Efavirenz tablets in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and in pediatric patients at least 3 months old and weighing at least 3.5 kg. Efavirenz is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 infection in adults and in pediatric patients at least 3 months old and weighing at least 3.5 kg.
(1)
Contraindications
Efavirenz tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (eg, 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 [see Warnings and Precautions (5.1) and Drug Interactions ( 7.1)].
Patients with previously demonstrated hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. (4)
Coadministration of efavirenz with elbasvir/grazoprevir.
Warnings and precautions
QTc prolongation: Consider alternatives to efavirenz in patients taking other medications with a known risk of Torsade de Pointes or in patients at higher risk of Torsade de Pointes. (5.2)
Do not use as a single agent or add on as a sole agent to a failing regimen. Consider potential for cross-resistance when choosing other agents. (5.3)
Not recommended with ATRIPLA, which contains efavirenz, emtricitabine, and tenofovir disoproxil fumarate, unless needed for dose adjustment when coadministered with rifampin. (5.4)
Serious psychiatric symptoms: Immediate medical evaluation is recommended for serious psychiatric symptoms such as severe depression or suicidal ideation. (5.5, 17)
Nervous system symptoms (NSS): NSS are frequent and usually begin 1 to 2 days after initiating therapy and resolve in 2 to 4 weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms. (5.6 , 6.1 , 17)
Embryo-Fetal Toxicity: Avoid administration in the first trimester of pregnancy as fetal harm may occur. (5.7 , 8.1)
Hepatotoxicity: Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis B or C coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, a few occurred in patients with no pre-existing hepatic disease. (5.9 , 6.1 , 8.6)
Rash: Rash usually begins within 1 to 2 weeks after initiating therapy and resolves within 4 weeks. Discontinue if severe rash develops. (5.8 , 6.1 , 17)
Convulsions: Use caution in patients with a history of seizures . (5.10)
Lipids: Total cholesterol and triglyceride elevations. Monitor before therapy and periodically thereafter. (5.11)
Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.12)
Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.13 , 17)
5.1Drug Interactions
Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A. Likewise, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A or CYP2B6. The most prominent effect of efavirenz at steady-state is induction of CYP3A and CYP2B6 [See Dosage and Administration (2.2) and Drug Interactions ( 7.1)].
5.2QTc Prolongation
QTc prolongation has been observed with the use of efavirenz [see Drug Interactions (7.3 , 7.4) and Clinical Pharmacology ( 12.2)]. Consider alternatives to efavirenz tablets when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes.
5.3Resistance
Efavirenz tablets must not be used as a single agent to treat HIV-1 infection or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when efavirenz is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with efavirenz should take into consideration the potential for viral cross-resistance.
5.4Coadministration with Related Products Coadministration
of efavirenz tablets with ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) is not recommended unless needed for dose adjustment (eg, with rifampin), since efavirenz is one of its active ingredients.
5.5Psychiatric Symptoms
Serious psychiatric adverse experiences have been reported in patients treated with efavirenz tablets. In controlled trials of 1,008 patients treated with regimens containing efavirenz tablets for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among patients who received efavirenz tablets or control regimens, respectively, were severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%).
When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study 006, treatment with efavirenz was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the efavirenz tablets and control treatment groups.
In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz tablets-treated and control-treated patients. One percent of efavirenz tablets-treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, psychosis-like behavior and catatonia, although a causal relationship to the use of efavirenz tablets cannot be determined from these reports.
Postmarketing cases of catatonia have also been reported and may be associated with increased efavirenz exposure. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of efavirenz tablets, and if so, to determine whether the risks of continued therapy outweigh the benefits. [See Adverse Reactions (6.1).]
5.6Nervous System Symptoms
Fifty-three percent (531/1,008) of patients receiving efavirenz tablets in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens [see Adverse Reactions (6.1 , Table 3)]. These symptoms included, but were not limited to, dizziness (28.1% of the 1,008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7%), abnormal dreams (6.2%), and hallucinations (1.2%).
These symptoms were severe in 2% of patients; and 2.1% of patients discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2 to 4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing efavirenz tablets and from 3% to 5% in patients treated with a control regimen.
Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms [see Warnings and Precautions (5.5)]. Dosing at bedtime may improve the tolerability of these nervous system symptoms [see Dosage and Administration ( 2)]. Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks, and 76 weeks for patients treated with efavirenz tablets + zidovudine + lamivudine, efavirenz tablets + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz tablets-treated patients were generally similar to those in the indinavir-containing control arm.
Patients receiving efavirenz tablets should be alerted to the potential for additive central nervous system effects when efavirenz tablets are used concomitantly with alcohol or psychoactive drugs. Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery.
5.7Embryo-Fetal Toxicity
Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman. Advise females of reproductive potential who are receiving efavirenz tablets to avoid pregnancy. [See Us
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Interactions
Coadministration of efavirenz can alter the concentrations of other drugs and other drugs may alter the concentrations of efavirenz. The potential for drug-drug interactions should be considered before and during therapy. (7)
7.1 Potential for Efavirenz to Affect other Drugs Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with efavirenz tablets.
7.2Potential for Other Drugs to Affect Efavirenz
Drugs that induce CYP3A activity (eg, phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations [see Dosage and Administration (2.2)].
7.3QT Prolonging Drugs
There is limited information available on the potential for a pharmacodynamic interaction between efavirenz and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of efavirenz [see Clinical Pharmacology ( 12.2)]. Consider alternatives to efavirenz when coadministered with a drug with a known risk of Torsade de Pointes.
7.4Established and Other Potentially Significant Drug Interactions
Drug interactions with efavirenz tablets are summarized in Tables 5. For pharmacokinetics data, [see Clinical Pharmacology (12.3)] Tables 7 and 8. This table includes potentially significant interactions, but is not all inclusive. Table 5: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class: Drug Name Effect Clinical Comment HIV antiviral agents Protease inhibitor: Fosamprenavir calcium ↓amprenavir Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established.
Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz tablets are administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz tablets are administered with fosamprenavir plus ritonavir twice daily. Protease inhibitor: Atazanavir ↓atazanavir * Treatment-naive patients: When coadministered with efavirenz tablets, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and efavirenz tablets 600 mg (once daily on an empty stomach, preferably at bedtime).
Treatment-experienced patients: Coadministration of efavirenz tablets and atazanavir is not recommended. Protease inhibitor: Indinavir ↓indinavir * The optimal dose of indinavir, when given in combination with efavirenz tablets, is not known. Increasing the indinavir dose to 1,000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz tablets. Protease inhibitor: Lopinavir/ritonavir ↓lopinavir * Lopinavir/ritonavir once daily dosing is not recommended when coadministered with efavirenz tablets.
The dose of lopinavir/ritonavir must be increased when coadministered with efavirenz tablets. See the lopinavir/ritonavir prescribing information for dose adjustments of lopinavir/ritonavir when coadministered with efavirenz in adult and pediatric patients. Protease inhibitor: Ritonavir ↑ritonavir * ↑efavirenz * Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz tablet is coadministered with ritonavir.
Protease inhibitor: Saquinavir ↓saquinavir * Appropriate doses of the combination of efavirenz tablets and saquinavir/ritonavir with respect to safety and efficacy have not been established. NNRTI: Other NNRTIs ↑ or ↓efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. ↑Efavirenz tablets should not be coadministered with other NNRTIs. CCR5 co-receptor antagonist: Maraviroc ↓maraviroc * Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz.
Hepatitis C antiviral agents Boceprevir ↓ boceprevir * Concomitant administration of boceprevir with efavirenz tablet is not recommended because it may result in loss of therapeutic effect of boceprevir. Elbasvir/Grazoprevir ↓ elbasvir ↓ grazoprevir Coadministration of clopidogrel with elbasvir/grazoprevir is contraindicated [ see Contraindications (4) ] because it may lead to loss of virologic response to elbasvir/grazoprevir.
Pibrentasvir/Glecaprevir ↓ pibrentasvir ↓ glecaprevir Coadministration of clopidogrel is not recommended because it may lead to reduced therapeutic effect of pibrentasvir/glecaprevir. Simeprevir ↓ simeprevir * ↔efavirenz * Concomitant administration of simprevir with efavirenz tablet is not recommended because it may result in loss of therapeutic effect of simeprevir. Velpatasvir/ Sofosbuvir ↓ velpatasvir Coadministration of efavirenz and sofosbuvir/velpatasvir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir.
Velpatasvir /Sofosbuvir /Voxilaprevir velpatasvir sofosbuvir Coadministration of efavirenz and sofosbuvir/velpatasvir/voxilaprevir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir. Other agents Anticoagulant: Warfarin ↑ or ↓warfarin Monitor INR and adjust warfarin dosage if necessary. Anticonvulsants: Carbamazepine ↓carbamazepine * ↓efavirenz * There are insufficient data to make a dose recommendation for efavirenz.
