Efavirenz

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 weeksc Efavirenz b + Indinavir (n=415) 102 weeksc Indinavir + ZDV/LAM (n=401) 76 weeksc Efavirenz b + Nelfinavir + NRTIs (n=64) 71.1 weeksc Efavirenz b + NRTIs (n=65) 70.9 weeksc Nelfinavir + NRTIs (n=66) 62.7 weeksc 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 weeksb Efavirenz a + Indinavir (n=415) 102 weeksb Indinavir + ZDV/LAM (n=401) 76 weeksb Efavirenz a + Nelfinavir + NRTIs (n=64) 71.1 weeksb Efavirenz a + NRTIs (n=65) 70.9 weeksb Nelfinavir + NRTIs (n=66) 62.7 weeksb 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

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.

11 DESCRIPTION Efavirenz is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI). Efavirenz is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its molecular formula is C 14 H 9 ClF 3 NO 2 and its structural formula is: Efavirenz USP is a white to off-white crystalline powder with a molecular mass of 315.68. It is practically insoluble in water (<10 microgram/mL). Efavirenz is available as capsules for oral administration containing either 50 mg, 100 mg, or 200 mg of efavirenz USP and the following inactive ingredients: lactose monohydrate, magnesium stearate, sodium lauryl sulfate and sodium starch glycolate (potato). The capsule shell contains gelatin, silicon dioxide and sodium lauryl sulfate. In addition 50 mg contains titanium dioxide and yellow iron oxide, 100 mg contains titanium dioxide and 200 mg contains yellow iron oxide. The capsules are printed with edible ink containing black iron oxide and shellac. structure

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 ).

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 )

10 OVERDOSAGE Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions. Treatment of overdose with efavirenz should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the drug from blood.

7 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 is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with fosamprenavir plus ritonavir twice daily. Protease inhibitor: Atazanavir ↓ atazanavir* Treatment-naive patients: When coadministered with efavirenz, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and efavirenz 600 mg (once daily on an empty stomach, preferably at bedtime). Treatment-experienced patients: Coadministration of efavirenz and atazanavir is not recommended. Protease inhibitor: Indinavir ↓ indinavir* The optimal dose of indinavir, when given in combination with efavirenz, is 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 coadministered with efavirenz. The dose of lopinavir/ritonavir must be increased when coadministered with efavirenz. 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 is coadministered 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 coadministration 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 Coadministration of efavirenz 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 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 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 ↓ voxilaprevir 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 and voriconazole should not be coadministered at standard doses. When voriconazole is coadministered 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. 