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Efavirenz, an antiretroviral agent, is a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI).
Although the complete mechanism(s) of antiviral activity of efavirenz has not been fully elucidated, the drug inhibits human immunodeficiency virus type 1 (HIV-1) by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase. Efavirenz binds directly to HIV-1 reverse transcriptase and exerts a virustatic effect by acting as a specific, noncompetitive HIV-1 reverse transcriptase inhibitor.
Efavirenz is a highly specific inhibitor of HIV-1 reverse transcriptase and does not appear to interfere with the activity of cellular DNA polymerases, including human alpha-, beta-, gamma-, or delta-polymerases.
The pharmacokinetics of efavirenz have been studied in healthy individuals, adults with human immunodeficiency virus (HIV) infection, and HIV-infected children 3-16 years of age. The pharmacokinetics of efavirenz capsules (or capsule contents mixed with soft food or infant formula) in pediatric patients were predicted using a population pharmacokinetic model.
Following oral administration of efavirenz 200, 400, or 600 mg once daily in HIV-infected adults, mean peak plasma concentration, mean trough plasma concentration, and AUC of the drug at steady-state were dose proportional. In HIV-infected adults receiving efavirenz 200, 400, or 600 mg once daily, peak plasma concentrations of the drug generally occur in 3-5 hours and steady-state plasma concentrations are achieved in 6-10 days. Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism.
Following continued administration of efavirenz, plasma concentrations are lower than expected from single-dose studies, presumably because of increased clearance of the drug. In one study in individuals receiving efavirenz 200-400 mg once daily for 10 days, plasma concentrations of the drug were 22-42% lower than those predicted from single-dose studies. Oral bioavailability of efavirenz may be affected by administration with food.
Administration of a single 600-mg dose of efavirenz as capsules with a high-fat, high-calorie meal (894 kcal, 54 g fat, 54% of calories from fat) or a reduced-fat, normal-calorie meal (440 kcal, 2 g fat, 4% of calories from fat) increases peak plasma concentrations of the drug by 39 or 51%, respectively, and AUC by 22 or 17%, respectively, compared with administration in the fasting state. Administration of a single 600-mg dose of efavirenz as tablets with a high-fat, high-calorie meal (approximately 1000 kcal, 500-600 kcal from fat) increases peak plasma concentrations and AUC of the drug by 79 and 28%, respectively, compared with administration in the fasting state. Therefore, the manufacturer states that efavirenz should be administered on an empty stomach.
In healthy adults who received a 600-mg efavirenz dose administered by opening 200-mg capsules and mixing the contents of 3 capsules with 2 teaspoonfuls of soft food (e.g., applesauce, grape jelly, yogurt) or infant formula, the AUC of efavirenz met bioequivalency criteria compared with intact capsules administered in the fasted state.
Efavirenz is about 99.5-99.75% bound to plasma proteins, principally albumin. Efavirenz appears to induce its own metabolism. The terminal elimination half-life of efavirenz reported in single-dose studies is longer than that reported in multiple-dose studies and has averaged 52-76 hours after a single oral dose and 40-55 hours following administration of 200-400 mg daily for 10 days.
In addition, following continued administration of efavirenz, plasma concentrations are lower than expected from single-dose studies, presumably because of increased clearance. The metabolic fate of efavirenz has not been fully determined, but the drug is metabolized in the liver. Efavirenz is principally metabolized by the cytochrome P-450 (CYP) isoenzymes 3A and 2B6 to several hydroxylated metabolites, which undergo subsequent glucuronidation.
Efavirenz is excreted principally in the feces. Following oral administration of 400 mg of radiolabeled efavirenz on day 8, 14-34% of the dose was excreted in urine (nearly all in the form of metabolites), and 16-61% was excreted in feces (predominantly as unchanged drug). Because efavirenz is highly protein bound, it is unlikely that substantial amounts of the drug would be removed from the body by dialysis.
Pharmacokinetic studies have not revealed gender- or race-related differences in the pharmacokinetics of efavirenz. Pharmacokinetics of efavirenz are not affected by mild hepatic impairment (Child-Pugh class A); data are insufficient to determine whether moderate or severe hepatic impairment (Child-Pugh class B or C) affects pharmacokinetics of the drug. The pharmacokinetics of efavirenz have not been specifically studied in patients with renal impairment.
USES: This drug is used with other HIV medications to help control HIV infection. It helps to decrease the amount of HIV in your body so your immune system can work better. This lowers your chance of getting HIV complications (such as new infections, cancer) and improves your quality of life.
Efavirenz belongs to a class of drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Efavirenz is not a cure for HIV infection. To decrease your risk of spreading HIV disease to others, continue to take all HIV medications exactly as prescribed by your doctor.
Use an effective barrier method (latex or polyurethane condoms/dental dams) during sexual activity as directed by your doctor. Do not share personal items (such as needles/syringes, toothbrushes, and razors) that may have contacted blood or other body fluids. Consult your doctor or pharmacist for more details.
