Efavirenz

4.6

4.6

Crystals from toluene:heptane

White to slightly pink crystalline powder

Practically insoluble in water (less than 10 mg/L)

8.55e-03 g/L

139-141 °C

139-141 °C

139 - 141 °C

Danger

H302 (52.3%): Harmful if swallowed [Warning Acute toxicity, oral]；H319 (47.7%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]；H360 (48.9%): May damage fertility or the unborn child [Danger Reproductive toxicity]；H372 (43.2%): Causes damage to organs through prolonged or repeated exposure [Danger Specific target organ toxicity, repeated exposure]；H400 (92%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]；H410 (94.3%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

P203, P260, P264, P264+P265, P270, P273, P280, P301+P317, P305+P351+P338, P318, P319, P330, P337+P317, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 88 reports by companies from 13 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including efavirenz, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Alcohol abuse complicates treatment of HIV disease and is linked to poor outcomes. Alcohol pharmacotherapies, including disulfiram (DIS), are infrequently utilized in co-occurring HIV and alcohol use disorders possibly related to concerns about drug interactions between antiretroviral (ARV) medications and DIS. This pharmacokinetics study (n?=?40) examined the effect of DIS on efavirenz (EFV), ritonavir (RTV), or atazanavir (ATV) and the effect of these ARV medications on DIS metabolism and aldehyde dehydrogenase (ALDH) activity which mediates the DIS-alcohol reaction. EFV administration was associated with decreased S-Methyl-N-N-diethylthiocarbamate (DIS carbamate), a metabolite of DIS (p?=?.001) and a precursor to the metabolite responsible for ALDH inhibition, S-methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO). EFV was associated with increased DIS inhibition of ALDH activity relative to DIS alone administration possibly as a result of EFV-associated induction of CYP 3A4 which metabolizes the carbamate to DETC-MeSO (which inhibits ALDH). Conversely, ATV co-administration reduced the effect of DIS on ALDH activity possibly as a result of ATV inhibition of CYP 3A4. DIS administration had no significant effect on any ARV studied.

Administration of efavirenz in patients receiving psychoactive drugs may result in increased CNS effects.

Efavirenz may decrease the plasma concentrations of amprenavir; no specific dosage adjustment can be recommended until additional studies are conducted.

Efavirenz may inhibit the metabolism of these medications /astemizole or cisapride/ through competition for the CYP3A4 isoenzyme, which may increase the potential for cardiac arrhythmias; use is contraindicated.

For more Interactions (Complete) data for EFAVIRENZ (15 total), please visit the HSDB record page.

Serum aminotransferase elevations above 5 times the upper limit of normal occur in 1% to 8% of patients on efavirenz, and this rate is higher in patients who have HCV coinfection. Clinically apparent hepatotoxicity due to efavirenz is rare, but many convincing cases have been published. The liver injury is usually immunoallergic in pattern and arises within 1 to 8 weeks of starting therapy. Signs of hypersensitivity are less common than with nevirapine hepatotoxicity, but symptoms can include rash, fever, and eosinophilia and sometimes facial edema, lymphadenoapthy and lymphocytosis (Cases 1 and 2). Autoantibody formation is rare. The serum enzyme pattern is variable, typically cholestatic or mixed, but sometimes hepatocellular, these cases being more severe, likely to show submassive necrosis on liver biopsy and associated with a high fatality rate. In general, however, recovery is rapid upon stopping therapy.；Likelihood score: A (well established cause of clinically apparent liver injury).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 17,000(SRC), determined from a structure estimation method(2), indicates that efavirenz is expected to be immobile in soil(SRC). Volatilization of efavirenz from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.0X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Efavirenz is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.8X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data in soil were not available(SRC, 2013).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 17,000(SRC), determined from a structure estimation method(2), indicates that efavirenz is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.0X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 580(SRC), from an estimated log Kow of 4.69(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Efavirenz may undergo hydrolysis in the environment due to the presence of functional groups that hydrolyze under environmental conditions(3). Biodegradation data in water were not available(SRC, 2013).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), efavirenz, which has an estimated vapor pressure of 3.8X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase efavirenz is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 8 hours(SRC), calculated from its rate constant of 4.2X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase efavirenz may be removed from the air by wet or dry deposition(SRC). Efavirenz contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