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 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 (e.g., felodipine, nicardipine, nifedipine, verapamil) ↓ calcium channel blocker When coadministered with efavirenz, dosage adjustment of calcium channels blocker may be needed and should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). HMG-CoA reductase inhibitors: Atorvastatin Pravastatin Simvastatin ↓ atorvastatin* ↓ pravastatin* ↓ simvastatin* Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. Hormonal contraceptives: Oral Ethinyl estradiol/ Norgestimate Implant Etonogestrel ↓ active metabolites of norgestimate* ↓ etonogestrel A reliable method of barrier contraception should be used in addition to hormonal contraceptives. A reliable method of barrier contraception should be used in addition to hormonal contraceptives. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A ↓ immunosuppressant Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz. Narcotic analgesic: Methadone ↓ methadone* Monitor for signs of methadone withdrawal and increase methadone dose if required to alleviate withdrawal symptoms. * The interaction between efavirenz and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. This table is not all-inclusive. 7.5 Drugs Without Clinically Significant Interactions with Efavirenz No dosage adjustment is recommended when efavirenz is given with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, lorazepam, nelfinavir, nucleoside reverse transcriptase inhibitors (abacavir, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), paroxetine, and raltegravir. 7.6 Cannabinoid Test Interaction Efavirenz does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected subjects receiving efavirenz. Confirmation of positive screening tests for cannabinoids by a more specific method is recommended.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Efavirenz is an antiviral drug [see Microbiology (12.4) ]. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of efavirenz on the QTc interval was evaluated in an open-label, positive and placebo controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean Cmax of efavirenz in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between efavirenz concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 ms and 11.3 ms in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days [ see Warnings and Precautions (5.2) ]. 12.3 Pharmacokinetics Absorption Peak efavirenz plasma concentrations of 1.6 to 9.1 µM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in C max and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. In HIV-1-infected patients at steady state, mean C max , mean C min , and mean AUC were dose proportional following 200 mg, 400 mg, and 600 mg daily doses. Time-to-peak plasma concentrations were approximately 3 to 5 hours and steady-state plasma concentrations were reached in 6 to 10 days. In 35 patients receiving efavirenz 600 mg once daily, steady-state C max was 12.9 ± 3.7 µM (mean ± SD), steady-state C min was 5.6 ± 3.2 µM, and AUC was 184 ± 73 µM•h. Effect of Food on Oral Absorption: Capsules : Administration of a single 600 mg dose of efavirenz capsules with a high-fat/high­-caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC ∞ and a mean increase of 39% and 51% in efavirenz C max , respectively, relative to the exposures achieved when given under fasted conditions [see Dosage and Administration (2) and Patient Counseling Information (17) ]. Bioavailability of capsule contents mixed with food vehicles: In healthy adult subjects, the efavirenz AUC when administered as the contents of three 200 mg capsules mixed with 2 teaspoons of certain food vehicles (applesauce, grape jelly or yogurt, or infant formula) met bioequivalency criteria for the AUC of the intact capsule formulation administered under fasted conditions. Distribution Efavirenz is highly bound (approximately 99.5 to 99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received