Generic name: efavirenz
Pronunciation: (eh-FAV-er-enz)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Efavirenz
Indications
The following indications are listed for Efavirenz:
- Hiv Infection
Also known as: Human Immunodeficiency Virus Disease, Human Immunodeficiency Virus Infection.
Dosing
If efavirenz is used for treatment of HIV-1 infection in patients receiving rifampin, those weighing >=50 kg should receive an increased efavirenz dosage of 800 mg daily.
If efavirenz is used for treatment of HIV-1 infection in patients receiving voriconazole, the voriconazole dosage should be increased to 400 mg every 12 hours and the efavirenz dosage should be reduced to 300 mg daily using the capsule formulation.
Single-entity efavirenz is commercially available as capsules or tablets.
Efavirenz capsules and tablets are administered orally once daily on an empty stomach, preferably at bedtime.
Because administration with food increases plasma efavirenz concentrations and may increase the incidence of adverse effects, the drug should be taken on an empty stomach. Administration of efavirenz at bedtime may make adverse CNS effects (e.g., dizziness, insomnia, impaired concentration, somnolence, abnormal dreams) more tolerable.
Efavirenz is used in conjunction with other antiretrovirals. Single-entity efavirenz should not be used concomitantly with efavirenz/emtricitabine/tenofovir disoproxil fumarate (tenofovir DF; e.g., Atripla(R)), unless needed for adjustment of efavirenz dosage (e.g., when the fixed combination is used concomitantly with rifampin).
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Drug interactions
Plasma concentrations of efavirenz may be altered if used concomitantly with drugs that are substrates, inhibitors, or inducers of cytochrome P-450 (CYP) 3A.
Efavirenz induces CYP3A and 2B6 and may alter plasma concentrations of drugs metabolized by these enzymes.
Efavirenz is a substrate of cytochrome P-450 (CYP) 3A and CYP2B6. Efavirenz has been shown to induce CYP3A and 2B6 in vivo; in vitro studies have shown that efavirenz is also an inhibitor of CYP2C9 and 2C19. Efavirenz did not inhibit CYP2E1 in vitro, and did not inhibit CYP2D6 or 1A2 at clinically relevant concentrations.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*Clinically important hypersensitivity reaction (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic skin eruption) to efavirenz or any other ingredient in the formulation.
*Concomitant use with elbasvir and grazoprevir.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Moderate to severe adverse effects occurring in >5% of patients receiving efavirenz include impaired concentration, abnormal dreams, rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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Safety and efficacy of single-entity efavirenz have not been established in neonates and infants <3 months of age or in those weighing <3.5 kg, and the drug should not be used in these pediatric patients.
Adverse effects reported in pediatric patients 3 months to 21 years of age receiving efavirenz are similar to those reported in adults receiving the drug. Rash has been reported more frequently in children than adults, and the incidence of grade 3 or 4 rash has been greater in children than adults. Because of the high incidence of dermatologic reactions in children, antihistamines should be considered for the prevention of rash when initiating efavirenz in children.
Efavirenz may cause fetal harm if administered during the first trimester of pregnancy. There are retrospective case reports of neural tube defects in infants born to mothers who were exposed to efavirenz during the first trimester of pregnancy. Although prospective data in humans are inadequate to assess risks and a causal relationship between efavirenz exposure in the first trimester and neural tube defects has not been established, similar malformations have been observed in animal studies. The manufacturer states that efavirenz should not be used during the first trimester of pregnancy.
The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to antiretroviral agents, including efavirenz, during pregnancy. Clinicians are encouraged to contact the registry at 800-258-4263 or https://www.apregistry.com to report cases of prenatal exposure to antiretroviral agents.
Based on prospective reports from the APR of approximately 1000 live births following exposure to efavirenz (including more than 800 live births following first-trimester exposures), there was no difference between overall birth defects with efavirenz compared with the background birth defect rate (2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program). An interim report issued in December 2014 that used data from the registry indicated that the prevalence of birth defects was 2.3% following first-trimester exposures to efavirenz. Defects reported prospectively in first-trimester exposures included 1 case of neural tube defect and 1 case of anophthalmia with severe oblique facial clefts and amniotic banding.
Females of reproductive potential should be advised about the teratogenic potential of efavirenz. Such patients should undergo pregnancy testing before initiation of therapy. If efavirenz is used during the first trimester, or if pregnancy occurs during therapy, the patient should be apprised of the potential risk to the fetus.
The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.
The manufacturer makes no specific dosage recommendations for geriatric patients, but recommends cautious dosage selection because of possible age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.
Clinical studies of efavirenz have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric individuals respond differently to the drug than younger adults. Dosage selection in elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, and/or cardiac function and the potential for concomitant disease and drug therapy.
ICD codes
No ICD codes are available for this drug.
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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