As a drug class, NNRTIs are commonly associated with central nervous system (CNS) effects. These effects include impaired concentration, vivid or abnormal dreams, insomnia, suicidal ideation, nausea, and vomiting. Patients who experience these adverse effects are more likely to be non-adherent and discontinue their antiretroviral therapy, leading to anti-virologic therapeutic failure. These symptoms typically arise in the first few days of treatment and decline within a few weeks of continued therapy. Lipodystrophy is also a common adverse effect of all NNRTIs and may occur during treatment with efavirenz. Other commonly encountered adverse events include rash, elevated AST or ALT, decreased neutrophils, hyperglycemia, and hyperlipidemia.；Resistance to NNRTIs, including efavirenz, occurs through reverse transcriptase gene mutations in the viral genome. Drug resistance can develop quickly when nonnucleoside reverse transcriptase inhibitors are used as monotherapy for HIV-1 infection. NNRTI-naïve patients with previous nucleoside analog reverse transcriptase inhibitor (NRTI) exposure with isolates with resistance mutations and phenotypic resistance to NRTIs appear more likely to have hypersusceptibility to the NNRTI class of drugs.；Drug-Drug Interactions；Like most NNRTIs, efavirenz correlates with many drug interactions due to the phase I cytochrome P450 (CYP) enzymes. Efavirenz is an in vitro inhibitor of CYP3A4, CYP2C9, and CYP2C19. The drug is a substrate, inducer, and inhibitor of CYP3A4. Medications that undergo metabolism through CYP2B6, 3A4, 2C9, and 2C19, and those that undergo glucuronidation, may also interact with efavirenz. Drugs that are contraindicated with efavirenz due to interactions include dasabuvir, grazoprevir, ritonavir, and voriconazole.

The toxicity of this drug is generally relative to serum concentrations. Overdose is uncommon, and life-threatening sequelae from acute overdose are rare. There is no antidote available for efavirenz overdose. Short-term toxicity is usually transient and does not require treatment interruption.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical.[Available from, as of November 15, 2013: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=154598-52-4]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of efavirenz can be estimated to be 17,000(SRC). According to a classification scheme(2), this estimated Koc value suggests that is expected to be immobile in soil.

/HUMAN EXPOSURE STUDIES/ As efforts intensify to eliminate perinatal HIV transmission, understanding kinetics of maternal-to-child transfer of antiretrovirals during pregnancy and breastfeeding is critical. Antiretroviral levels in plasma, cord blood, and breastmilk reflect exposure over short intervals. Hair concentrations reflect cumulative exposure and can uniquely quantify in utero transfer of maternal medications to infants. We measured plasma and hair antiretroviral levels in HIV-infected Ugandan mothers and their infants at delivery and during breastfeeding to assess transfer. HIV-infected pregnant women were randomized to lopinavir/ritonavir- or efavirenz-based therapy in a larger trial (the Prevention of Malaria and HIV disease in Tororo, PROMOTE). At 0, 8, and 12 weeks postpartum, plasma antiretroviral levels were measured in 117 mother-infant pairs; hair levels were assayed at 12 weeks. Ratios and correlations of infant:maternal concentrations were calculated. By 12 weeks, 90.4% of mothers reported exclusive breastfeeding. ... Moderate transfer of efavirenz occurs during pregnancy and breastfeeding (40% cumulative; 15% during breastfeeding). Despite differences in exposure, no infant seroconversions or correlations between infant hair/plasma antiretroviral levels and adverse effects were observed. Using a unique approach combining hair and plasma data, we found that different antiretrovirals have distinct kinetics of mother-to-infant transfer. Efavirenz transfers during both pregnancy and breastfeeding, whereas lopinavir and ritonavir transfer only in utero. Further study of the degree and timing of maternal-to-child transfer by antiretroviral will help optimize strategies that protect infants and minimize toxicities during periods of risk.