efavirenz 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma. Metabolism Studies in humans and in vitro studies using human liver microsomes have demonstrated that 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. The in vitro studies suggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200 to 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22 to 42% lower) and a shorter terminal half-life of 40 to 55 hours (single dose half-life 52 to 76 hours). Elimination Efavirenz has a terminal half-life of 52 to 76 hours after single doses and 40 to 55 hours after multiple doses. A one-month mass balance/excretion study was conducted using 400 mg per day with a 14 C-labeled dose administered on Day 8. Approximately 14 to 34% of the radiolabel was recovered in the urine and 16 to 61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces. Special Populations Pediatric: The pharmacokinetic parameters for efavirenz at steady state in pediatric patients were predicted by a population pharmacokinetic model and are summarized in Table 6 by weight ranges that correspond to the recommended doses. Table 6: Predicted Steady-State Pharmacokinetics of Recommended Doses of Efavirenz (Capsules/Capsule Sprinkles) in HIV-Infected Pediatric Patients Body Weight Dose Mean AUC (0-24) µM·h Mean C max mcg/mL Mean C min mcg/mL 3.5 to 5 kg 100 mg 220.52 5.81 2.43 5 to 7.5 kg 150 mg 262.62 7.07 2.71 7.5 to 10 kg 200 mg 284.28 7.75 2.87 10 to 15 kg 200 mg 238.14 6.54 2.32 15 to 20 kg 250 mg 233.98 6.47 2.3 20 to 25 kg 300 mg 257.56 7.04 2.55 25 to 32.5 kg 350 mg 262.37 7.12 2.68 32.5 to 40 kg 400 mg 259.79 6.96 2.69 >40 kg 600 mg 254.78 6.57 2.82 Gender and race: The pharmacokinetics of efavirenz in patients appear to be similar between men and women and among the racial groups studied. Renal impairment: The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal. Hepatic impairment: A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics. Drug Interaction Studies Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have shown that efavirenz inhibited CYP isozymes 2C9 and 2C19 with K i values (8.5 to 17 μM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (K i values 82 to 160 μM) only at concentrations well above those achieved clinically. Coadministration of efavirenz with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A, or CYP2B6 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A and CYP2B6 activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. Drug interaction studies were performed with efavirenz and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. The effects of coadministration of efavirenz on the C max , AUC, and C min are summarized in Table 7 (effect of efavirenz on other drugs) and Table 8 (effect of other drugs on efavirenz). For information regarding clinical recommendations see Drug Interactions (7.1). Table 7: Effect of Efavirenz on Coadministered Drug Plasma C max, AUC, and C min Coadministered Drug Dose Efavirenz Dose Number of Subjects Coadministered Drug (mean % change) C max (90% CI) AUC (90% CI) C min (90% CI) Atazanavir 400 mg qd with a light meal d 1-20 600 mg qd with a light meal d 7-20 27 ↓ 59% (49-67%) ↓ 74% (68-78%) ↓ 93% (90-95%) 400 mg qd d 1-6, then 300 mg qd d 7-20 with ritonavir 100 mg qd and a light meal 600 mg qd 2 h after atazanavir and ritonavir d 7-20 13 ↑ 14% a (↓ 17-↑ 58%) ↑ 39% a (2-88%) ↑ 48% a (24-76%) 300 mg qd/ritonavir 100 mg qd d 1-10 (pm), then 400 mg qd/ritonavir 100 mg qd d 11-24 (pm) (simultaneous with efavirenz) 600 mg qd with a light snack d 11-24 (pm) 14 ↑ 17% (8-27%) ↔ ↓ 42% (31-51%) Indinavir 1000 mg q 8 h x 10 days 