EFAVIR

Efavirenz (brand names Sustiva® and Stocrin®) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and is used as part of highly active antiretroviral therapy (HAART) for the treatment of a human immunodeficiency virus (HIV) type 1.

HIV infection that has not previously been treated, efavirenz and lamivudine in combination with zidovudine or tenofovir is the preferred NNRTI-based regimen.

Efavirenz is also used in combination with other antiretroviral agents as part of an expanded postexposure prophylaxis regimen to prevent HIV transmission for those exposed to materials associated with a high risk for HIV transmission.

For use in combination treatment of

HIV infection (AIDS)

Efavirenz (dideoxyinosine, ddI) is an oral non-nucleoside reverse transcriptase inhibitor (NNRTI).

It is a synthetic purine derivative and, similar to zidovudine, zalcitabine, and stavudine.

Efavirenz was originally approved specifically for the treatment of HIV infections in patients who failed therapy with zidovudine.

Currently, the CDC recommends that Efavirenz be given as part of a three-drug regimen that includes another nucleoside reverse transcriptase inhibitor (e.g., lamivudine, stavudine, zidovudine) and a protease inhibitor or efavirenz when treating HIV infection.

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

Hover over products below to view reaction partners Efavirenz 8-OH-efavirenz.

Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites.

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Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms.

One patient experienced involuntary muscle contractions.

Treatment of overdose with efavirenz should consist of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status.

Administration of activated charcoal may be used to aid removal of unabsorbed drug.

There is no specific antidote for overdose with efavirenz.

Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the drug from blood.

• Efavirenz is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product.

• Coadministration of efavirenz with elbasvir and grazoprevir is contraindicated. •Patients with previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions to any of the components of this product. •Coadministration of efavirenz with elbasvir/grazoprevir.

• Efavirenz should be taken orally once daily on an empty stomach, preferably at bedtime.

• Recommended adult dose: 600 mg.

• With rifampin, increase efavirenz dose to 800 mg once daily for patients weighing 50 kg or more.

• Pediatric dosing is based on weight. 2.1 Hepatic Function Monitor hepatic function prior to and during treatment with efavirenz.

Efavirenz is not recommended in patients with moderate or severe hepatic impairment (Child Pugh B or C) . 2.2 Adults 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.

Efavirenz capsules or tablets should be swallowed intact with liquid.

Efavirenz must be given in combination with other antiretroviral medications.

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 must not be broken. .

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. 2.3 Pediatric Patients It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime.

Table 1 describes the recommended dose of efavirenz for pediatric patients 3 months of age or older and weighing between 3.5 kg and 40 kg.

The recommended dosage of efavirenz for pediatric patients weighing 40 kg or greater is 600 mg once daily.

For pediatric patients who cannot swallow capsules, the capsule contents can be administered with a small amount of food or infant formula using the capsule sprinkle method of administration.

Table 1: Efavirenz Dosing in Pediatric Patients Patient Body Weight Efavirenz Daily Dose Number of Capsules a or Tablets b and Strength to Administer 3.5 kg to less than 5 kg 100 mg two 50 mg capsules 5 kg to less than 7.5 kg 150 mg three 50 mg capsule 7.5 kg to less than 15 kg 200 mg one 200 mg capsule 15 kg to less than 20 kg 250 mg one 200 mg + one 50 mg capsule 20 kg to less than 25 kg 300 mg one 200 mg + two 50 mg capsules 25 kg to less than 32.5 kg 350 mg one 200 mg + three 50 mg capsules 32.5 kg to less than 40 kg 400 mg two 200 mg capsules at least 40 kg 600 mg one 600 mg tablet OR three 200 mg capsules a Capsules can be administered intact or as sprinkles. b Tablets must not be crushed.

Efavirenz tablets, USP are available as follows: Tablets 600 mg are yellow, biconvex, capsule-shaped, film-coated tablets, engraved with "ML 12" on one side and plain on the other side.

Bottles of 30 NDC 33342-013-07 16.3 Storage Efavirenz tablets should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz during pregnancy.

Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

There are retrospective case reports of neural tube defects in infants whose mothers were exposed to efavirenz-containing regimens in the first trimester of pregnancy.

Prospective pregnancy data from the Antiretroviral Pregnancy Registry are not sufficient to adequately assess this risk.

Available data from the Antiretroviral Pregnancy

Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program(MACDP).

Although a causal relationship has not been established between exposure to efavirenz in the first trimester and neural tube defects, similar malformations have been observed in studies conducted in monkeys at doses similar to the human dose.

In addition, fetal and embryonic toxicities occurred in rats, at a dose ten times less than the human exposure at recommended clinical dose.

Because of the potential risk of neural tube defects, efavirenz should not be used in the first trimester of pregnancy.

Advise pregnant women of the potential risk to a fetus.

There are retrospective postmarketing reports of findings consistent with neural tube defects, including meningomyelocele, all in infants of mothers exposed to efavirenz-containing regimens in the first trimester.

Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of approximately 1000 live births following exposure to efavirenz-containing regimens (including over 800 live births exposed in the first trimester), there was no difference between efavirenz and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program.

As of the interim APR report issued December 2014, the prevalence of birth defects following first-trimester exposure was 2.3% (95% CI: 1.4%-3.6%).

One of these prospectively 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 prospectively reported.

This case also included severe oblique facial clefts and amniotic banding, which have a known association with anophthalmia.

Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits).

In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150).

The maternalsystemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values.

Three of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers.

The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in a second, and cleft palate in the third.

There was no

NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated.

In rats, efavirenz was administered either during organogenesis (gestation days to 18) or from gestation day 7 through lactation day at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with increase in the incidence of early resorptions; and doses 100 mg/kg/day and greater were associated with early neonatal mortality.

The AUC at the

NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose.

Drug concentrations in the milk on lactation day were approximately 8 times higher than those in maternal plasma.

In pregnant rabbits, efavirenz was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation days 6 through 18).

NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose.

The safety, pharmacokinetic profile, and virologic and immunologic responses of efavirenz were evaluated in antiretroviral-naive and -experienced HIV-1 infected pediatric patients 3 months to 21 years of age in three open-label clinical trials.

The type and frequency of adverse reactions in these trials were generally similar to those of adult patients with the exception of a higher frequency of rash, including a higher frequency of Grade 3 or 4 rash, in pediatric patients compared to adults.

Use of efavirenz in patients younger than 3 months of age OR less than 3.5 kg body weight is not recommended because the safety, pharmacokinetics, and antiviral activity of efavirenz have not been evaluated in this and there is a risk of developing HIV resistance if efavirenz is underdosed.

See Dosage and

Administration for dosing recommendations for pediatric patients.

Clinical studies of efavirenz did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy.