Efavirenz

315.67

315.67

1806241-263-5

JE6H2O27P8

742403

DTXSID9046029

C29027

Crystals from toluene:heptane|White to slightly pink crystalline powder

J05AR06|J05AG03|J - Antiinfectives for systemic use

2934990002

38.3

4.6

white to beige

1.53±0.1 g/cm3(Predicted)

139-141 °C

340.6±42.0 °C(Predicted)

2℃

1.582

DMSO: soluble15mg/mL, clear

-20°C Freezer

3.8X10-7 mm Hg at 25 deg C (est)

D20 -84.7° (c = 0.005 g/ml in CH3Cl); D25 -94.1° (c = 0.300 in methanol)

Henry's Law constant = 7X10-9 atm-cu m/mol at 25 °C (est)

pKa = 10.2|pKa = 12.52 (amine) (est)

Hydroxyl radical reaction rate constant = 4.2X10-11cu cm/molec-sec at 25 °C (est)

UN3082 - class 9 - PG 3 - DOT NA1993 - Environmentally hazardous substances, liquid, n.o.s. HI: all (not BR)

3

50

61

DM3440000

N

P273

H410

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.

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.

|Danger|H302 (51.72%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P264, P270, P273, P280, P281, P301+P312, P305+P351+P338, P308+P313, P314, P330, P337+P313, P391, P405, and P501|Aggregated GHS information provided by 87 companies from 11 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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.

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.

The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that initiation of efavirenz should be avoided during the first trimester of pregnancy, but initiation after the first trimester can be considered if efavirenz is the best choice for a specific woman after consideration of other alternatives.

99.5-99.75%

Efavirenz's production and use as an antiviral(1) may result in its release to the environment through various waste streams(SRC).

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).

The rate constant for the vapor-phase reaction of efavirenz with photochemically-produced hydroxyl radicals has been estimated as 4.2X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 8 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Efavirenz may undergo hydrolysis in the environment due to the presence of functional groups that hydrolyze under environmental conditions(2). A base-catalyzed second-order hydrolysis rate constant of 4.2X10+2 L/mole-sec(SRC) was estimated using a structure estimation method(3); this corresponds to half-lives of 6 hours and 27 minutes at pH values of 7 and 8, respectively(3). Efavirenz contains chromophores that absorb at wavelengths >290 nm(2) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 580 was calculated in fish for efavirenz(SRC), using an estimated log Kow of 4.69(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC).

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.

The Henry's Law constant for efavirenz is estimated as 7.0X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that efavirenz is expected to be essentially nonvolatile from water and moist soil surfaces(2). Efavirenz is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.8X10-7 mm Hg(SRC), determined from a fragment constant method(3).

While data specific to efavirenz were not located(SRC, 2013), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

Efavirenz is distributed into human milk.

Occupational exposure to efavirenz may occur through inhalation and dermal contact with this compound at workplaces where efavirenz is produced or used. Use data indicate that the general population may be exposed to efavirenz via medical administration of this compound for the treatment of viral infection. (SRC)

Efavirenz is distributed into human milk.