600 mg qd x 10 days 20 After morning dose ↔ b ↓ 33% b (26-39%) ↓ 39% b (24-51%) After afternoon dose ↔ b ↓ 37% b (26-46%) ↓ 52% b (47-57%) After evening dose ↓ 29% b (11-43%) ↓ 46% b (37-54%) ↓ 57% b (50-63%) Lopinavir/ ritonavir 400/100 mg capsule q12h × 9 days 500/125 mg tablet q12h x 10 days with efavirenz compared to 400/100 mg q12h alone 600/150 mg tablet q12h x 10 days with efavirenz compared to 400/100 mg q12h alone 600 mg qd x 9 days 600 mg qd x 9 days 600 mg qd x 9 days 11,7 c 19 23 ↔ d ↑ 12% d (2-23%) ↑ 36% d (28-44%) ↓ 19% d (↓ 36-↑3%) ↔ d ↑ 36% d (28-44%) ↓ 39% d (3-62%) ↓ 10% d (↓ 22-↑ 4%) ↑ 32% d (21-44%) Nelfinavir 750 mg q8h x 7 days 600 mg qd x 7 days 10 ↑ 21% (10-33%) ↑ 20% (8-34%) ↔ Metabolite AG-1402 ↓ 40% (30-48%) ↓ 37% (25-48%) ↓ 43% (21-59%) Ritonavir 500 mg q12h x 8 days 600 mg qd x 10 days 11 After AM dose ↑ 24% (12-38%) ↑ 18% (6-33%) ↑ 42% (9-86%) e After PM dose ↔ ↔ ↑ 24% (3-50%) e Saquinavir 1200 mg q8h x 10 days 600 mg qd x 10 days 12 ↓ 50% (28-66%) ↓ 62% (45-74%) ↓ 56% (16-77%) e SGC f Lamivudine 150 mg q12h x 14 days 600 mg qd x 14 days 9 ↔ ↔ ↑ 265% (37-873%) Tenofovir g 300 mg qd 600 mg qd x 14 days 29 ↔ ↔ ↔ Zidovudine 300 mg q12h x 14 days 600 mg qd x 14 days 9 ↔ ↔ ↑ 225% (43-640%) Maraviroc 100 mg bid 600 mg qd 12 ↓ 51% (37-62%) ↓ 45% (38-51%) ↓ 45% (28-57%) Raltegravir 400 mg single dose 600 mg qd 9 ↓ 36% (2-59%) ↓ 36% (20-48%) ↓ 21% (↓ 51-↑ 28%) Boceprevir 800 mg tid x 6 days 600 mg qd x 16 days NA ↓ 8% (↓22-↑8%) ↓ 19% (11-25%) ↓ 44% (26-58%) Simeprevir 150 mg qd x 14 days 600 mg qd x 14 days 23 ↓ 51% (↓46-↓56%) ↓ 71% (↓67-↓ 74%) ↓ 91% (↓ 88-↓ 92%) Azithromycin 600 mg single dose 400 mg qd x 7 days 14 ↑ 22% (4-42%) ↔ NA Clarithromycin 500 mg q12h x 7 days 400 mg qd x 7 days 11 ↓ 26% (15-35%) ↓ 39% (30-46%) ↓ 53% (42-63%) 14-OH metabolite ↑ 49% (32-69%) ↑ 34% (18-53%) ↑ 26% (9-45%) Fluconazole 200 mg x 7 days 400 mg qd x 7 days 10 ↔ ↔ ↔ Itraconazole 200 mg q12h x 28 days 600 mg qd x 14 days 18 ↓ 37% (20-51%) ↓ 39% (21-53%) ↓ 44% (27-58%) Hydroxy-itraconazole ↓ 35% (12-52%) ↓ 37% (14-55%) ↓ 43% (18-60%) Posaconazole 400 mg (oral suspension) bid x 10 and 20 days 400 mg qd x 10 and 20 days 11 ↓ 45% (34-53%) ↓ 50% (40-57%) NA Rifabutin 300 mg qd x 14 days 600 mg qd x 14 days 9 ↓ 32% (15-46%) ↓ 38% (28-47%) ↓ 45% (31-56%) Voriconazole 400 mg po q12h x 1 day, then 200 mg po q12h x 8 days 400 mg qd x 9 days NA ↓ 61% h ↓ 77% h NA 300 mg po q12h days 2-7 300 mg qd x 7 days NA ↓ 36% i (21-49%) ↓ 55% i (45-62%) NA 400 mg po q12h days 2-7 300 mg qd x 7 days NA ↑ 23% i (↓ 1-↑ 53%) ↓ 7% i (↓ 23-↑ 13%) NA Artemether/ lumefantrine Artemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over 3 days) 600 mg qd × 26 days 12 Artemether ↓ 21% ↓ 51% NA dihydroartemisinin ↓ 38% ↓ 46% NA Lumefantrine ↔ ↓ 21% NA Atorvastatin 10 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 14% (1-26%) ↓ 43% (34-50%) ↓ 69% (49-81%) Total active (including metabolites) ↓ 15% (2-26%) ↓ 32% (21-41%) ↓ 48% (23-64%) Pravastatin 40 mg qd x 4 days 600 mg qd x 15 days 13 ↓ 32% (↓ 59 -↑ 12%) ↓ 44% (26-57%) ↓ 19% (0-35%) Simvastatin 40 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 72% (63-79%) ↓ 68% (62-73%) ↓ 45% (20-62%) Total active (including metabolites) ↓ 68% (55-78%) ↓ 60% (52-68%) NA j Carbamazepine Epoxide metabolite 200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 29 days 600 mg qd x 14 days 12 ↓ 20% (15-24%) ↓ 27% (20-33%) ↓ 35% (24-44%) ↔ ↔ ↓ 13% (↓ 30 -↑ 7%) Cetirizine 10 mg single dose 600 mg qd x 10 days 11 ↓ 24% (18-30%) ↔ NA Diltiazem 240 mg x 21 days 600 mg qd x 14 days 13 ↓ 60% (50-68%) ↓ 69% (55-79%) ↓ 63% (44-75%) Desacetyl diltiazem ↓ 64% (57-69%) ↓ 75% (59-84%) ↓ 62% (44-75%) N‑monodes-methyl diltiazem ↓ 28% (7-44%) ↓ 37% (17-52%) ↓ 37% (17-52%) Ethinyl estradiol/ Norgestimate Ethinyl estradiol Norelgestromin Levonorgestrel 0.035 mg/0.25 mg x 14 days 600 mg qd x 14 days 21 21 6 ↔ ↓ 46% (39-52%) ↓ 80% (77-83%) ↔ ↓ 64% (62-67%) ↓ 83% (79-87%) ↔ ↓ 82% (79-85%) ↓ 86% (80-90%) Lorazepam 2 mg single dose 600 mg qd x 10 days 12 ↑ 16% (2-32%) ↔ NA Methadone Stable maintenance 35 to 100 mg daily 600 mg qd x 14-21 days 11 ↓ 45% (25-59%) ↓ 52% (33-66%) NA Bupropion Hydroxy-bupropion 150 mg single dose (sustained-release) 600 mg qd x 14 days 13 ↓34% (21-47%) ↑50% (20-80%) ↓ 55% (48-62%) ↔ NA NA Paroxetine 20 mg qd x 14 days 600 mg qd x 14 days 16 ↔ ↔ ↔ Sertraline 50 mg qd x 14 days 600 mg qd x 14 days 13 ↓ 29% (15-40%) ↓ 39% (27-50%) ↓ 46% (31-58%) ↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of <10%. a Compared with atazanavir 400 mg qd alone. b Comparator dose of indinavir was 800 mg q8h x 10 days. c Parallel-group design; n for efavirenz + lopinavir/ritonavir, n for lopinavir/ritonavir alone. d Values are for lopinavir; the pharmacokinetics of ritonavir in this study were unaffected by concurrent efavirenz. e 95% CI. f Soft Gelatin Capsule. g Tenofovir disoproxil fumarate. h 90% CI not available. i Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days). j Not available because of insufficient data. NA = not available. Table 8: Effect of Coadministered Drug on Efavirenz Plasma C max, AUC, and C min Efavirenz (mean % change) Coadministered Drug Dose Efavirenz Dose Number of Subjects C max (90% CI) AUC (90% CI) C min (90% CI) Indinavir 800 mg q8h x 14 days 200 mg qd x 14 days 11 ↔ ↔ ↔ Lopinavir/ ritonavir 400/100 mg q12h x 9 days 600 mg qd x 9 days 11,12 a ↔ ↓ 16% (↓ 38-↑ 15%) ↓ 16% (↓ 42-↑ 20%) Nelfinavir 750 mg q8h x 7 days 600 mg qd x 7 days 10 ↓ 12% (↓ 32-↑ 13%) b ↓ 12% (↓ 35-↑ 18%) b ↓ 21% (↓ 53-↑ 33%) Ritonavir 500 mg q12h x 8 days 600 mg qd x 10 days 9 ↑ 14% (4-26%) ↑ 21% (10-34%) ↑ 25% (7-46%) b Saquinavir SGC c 1200 mg q8h x 10 days 600 mg qd x 10 days 13 ↓ 13% (5-20%) ↓ 12% (4-19%) ↓ 14% (2-24%) b Tenofovir d 300 mg qd 600 mg qd x 14 days 30 ↔ ↔ ↔ Boceprevir 800 mg tid x 6 days 600 mg qd x 16 days NA ↑11% (2-20%) ↑ 20% (15-26%) NA Simeprevir 150 mg qd x 14 days 600 mg qd x 14 days 23 ↔ ↓ 10% (5-15%) ↓ 13% (7-19%) Azithromycin 600 mg single dose 400 mg qd x 7 days 14 ↔ ↔ ↔ Clarithromycin 500 mg q12h x 7 days 400 mg qd x 7 days 12 ↑ 11% (3-19%) ↔ ↔ Fluconazole 200 mg x 7 days 400 mg qd x 7 days 10 ↔ ↑ 16% (6-26%) ↑ 22% (5-41%) Itraconazole 200 mg q12h x 14 days 600 mg qd x 28 days 16 ↔ ↔ ↔ Rifabutin 300 mg qd x 14 days 600 mg qd x 14 days 11 ↔ ↔ ↓ 12% (↓ 24-↑ 1%) Rifampin 600 mg x 7 days 600 mg qd x 7 days 12 ↓ 20% (11-28%) ↓ 26% (15-36%) ↓ 32% (15-46%) Voriconazole 400 mg po q12h x 1 day, then 200 mg po q l2 h x 8 days 400 mg qd x 9 days NA ↑ 38% e ↑ 44% e NA 300 mg po q12h days 2-7 300 mg qd x 7 days NA ↓ 14% f (7-21%) ↔ f NA 400 mg po q12h days 2-7 300 mg qd x 7 days NA ↔ f ↑ 17% f (6-29%) NA Artemether/ Lumefantrine Artemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over 3 days) 600 mg qd × 26 days 12 ↔ ↓ 17% NA Atorvastatin 10 mg qd x 4 days 600 mg qd x 15 days 14 ↔ ↔ ↔ Pravastatin 40 mg qd x 4 days 600 mg qd x 15 days 11 ↔ ↔ ↔ Simvastatin 40 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 12% (↓ 28-↑ 8%) ↔ ↓ 12% (↓ 25-↑ 3%) Aluminum hydroxide 400 mg, magnesium hydroxide 400 mg, plus simethicone 40 mg 30 mL single dose 400 mg single dose 17 ↔ ↔ NA Carbamazepine 200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 15 days 600 mg qd x 35 days 14 ↓ 21% (15-26%) ↓ 36% (32-40%) ↓ 47% (41-53%) Cetirizine 10 