Alternative anticonvulsant treatment should be used. Phenytoin Phenobarbital ↓anticonvulsant ↓efavirenz Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. Antidepressants: Bupropion Sertraline ↓bupropion * ↓sertraline * Increases in bupropion dosage should be guided by clinical response. Bupropion dose should not exceed the maximum recommended dose.
Increases in sertraline dosage should be guided by clinical response. Antifungals: Voriconazole ↓voriconazole * ↑efavirenz * Efavirenz tablets and voriconazole should not be coadministered at standard doses. When voriconazole is coadministered with efavirenz tablets, voriconazole maintenance dose should be increased to 400 mg every 12 hours and efavirenz tablets dose should be decreased to 300 mg once daily using the capsule formulation.
Efavirenz tablets must not be broken. [ See Dosage and Administration (2.2) and Clinical Pharmacology (12.3, Tables 7 and 8) .] Itraconazole ↓itraconazole * ↓hydroxyitraconazole * Consider alternative antifungal treatment because no dose recommendation for itraconazole can be made. Ketoconazole ↓ketoconazole Consider alternative antifungal treatment because no dose recommendation for ketoconazole can be made. Posaconazole ↓posaconazole * Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: Clarithromycin ↓ clarithromycin * ↑14-OH metabolite * Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation. Antimycobacterials: Rifabutin ↓ rifabutin * Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. Rifampin ↓efavirenz * Increase efavirenz tablets to 800 mg once daily when coadministered with rifampin to patients weighing 50 kg or more.
Antimalarials: Artemether/ lumefantrine Atovaquone/ proguanil ↓ artemether* ↓ dihydroartemisinin* ↓ lumefantrine* ↓ atovaquone ↓ proguanil Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation. Concomitant administration is not recommended. Calcium channel blockers: Diltiazem ↓diltiazem * ↓desacetyl diltiazem * ↓N-monodesmethyl diltiazem * Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem).
No dose adjustment of efavirenz is necessary when administered with diltiazem. Others (eg,
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There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz tablets during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Risk Summary 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. Data Human Data 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 1,000 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% to 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.
Animal Data 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 maternal systemic 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 7 to 18) or from gestation day 7 through lactation day 21 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 10 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). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose.
Adverse reactions
The most significant adverse reactions observed in patients treated with efavirenz tablets are:
psychiatric symptoms [see Warnings and Precautions ( 5.5)],
nervous system symptoms [see Warnings and Precautions (5.6)],
rash [see Warnings and Precautions (5.8)].
hepatotoxicity [see Warnings and Precautions ( 5.9)] Most common adverse reactions (>5%, moderate-severe) are impaired concentration, abnormal dreams, rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. (6) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice. Adverse Reactions in Adults The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with efavirenz tablets in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting.
Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of efavirenz tablets-treated patients in two controlled clinical trials are presented in Table 2. Table 2: Selected Treatment-Emergent a Adverse Reactions of Moderate or Severe Intensity Reported in ≥2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364 Adverse Reactions Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients Efavirenz tablets b + ZDV/LAM (n=412) 180 weeks c Efavirenz tablets b + Indinavir (n=415) 102 weeks c Indinavir + ZDV/LAM (n=401) 76 weeks c Efavirenz tablets b + Nelfinavir + NRTIs (n=64) 71.1 weeks c Efavirenz tablets b + NRTIs (n=65) 70.9 weeks c Nelfinavir + NRTIs (n=66) 62.7 weeks c Body as a Whole Fatigue 8% 5% 9% 0 2% 3% Pain 1% 2% 8% 13% 6% 17% Central and Peripheral Nervous System Dizziness 9% 9% 2% 2% 6% 6% Headache 8% 5% 3% 5% 2% 3% Insomnia 7% 7% 2% 0 0 2% Concentration impaired 5% 3% <1% 0 0 0 Abnormal dreams 3% 1% 0 — — — Somnolence 2% 2% <1% 0 0 0 Anorexia 1% <1% <1% 0 2% 2% Gastrointestinal Nausea 10% 6% 24% 3% 2% 2% Vomiting 6% 3% 14% — — — Diarrhea 3% 5% 6% 14% 3% 9% Dyspepsia 4% 4% 6% 0 0 2% Abdominal pain 2% 2% 5% 3% 3% 3% Psychiatric Anxiety 2% 4% <1% — — — Depression 5% 4% <1% 3% 0 5% Nervousness 2% 2% 0 2% 0 2% Skin & Appendages Rash d 11% 16% 5% 9% 5% 9% Pruritus <1% 1% 1% 9% 5% 9% a Includes adverse events at least possibly related to study drug or of unknown relationship for Study 006.
Includes all adverse events regardless of relationship to study drug for Study ACTG 364. b Efavirenz tablets provided as 600 mg once daily. c Median duration of treatment. d Includes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for Study 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and pruritus for ACTG 364. — = Not Specified.
ZDV = zidovudine, LAM=lamivudine. Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients (see Laboratory Abnormalities ). Nervous System Symptoms For 1,008 patients treated with regimens containing efavirenz tablets and 635 patients treated with a control regimen in controlled trials, Table 3 lists the frequency of symptoms of different degrees of severity and gives the discontinuation rates for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking, and depersonalization [see Warnings and Precautions (5.6)].
The frequencies of specific central and peripheral nervous system symptoms are provided in Table 2. Table 3: Percent of Patients with One or More Selected Nervous System Symptoms a,b Percent of Patients with: Efavirenz Tablets 600 mg Once Daily (n=1,008) % Control Groups (n=635) % Symptoms of any severity 52.7
24.6 Mild symptoms c 33.3
15.6 Moderate symptoms d 17.4
7.7 Severe symptoms e 2
1.3 Treatment discontinuation as a result of symptoms 2.1 1.1 a Includes events reported regardless of causality. b Data from Study 006 and three Phase 2/3 studies. c “Mild” = Symptoms which do not interfere with patient’s daily activities. d “Moderate” = Symptoms which may interfere with daily activities. e “Severe” = Events which interrupt patient’s usual daily activities. Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with efavirenz tablets.
In controlled trials, psychiatric symptoms observed at a frequency greater than 2% among patients treated with efavirenz tablets or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%). Rash In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1,008 adults treated with regimens containing efavirenz tablets and 17% for 635 adults treated with a control regimen.
Most reports of rash were mild or moderate in severity. The frequency of Grade 3 rash was 0.8% for efavirenz tablets-treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz tablets and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz tablets-treated patients and 0.3% for control groups [see Warnings and Precautions (5.8)]. Experience with efavirenz tablets in patients who discontinued other antiretroviral agents of the NNRTI class is limited.
Nineteen patients who discontinued nevirapine because of rash have been treated with efavirenz tablets. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz tablets, and two of these patients discontinued because of rash. Laboratory Abnormalities Selected Grade 3 to 4 laboratory abnormalities reported in ≥2% of efavirenz tablets-treated patients in two clinical trials are presented in Table 4.
Table 4: Selected Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364 Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients Variable Limit Efavirenz tablets a +ZDV/LAM(n=412) 180 weeks b Efavirenz tablets a +Indinavir (n=415) 102 weeks b Indinavir +ZDV/LAM (n=401) 76 weeks b Efavirenz tablets a +Nelfinavir + NRTIs (n=64) 71.1 weeks b Efavirenz tablets a + NRTIs (n=65) 70.9 weeks b Nelfinavir + NRTIs (n=66) 62.7 weeks b Chemistry ALT >5 x ULN 5% 8% 5% 2% 6% 3% AST >5 x ULN 5% 6% 5% 6% 8% 8% GGT c >5 x ULN 8% 7% 3% 5% 0 5% Amylase >2 x ULN 4% 4% 1% 0 6% 2% Glucose >250 mg/dL 3% 3% 3% 5% 2% 3% Triglycerides d ³751mg/dL 9% 6% 6% 11% 8% 17% Hematology Neutrophils <750/mm 3 10% 3% 5% 2% 3% 2% a Efavirenz tablets provided as 600 mg once daily. b Median duration of treatment. c Isolated elevations of GGT in patients receiving efavirenz tablets may reflect enzyme induction not associated with liver toxicity. d Nonfasting.
ZDV = zidovudine, LAM = lamivudine, ULN = upper limit of normal, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyltransferase. Patients Coinfected with Hepatitis B or C Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with efavirenz tablets-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a cont
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Composition
Active ingredients
EFAVIRENZ 600MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
At a glance
Brand name
Efavirenz
Pharmacologic class
Human Immunodeficiency Virus 1 Non-Nucleoside Analog Reverse Transcriptase Inhibitor