For use in combination treatment of HIV infection (AIDS)|FDA Label|Atripla is a fixed-dose combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate. It is indicated for the treatment of human-immunodeficiency-virus-1 (HIV-1) infection in adults with virologic suppression to HIV-1 RNA levels of < 50 copies/ml on their current combination antiretroviral therapy for more than three months. Patients must not have experienced virological failure on any prior antiretroviral therapy and must be known not to have harboured virus strains with mutations conferring significant resistance to any of the three components contained in Atripla prior to initiation of their first antiretroviral treatment regimen.The demonstration of the benefit of Atripla is primarily based on 48-week data from a clinical study in which patients with stable virologic suppression on a combination antiretroviral therapy changed to Atripla.No data are currently available from clinical studies with Atripla in treatment-naive or in heavily pretreated patients.No data are available to support the combination of Atripla and other antiretroviral agents.|Efavirenz/Emtricitabine/Tenofovir disoproxil Krka is a fixed-dose combination of efavirenz, emtricitabine and tenofovir disoproxil. It is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults aged 18 years and over with virologic suppression to HIV-1 RNA levels of < 50 copies/ml on their current combination antiretroviral therapy for more than three months. Patients must not have experienced virological failure on any prior antiretroviral therapy and must be known not to have harboured virus strains with mutations conferring significant resistance to any of the three components contained in Efavirenz/Emtricitabine/Tenofovir disoproxil Krka prior to initiation of their first antiretroviral treatment regimen.The demonstration of the benefit of efavirenz/emtricitabine/tenofovir disoproxil is primarily based on 48-week data from a clinical study in which patients with stable virologic suppression on a combination antiretroviral therapy changed to efavirenz/emtricitabine/tenofovir disoproxil.No data are currently available from clinical studies with efavirenz/emtricitabine/tenofovir disoproxil in treatment-naïve or in heavily pretreated patients.No data are available to support the combination of efavirenz/emtricitabine/tenofovir disoproxil and other antiretroviral agents.|Stocrin is indicated in antiviral combination treatment of human-immunodeficiency-virus-1 (HIV-1)-infected adults, adolescents and children three years of age and older.Stocrin has not been adequately studied in patients with advanced HIV disease, namely in patients with CD4 counts < 50 cells/mm3, or after failure of protease-inhibitor (PI)-containing regimens. Although cross-resistance of efavirenz with PIs has not been documented, there are at present insufficient data on the efficacy of subsequent use of PI-based combination therapy after failure of regimens containing Stocrin.|Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan is a fixed-dose combination of efavirenz, emtricitabine and tenofovir disoproxil. It is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults aged 18 years and over with virologic suppression to HIV-1 RNA levels of < 50 copies/ml on their current combination antiretroviral therapy for more than three months. Patients must not have experienced virological failure on any prior antiretroviral therapy and must be known not to have harboured virus strains with mutations conferring significant resistance to any of the three components contained in Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan prior to initiation of their first antiretroviral treatment regimen.The demonstration of the benefit of efavirenz/emtricitabine/tenofovir disoproxil is primarily based on 48-week data from a clinical study in which patients with stable virologic suppression on a combination antiretroviral therapy changed to efavirenz/emtricitabine/tenofovir disoproxil. No data are currently available from clinical studies with efavirenz/emtricitabine/tenofovir disoproxil in treatment-naïve or in heavily pretreated patients.No data are available to support the combination of efavirenz/emtricitabine/tenofovir disoproxil and other antiretroviral agents.|Efavirenz is indicated in antiviral combination treatment of human-immunodeficiency-virus-1 (HIV-1)-infected adults, adolescents and children 3 years of age and older.Efavirenz has not been adequately studied in patients with advanced HIV disease, namely in patients with CD4 counts < 50 cells/mm3, or after failure of protease inhibitor (PI)-containing regimens. Although cross-resistance of efavirenz with protease inhibitors (PIs) has not been documented, there are at present insufficient data on the efficacy of subsequent use of PI-based combination therapy after failure of regimens containing efavirenz.|Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva is a fixed-dose combination of efavirenz, emtricitabine and tenofovir disoproxil.It is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adults aged 18 years and over with virologic suppression to HIV-1 RNA levels of < 50 copies/ml on their current combination antiretroviral therapy for more than three months.Patients must not have experienced virological failure on any prior antiretroviral therapy and must be known not to have harboured virus strains with mutations conferring significant resistance to any of the three components contained in Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva prior to initiation of their first antiretroviral treatment regimen.The demonstration of the benefit of the combination efavirenz/emtricitabine/tenofovir disoproxil is primarily based on 48-week data from a clinical study in which patients with stable virologic suppression on a combination antiretroviral therapy changed to efavirenz/emtricitabine/tenofovir disoproxil.No data are currently available from clinical studies with combination efavirenz/emtricitabine/tenofovir disoproxil in treatment-naïve or in heavily pretreated patients.No data are available to support the combination of efavirenz/emtricitabine/tenofovir disoproxil and other antiretroviral agents.|Sustiva is indicated in antiviral combination treatment of human-immunodeficiency-virus-1 (HIV-1)-infected adults, adolescents and children three years of age and older.Sustiva has not been adequately studied in patients with advanced HIV disease, namely in patients with CD4 counts < 50 cells/mm3, or after failure of protease-inhibitor (PI)-containing regimens. Although cross-resistance of efavirenz with PIs has not been documented, there are at present insufficient data on the efficacy of subsequent use of PI-based combination therapy after failure of regimens containing Sustiva.|Treatment of human immunodeficiency virus (HIV-1) infection

Efavirenz is a nonnucleoside reverse transcriptase inhibitor used in combination with other agents in the therapy of human immunodeficiency virus (HIV) infection. Efavirenz is associated with a low rate of serum enzyme elevations during therapy and is an uncommon, but well established cause of clinically apparent acute liver injury.

Antiviral Agents

Anti-HIV Agents; Reverse Transcriptase Inhibitors|Due to ongoing neuropsychiatric adverse events in some efavirenz (EFV)-treated patients, a switch to an alternative non-nucleoside reverse transcriptase inhibitor may be considered. Rilpivirine (RPV) has been coformulated as a single-tablet regimen (STR) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and the components have demonstrated noninferior efficacy to EFV+FTC/TDF, good tolerability profile, and high adherence. After discontinuation, EFV has an extended inductive effect on cytochrome P450 (CYP) 3A4 that, after switching, may reduce RPV exposures and adversely impact clinical outcomes. This study examines the clinical implications of reduced RPV exposures with concomitant FTC/TDF and declining EFV exposures when patients, intolerant to EFV, switch from EFV/FTC/TDF to RPV/FTC/TDF. This 48-week, phase 2b, open-label, multicenter study evaluated the efficacy and safety of switching from EFV/FTC/TDF (>/= 3 months duration) to RPV/FTC/TDF. Virologic suppression (HIV-1 RNA <50 copies/mL), safety, and EFV and RPV pharmacokinetics were assessed. At weeks 12 and 24, all 49 dosed subjects remained suppressed on RPV/FTC/TDF. At week 48, 46 (93.9%) subjects remained suppressed and virologic failure occurred in 2/49 (4.1%) subjects with no emergence of resistance. EFV concentrations were above the 90th percentile for inhibitory concentration (IC90) for several weeks after EFV discontinuation, and RPV exposures were in the range observed in phase 3 studies by approximately 2 weeks post switch. No subjects discontinued the study due to an adverse event. Switching from EFV/FTC/TDF to RPV/FTC/ TDF was a safe, efficacious option for virologically suppressed HIV-infected patients with EFV intolerance wishing to remain on an STR.|Efavirenz is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. /Included in US product labeling/

To report a case of acquired long QT syndrome that, after exclusion of all other possible causes, was probably related to therapy with efavirenz, a novel nonnucleoside reverse transcriptase inhibitor.|About 53% of adults receiving efavirenz (600 mg once daily) in controlled clinical studies reported adverse CNS effects such as abnormal dreams, abnormal thinking, agitation, amnesia, confusion, depersonalization, dizziness, euphoria, hallucinations, impaired concentration, insomnia, somnolence, and stupor; these adverse effects were reported in 25% of adults in the control groups not receiving efavirenz. These effects were described as mild (do not interfere with daily activities) in 33.3%, moderate (may interfere with daily activities) in 17.4%, or severe (interrupt usual daily activities) in 2% of patients receiving efavirenz and required discontinuance of the drug in 2.1%. Dizziness was reported in 28.1% and insomnia was reported in 16.3% of patients receiving the drug. Impaired concentration, somnolence, or abnormal dreams were reported in 6.2-8.3% and hallucinations were reported in 1.2% of patients.|Serious adverse psychiatric symptoms have been reported rarely in adults receiving efavirenz. Severe depression, suicidal ideation, nonfatal suicide attempts, aggressive behavior, paranoid reactions, or manic reactions have been reported in 0.4-1.6% of patients receiving efavirenz in controlled clinical studies; these psychiatric symptoms were reported in up to 0.6% of those in the control groups not receiving the drug. The incidence of each of these psychiatric symptoms ranges from 0.3% (for manic reactions) to 2% (for severe depression or suicidal ideation) in patients with a prior history of psychiatric disorders, and these individuals appear to be at greater risk of such symptoms than other individuals. Other psychiatric symptoms reported in controlled clinical studies in adults receiving efavirenz include depression (15.8%), anxiety (11.1%), and nervousness (6.3%); these symptoms were reported in 13.1, 7.6, or 2%, respectively, of those in the control groups not receiving the drug. Although a causal relationship with efavirenz has not been established, there have been occasional postmarketing reports of death by suicide, delusions, or psychosis-like behavior in patients receiving efavirenz. In addition, aggressive reactions, agitation, emotional lability, mania, neurosis,and paranoia have been reported during postmarketing surveillance. There is no evidence that patients who develop adverse CNS effects (e.g., dizziness, insomnia, impaired concentration, abnormal dreams) during efavirenz therapy are at greater risk of developing psychiatric symptoms.|Fatigue has been reported in up to 7% of adults receiving efavirenz in clinical studies. Other adverse nervous system effects reported during postmarketing surveillance include abnormal coordination, ataxia, seizures, hypoesthesia, paresthesia, neuropathy, and tremor. Adverse CNS effects occurred in 18% of children receiving efavirenz in clinical studies.|For more Drug Warnings (Complete) data for EFAVIRENZ (21 total), please visit the HSDB record page.

High-level resistance to efavirenz can develop in vitro and in vivo. Passage of HIV-1 in the presence of efavirenz yielded a strain with a greater than 300 fold decreased susceptibility. This strain had mutations at reverse transcriptase codons 100, 179, and 181. High-level in vitro resistance also was associated with mutations at codon 188. The most frequent resistance-associated mutation in patients receiving efavirenz is at codon 103. Additional mutations have been reported at codons 100, 106, 188, and 190.

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.

Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP2B6. (See all compounds classified as Cytochrome P-450 CYP2B6 Inducers.)|Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP2C9. (See all compounds classified as Cytochrome P-450 CYP2C9 Inhibitors.)|Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP2C19. (See all compounds classified as Cytochrome P-450 CYP2C19 Inhibitors.)|Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP3A. (See all compounds classified as Cytochrome P-450 CYP3A Inducers.)|Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template. (See all compounds classified as Reverse Transcriptase Inhibitors.)

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.

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.

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.

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.

Treatment of overdose: To decrease absorption: Patients may benefit from treatment with activated charcoal. Monitoring: Patient's vital signs should be monitored. Supportive care: Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|For more Antidote and Emergency Treatment (Complete) data for EFAVIRENZ (7 total), please visit the HSDB record page.

/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.

(s)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

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)

Human drugs -> Atripla -> EMA Drug Category|Antivirals for systemic use -> Human pharmacotherapeutic group|Human drugs -> Efavirenz/Emtricitabine/Tenofovir disoproxil Krka -> EMA Drug Category|Human drugs -> Stocrin -> EMA Drug Category|Human drugs -> Efavirenz/Emtricitabine/Tenofovir disoproxil Mylan -> EMA Drug Category|Human drugs -> Efavirenz Teva -> EMA Drug Category|Human drugs -> Efavirenz/Emtricitabine/Tenofovir disoproxil Zentiva -> EMA Drug Category|Human drugs -> Sustiva -> EMA Drug Category|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients