Efavirenz

1 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 )

2 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 ).

4 CONTRAINDICATIONS Efavirenz capsules are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. Coadministration of efavirenz with elbasvir and grazoprevir is contraindicated [see Warnings and Precautions (5.1) and Drug Interactions (7.1) ]. Patients with previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. (4) Coadministration of efavirenz with elbasvir/grazoprevir.

Not available.

6 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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 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-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) 180 weeks c Efavirenz b + Indinavir (n=415) 102 weeks c Indinavir + ZDV/LAM (n=401) 76 weeks c Efavirenz b + Nelfinavir + NRTIs (n=64) 71.1 weeks c Efavirenz 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 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 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. In controlled trials, psychiatric symptoms observed at a frequency 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 to 4 laboratory abnormalities reported in ≥2% of efavirenz-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 a + ZDV/LAM (n=412) 180 weeks b Efavirenz a + Indinavir (n=415) 102 weeks b Indinavir + ZDV/LAM (n=401) 76 weeks b Efavirenz a + Nelfinavir + NRTIs (n=64) 71.1 weeks b Efavirenz 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 ≥751 mg/dL 9% 6% 6% 11% 8% 17% Hematology Neutrophils <750/mm 3 10% 3% 5% 2% 3% 2% a Efavirenz 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 positive) and/or C (hepatitis C antibody positive). Among these coinfected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the efavirenz arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the efavirenz arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders [see Warnings and Precautions (5.9) ] . Lipids Increases from baseline in total cholesterol of 10 to 20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz + indinavir, increases from baseline in nonfasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels ≥240 mg/dL and ≥300 mg/dL were reported in 34% and 9%, respectively, of patients treated with efavirenz + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with efavirenz + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of efavirenz on triglycerides and LDL in this study were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown [see Warnings and Precautions (5.11) ] . Adverse Reactions in Pediatric Patients 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. Assessment of adverse reactions is based on three clinical trials in 182 HIV-1 infected pediatric patients (3 months to 21 years of age) who received efavirenz in combination with other antiretroviral agents for a median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in pediatric patients (32% for all grades regardless of causality) and more often of higher grade (i.e., more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash [see Warnings and Precautions (5.8) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of efavirenz. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: allergic reactions, asthenia, redistribution/accumulation of body fat [see Warnings and Precautions (5.13) ] Central and Peripheral Nervous System: abnormal coordination, ataxia, encephalopathy, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, vertigo Endocrine: gynecomastia Gastrointestinal: constipation, malabsorption Cardiovascular: flushing, palpitations Liver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis. Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia Musculoskeletal: arthralgia, myalgia, myopathy Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia Respiratory: dyspnea Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome Special Senses: abnormal vision, tinnitus