Efavirenz for HIV

INDICATIONS AND USAGE Efavirenz capsules in combination with other antiretroviral agents are 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 )

DOSAGE AND ADMINISTRATION Efavirenz capsules should be taken orally once daily on an empty stomach, preferably at bedtime. ( 2 ) Recommended adult dose: 600 mg. ( 2.2 ) With voriconazole, increase voriconazole maintenance dose to 400 mg every 12 hours and decrease efavirenz dose to 300 mg once daily using the capsule formulation. (2.2) With rifampin, increase efavirenz capsules dose to 800 mg once daily for patients weighing 50 kg or more. (2.2) Pediatric dosing is based on weight. (2.3) 2.1 Hepatic Function Monitor hepatic function prior to and during treatment with efavirenz capsules [see Warnings and Precautions (5.9) ] . Efavirenz capsules are not recommended in patients with moderate or severe hepatic impairment (Child Pugh B or C) [see Warnings and Precautions (5.9) and Use in Specific Populations (8.6) ] . 2.2 Adults The recommended dosage of efavirenz capsules is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz capsules be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz capsules with food may lead to an increase in frequency of adverse reactions [see Clinical Pharmacology (12.3) ]. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Warnings and Precautions (5.6) , Adverse Reactions (6.1) , and Patient Counseling Information (17) ]. Efavirenz capsules should be swallowed intact with liquid. For patients who cannot swallow capsules, the capsule sprinkle method of administration is recommended [see Dosage and Administration (2.4) ]. Concomitant Antiretroviral Therapy Efavirenz capsules must be given in combination with other antiretroviral medications [see Indications and Usage (1) , Warnings and Precautions (5.3) , Drug Interactions (7.1) , and Clinical Pharmacology (12.3) ] . Dosage Adjustment If efavirenz capsules are coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz dose should be decreased to 300 mg once daily using the capsule formulation (one 200 mg and two 50 mg capsules or six 50 mg capsules). If efavirenz capsules are coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of efavirenz capsules to 800 mg once daily is recommended [see Drug Interactions (7.1, Table 5 ) and Clinical Pharmacology (12.3, Table 8) ]. 2.3 Pediatric Patients It is recommended that efavirenz capsules be taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended dose of efavirenz capsules for pediatric patients 3 months of age or older and weighing between 3.5 kg and 40 kg [see Clinical Pharmacology (12.3) ] . The recommended dosage of efavirenz capsules for pediatric patients weighing 40 kg or greater is 600 mg once daily. For pediatric patients who cannot swallow capsules, the capsule contents can be administered with a small amount of food or infant formula using the capsule sprinkle method of administration [see Dosage and Administration (2.4) ]. Table 1: Efavirenz Capsules Dosing in Pediatric Patients Patient Body Weight Efavirenz Capsules Daily Dose Number of Capsules a and Strength to Administer 3.5 kg to less than 5 kg 100 mg two 50 mg capsules 5 kg to less than 7.5 kg 150 mg three 50 mg capsules 7.5 kg to less than 15 kg 200 mg one 200 mg capsule 15 kg to less than 20 kg 250 mg one 200 mg + one 50 mg capsule 20 kg to less than 25 kg 300 mg one 200 mg + two 50 mg capsules 25 kg to less than 32.5 kg 350 mg one 200 mg + three 50 mg capsules 32.5 kg to less than 40 kg 400 mg two 200 mg capsules at least 40 kg 600 mg three 200 mg capsules a Capsules can be administered intact or as sprinkles [see Dosage and Administration (2.4) ]. 2.4 Capsule Sprinkle Method of Administration For pediatric patients at least 3 months old and weighing at least 3.5 kg and adults who cannot swallow capsules, the capsule contents may be administered with a small amount (1 to 2 teaspoons) of food. Use of infant formula for mixing should only be considered for those young infants who cannot reliably consume solid foods. Patients and caregivers should be instructed to open the capsule carefully to avoid spillage or dispersion of the capsule contents into the air. The capsule should be held horizontally over a small container and carefully twisted to open. For patients able to tolerate solid foods, the entire capsule contents should be gently mixed with an age-appropriate soft food, such as applesauce, grape jelly, or yogurt, in the small container. For young infants receiving the capsule sprinkle-infant formula mixture, the entire capsule contents should be gently mixed into 2 teaspoons of reconstituted room temperature infant formula in a small container by carefully stirring with a small spoon, and then drawing up the mixture into a 10 mL oral dosing syringe for administration. After administration of the efavirenz capsules-food or -formula mixture, an additional small amount (approximately 2 teaspoons) of food or formula must be added to the empty mixing container, stirred to disperse any remaining efavirenz residue, and administered to the patient. The efavirenz capsules-food or -formula mixture should be administered within 30 minutes of mixing. No additional food should be consumed for 2 hours after administration of efavirenz capsules. Further patient instructions on the capsule sprinkle method of administration are provided in the FDA-approved patient labeling (see Patient Information and Instructions for Use ).

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 1-2 days after initiating therapy and resolve in 2-4 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 1-2 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 ) 5.1 Drug 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 )]. 5.2 QTc 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 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. 5.3 Resistance Efavirenz 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. 5.4 Coadministration with Related Products Coadministration of efavirenz with ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) is not recommended unless needed for dose adjustment (e.g., with rifampin), since efavirenz is one of its active ingredients. 5.5 Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1008 patients treated with regimens containing efavirenz 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 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 and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both efavirenz-treated and control-treated patients. One percent of efavirenz -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, and psychosis-like behavior although a causal relationship to the use of efavirenz 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, and if so, to determine whether the risks of continued therapy outweigh the benefits [see Adverse Reactions ( 6.1 )]. 5.6 Nervous System Symptoms Fifty-three percent (531/1008) of patients receiving efavirenz 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 1008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). These symptoms were severe in 2.0% 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 2-4 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 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 + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated patients were generally similar to those in the indinavir-containing control arm. Late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning efavirenz therapy. Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased efavirenz levels despite standard dosing of efavirenz. Patients presenting with signs and symptoms of serious neurologic adverse experiences should be evaluated promptly to assess the possibility that these events may be related to efavirenz use, and whether discontinuation of efavirenz is warranted. Patients receiving efavirenz should be alerted to the potential for additive central ner

DRUG 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 7.2 Potential for Other Drugs to Affect efavirenz Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations [see Dosage and Administration ( 2.2 )]. 7.3 QT 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. 7.4 Established and Other Potentially Significant Drug Interactions Drug interactions with efavirenz are summarized in Table 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 –naïve patients : When co-administered 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: Co-administration of efavirenz tablets and atazanavir is not recommended. Protease inhibitor: Indinavir ↓ indinavir * The optimal dose of indinavir, when given in combination with efavirenz tablets are not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz . Protease inhibitor: Lopinavir/ritonavir ↓ lopinavir * Lopinavir/ritonavir once daily dosing is not recommended when co-administered with efavirenz. The dose of lopinavir/ritonavir must be increased when co-administered with efavirenz. See the lopinavir/ritonavir prescribing information for dose adjustments of lopinavir/ritonavir when co-administered 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 is co-administered with ritonavir. Protease inhibitor: Saquinavir ↓ saquinavir * Appropriate doses of the combination of efavirenz 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 should not be coadministered with other NNRTIs. CCR5 co-receptor antagonist: Maraviroc ↓ maraviroc* Refer to the full prescribing information for maraviroc for guidance on co-administration with efavirenz. Hepatitis C antiviral agents Boceprevir ↓ boceprevir* Concomitant administration of boceprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of boceprevir Elbasvir/Grazoprevir ↓ elbasvir ↓ grazoprevir Co-administration o efavirenz with elbasvir/grazoprevir is contraindicated [see Contraindications ( 4 )] because it may lead to loss of virologic response to elbasvir/grazoprevir. Pibrentasvir/Glecaprevir ↓ pibrentasvir Co-administration of efavirenz is not recommended because it may lead to reduced therapeutic effect of pibrentasvir/glecaprevir Simeprevir ↓simeprevir* ↔efavirenz* Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss oftherapeutic effect of simeprevir. Velpatasvir/ Sofosbuvir ↓ velpatasvir Co-administration of efavirenz and sofosbuvir/velpatasvir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir Velpatasvir /Sofosbuvir/Voxilaprevir ↓ velpatasvir ↓ voxilaprevir Co-administration 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. Antidepressant: 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 and voriconazole should not be co-administered at standard doses. When voriconazole is co-administered with efavirenz, voriconazole maintenance dose should be increased to 400 mg every 12 hours and efavirenz 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 * Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. Ketoconazole ↓ ketoconazole Drug interaction studies with efavirenz and ketoconazole have not been conducted. efavirenz has the potential to decrease plasma concentrations of ketoconazole. Posaconazole ↓ posaconazole* Avoid concomitant use unless the benefit outweighs the risks. Anthelmintic: Praziquantel ↓ praziquantel Co-administration with efavirenz is not recommended due to significant decrease in plasma concentrations of praziquantel, with risk of treatment failure due to increased hepatic metabolism by efavirenz. Anti-infective: Clarithromycin ↓ clarithromycin * ↑ 14-OH metabolite * Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation. Antimycobacterial: 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 to 800 mg once daily when co-administered with rifampin to patients weighing 50 kg or more. Antimalarials: Artemether/ lumefantrine ↓ artemether* ↓ dihydroartemisinin* ↓ lumefantrine* Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation. Atovaquone/ proguanil ↓ atovaquone ↓ proguanil Concomitant administration is not recommended. Calcium channel blockers: Diltiazem ↓ diltiazem * ↓ desacetyl diltiazem * ↓ N-monodesmethyl diltiazem

ADVERSE REACTIONS The most significant adverse reactions observed in patients treated with efavirenz 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 Macleods Pharmaceutical Ltd at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical 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 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-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 TABLETS-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 Adverse Reactions Efavirenz b + ZDV/LAM (n=412) Efavirenz b + Indinavir (n=415) Indinavir + ZDV/LAM (n=401) Efavirenz b + Nelfinavir + NRTIs (n=64) Efavirenz b + NRTIs (n=65) Nelfinavir + NRTIs (n=66) 180 weeks c 102 weeks c 76 weeks c 71.1 weeks c 70.9 weeks c 62.7 weeks c Psychiatric 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% 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% Pruritis <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 1008 patients treated with regimens containing efavirenz 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=1008) 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 2.0 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 of greater than 2% among patients treated with efavirenz 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 1008 adults treated with regimens containing efavirenz 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 -treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz -treated patients and 0.3% for control groups [see Warnings and Precautions ( 5.8 )]. Experience with efavirenz 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. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these patients discontinued because of rash. Laboratory Abnormalities Selected Grade 3-4 laboratory abnormalities reported in greater than 2% of efavirenz tablets-treated patients in two clinical trials are presented in Table 4. Table 4: Selected Grade 3-4 Laboratory Abnormalities Reported in≥2% of EFAVIRENZ TABLETS-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 EFAVI RENZ a + ZDV/ LAM (n=412) EFAVI RENZ a + Indinavir (n=415) Indina vir + ZDV/ LAM (n=401) EFAVI RENZ a + Nelfinavir + NRTIs (n=64) EFAVI RENZ a + NRTIs (n=65) Nelfi navir + NRTIs (n=66) 180 weeks b 102 weeks b 76 weeks b 71.1 weeks b 70.9 weeks b 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% Triglyce rides d ≥751 mg/dL 9% 6% 6% 11% 8% 17% Hematology Neutrophils <750/mm 3 10% 3% 5% 2% 3% 2% a Efairenz tablets provided as 600 mg once daily. b Median duration of treatment. c Isolated elevations of GGT in patients receiving efavirenz 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-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen posi