/HUMAN EXPOSURE STUDIES/ Substantial increases in serum concentrations of AST (SGOT) or ALT (SGPT) (more than 5 times the upper limit of normal) occurred in 3% of evaluated adults receiving efavirenz in clinical studies; the frequency of increases in AST or ALT in patients receiving efavirenz was similar to that in patients receiving regimens that did not include efavirenz. In patients who were seropositive for hepatitis B and/or C, substantial increases in serum concentrations of AST or ALT (more than 5 times the upper limit of normal) occurred in 7 or 8%, respectively, of adults receiving efavirenz and in 5 or 4%, respectively, of adults receiving regimens that did not include efavirenz. Increases in Gamma-glutamyltransferase (GGT, GGPT) (more than 5 times the upper limit of normal) occurred in 4% of patients receiving efavirenz in clinical studies, in 1.5-2% of patients receiving regimens that did not include efavirenz, and in 10% of those receiving efavirenz who were seropositive for hepatitis B and/or C. Isolated increases in GGT (i.e., increases in GGT without increases in AST and ALT) in patients receiving efavirenz may reflect drug-induced enzyme induction rather than liver toxicity. Hepatic failure and hepatitis have been reported during postmarketing surveillance.

/HUMAN EXPOSURE STUDIES/ Although a causal relationship has not been established, pancreatitis has been reported in a few patients receiving efavirenz. In addition, asymptomatic increases in serum amylase concentrations to greater than 1.5 times the upper limit of normal have been reported in 10% of patients receiving efavirenz compared with 6% of patients in control groups not receiving the drug.

/SIGNS AND SYMPTOMS/ Rash has occurred in 26% of adults receiving efavirenz in clinical studies and in 18% of adults in control groups not receiving the drug. Although treatment-emergent rash generally manifests as mild to moderate maculopapular skin eruptions (NCI grade 1 and 2 reactions), rash associated with blistering, moist desquamation, or ulceration (NCI grade 3 reaction) has been reported in about 1% of adults receiving efavirenz in clinical studies. The incidence of grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in patients receiving efavirenz in clinical studies or in the expanded access program has been reported to be 0.1%.

For more Human Toxicity Excerpts (Complete) data for EFAVIRENZ (7 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Efavirenz

vMost-DILI-concern

7

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including efavirenz, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

J05AG03

J - Antiinfectives for systemic use；J05 - Antivirals for systemic use；J05A - Direct acting antivirals；J05AG - Non-nucleoside reverse transcriptase inhibitors；J05AG03 - Efavirenz

QJ - Antiinfectives for systemic use；QJ05 - Antivirals for systemic use；QJ05A - Direct acting antivirals；QJ05AG - Non-nucleoside reverse transcriptase inhibitors；QJ05AG03 - Efavirenz

J05AG03

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.

Similar to zidovudine, efavirenz inhibits the activity of viral RNA-directed DNA polymerase (i.e., reverse transcriptase). Antiviral activity of efavirenz is dependent on intracellular conversion to the active triphosphorylated form. The rate of efavirenz phosphorylation varies, depending on cell type. It is believed that inhibition of reverse transcriptase interferes with the generation of DNA copies of viral RNA, which, in turn, are necessary for synthesis of new virions. Intracellular enzymes subsequently eliminate the HIV particle that previously had been uncoated, and left unprotected, during entry into the host cell. Thus, reverse transcriptase inhibitors are virustatic and do not eliminate HIV from the body. Even though human DNA polymerase is less susceptible to the pharmacologic effects of triphosphorylated efavirenz, this action may nevertheless account for some of the drug's toxicity.

Efavirenz diffuses into the cell where it binds adjacent to the active site of reverse transcriptase. This produces a conformational change in the enzyme that inhibits function.

40-55 hours

The terminal elimination half-life of efavirenz is prolonged in patients with chronic liver disease. Following oral administration of a single 400-mg dose of efavirenz, an elimination half-life of 152 or 118 hours was reported in individuals with or without chronic liver disease, respectively.

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.

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 HIV-1.

Efavirenz was metabolized extensively by all the species as evidenced by the excretion of none or trace quantities of parent compound in urine. Significant species differences in the metabolism of efavirenz were observed. The major metabolite excreted in the urine of all species was the O-glucuronide conjugate (M1) of the 8-hydroxylated metabolite. Efavirenz was also metabolized by direct conjugation with glucuronic acid, forming the N-glucuronide (M2) in all five species. The sulfate conjugate of 8-OH efavirenz (M3) was found in the urine of rats and cynomolgus monkeys but not in humans. In addition to the aromatic ring-hydroxylated products, metabolites with a hydroxylated cyclopropane ring (at C14) were also isolated. GSH-related products of efavirenz were identified in rats and guinea pigs. The cysteinylglycine adduct (M10), formed from the GSH adduct (M9), was found in significant quantities in only rat and guinea pig urine and was not detected in other species. In vitro metabolism studies were conducted to show that the GSH adduct was produced from the cyclopropanol intermediate (M11) in the presence of only rat liver and kidney subcellular fractions and was not formed by similar preparations from humans or cynomolgus monkeys. These studies indicated the existence of a specific glutathione-S-transferase in rats capable of metabolizing the cyclopropanol metabolite (M11) to the GSH adduct, M9.

Efavirenz is a substrate for cytochrome p450 isoforms, particularly CYP3A4 and CYP2B6. The 8-hydroxy metabolite is excreted in the urine, and the glucuronide conjugate of 8-hydroxy-efavirenz is present in plasma and urine. Sixty percent of the dose is excreted in urine as the glucuronide conjugate.

Efavirenz has known human metabolites that include 8-hydroxyefavirenz.

JE6H2O27P8

EFAVIRENZ

Established Pharmacologic Class [EPC] - Human Immunodeficiency Virus 1 Non-Nucleoside Analog Reverse Transcriptase Inhibitor

Non-Nucleoside Analog [EXT]

Mechanisms of Action [MoA] - Non-Nucleoside Reverse Transcriptase Inhibitors

Mechanisms of Action [MoA] - Cytochrome P450 3A Inducers

Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template.

Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP2C9.

Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP2C19.

Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP2B6.

Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP3A.

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

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.

Efavirenz is excreted principally in the feces, both as unchanged drug and metabolites. Excretion of efavirenz has been evaluated in individuals receiving 400 mg daily for 1 month. Following oral administration of 400 mg of radiolabeled efavirenz on day 8, 14-34% of the dose was excreted in urine (less than 1% as unchanged drug), and 16-61% was excreted in feces (predominantly as unchanged drug).

Efavirenz is about 99.5-99.75% bound to plasma proteins, principally albumin.

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. 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. Following oral administration of efavirenz 600 mg once daily in HIV-infected adults, peak plasma concentration, trough plasma concentration, and AUC of the drug at steady-state averaged 4.1 mcg/mL, 1.8 mcg/mL, and 58. mcg*hour/mL, respectively.

For more Absorption, Distribution and Excretion (Complete) data for EFAVIRENZ (8 total), please visit the HSDB record page.

MEDICATION

Anti-HIV Agents; Reverse Transcriptase Inhibitors

Use (kg; approx.) in Germany (2009): >1000；Use (kg; exact) in Germany (2009): 2025；Use (kg) in USA (2002): 10100；Consumption (g per capita; approx.) in Germany (2009): 0.0122；Consumption (g per capita; exact) in Germany (2009): 0.0247；Consumption (g per capita) in the USA (2002): 0.0358；Excretion rate: 0.21；Calculated removal (%): 65.5

Oral: Capsules: 50 mg, Sustiva, Bristol-Myers Squibb, 100 mg, Sustiva, Bristol-Myers Squibb, 200 mg, Sustiva, Bristol-Myers Squibb; Tablets: 600 mg, Sustiva, Bristol-Myers Squibb

Oral: Tablets, film-coated: 600 mg with Emtricitabine, 200 mg and tenofovir, disoproxil fumarate 300 mg, Atripla (Bristol-Myers Squibb and Gilead). /Efavirenz combination/

Trade Name: Stocrin (Merck & Co)