mg single dose 600 mg qd x 10 days 11 ↔ ↔ ↔ Diltiazem 240 mg x 14 days 600 mg qd x 28 days 12 ↑ 16% (6-26%) ↑ 11% (5-18%) ↑ 13% (1-26%) Famotidine 40 mg single dose 400 mg single dose 17 ↔ ↔ NA Paroxetine 20 mg qd x 14 days 600 mg qd x 14 days 12 ↔ ↔ ↔ Sertraline 50 mg qd x 14 days 600 mg qd x 14 days 13 ↑ 11% (6-16%) ↔ ↔ ↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of <10%. a Parallel-group design; n for efavirenz + lopinavir/ritonavir, n for efavirenz alone. b 95% CI. c Soft Gelatin Capsule. d Tenofovir disoproxil fumarate. e 90% CI not available. f Relative to steady-state administration of efavirenz (600 mg once daily for 9 days). NA = not available. 12.4 Microbiology Mechanism of Action Efavirenz is an NNRTI of HIV-1. Efavirenz activity is mediated predominantly by noncompetitive inhibition of HIV-1 reverse transcriptase. HIV-2 reverse transcriptase and human cellular DNA polymerases α, β, γ, and δ are not inhibited by efavirenz. Antiviral Activity in Cell Culture The concentration of efavirenz inhibiting replication of wild-type laboratory adapted strains and clinical isolates in cell culture by 90 to 95% (EC 90-95 ) ranged from 1.7 to 25 nM in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs), and macrophage/monocyte cultures. Efavirenz demonstrated antiviral activity against clade B and most non-clade B isolates (subtypes A, AE, AG, C, D, F, G, J, N), but had reduced antiviral activity against group O viruses. Efavirenz demonstrated additive antiviral activity without cytotoxicity against HIV-1 in cell culture when combined with the NNRTIs delavirdine and nevirapine, NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir), and the fusion inhibitor enfuvirtide. Efavirenz demonstrated additive to antagonistic antiviral activity in cell culture with atazanavir. Efavirenz was not antagonistic with adefovir, used for the treatment of hepatitis B virus infection, or ribavirin, used in combination with interferon for the treatment of hepatitis C virus infection. Resistance In cell culture In cell culture, HIV-1 isolates with reduced susceptibility to efavirenz (>380-fold increase in EC 90 value) emerged rapidly in the presence of drug. Genotypic characterization of these viruses identified single amino acid substitutions L100I or V179D, double substitutions L100I/V108I, and triple substitutions L100I/V179D/Y181C in reverse transcriptase. Clinical studies Clinical isolates with reduced susceptibility in cell culture to efavirenz have been obtained. One or more substitutions at amino acid positions 98, 100, 101, 103, 106, 108, 188, 190, 225, and 227 in reverse transcriptase were observed in patients failing treatment with efavirenz in combination with indinavir, or with zidovudine plus lamivudine. The K103N substitution was the most frequently observed. Long-term resistance surveillance (average 52 weeks, range 4 to 106 weeks) analyzed 28 matching baseline and virologic failure isolates. Sixty-one percent (17/28) of these failure isolates had decreased efavirenz susceptibility in cell culture with a median 88-fold change in efavirenz susceptibility (EC 50 value) from reference. The most frequent NNRTI substitution to develop in these patient isolates was K103N (54%). Other NNRTI substitutions that developed included L100I (7%), K101E/Q/R (14%), V108I (11%), G190S/T/A (7%), P225H (18%), and M230I/L (11%). Cross-Resistance Cross-resistance among NNRTIs has been observed. Clinical isolates previously characterized as efavirenz-resistant were also phenotypically resistant in cell culture to delavirdine and nevirapine compared to baseline. Delavirdine- and/or nevirapine-resistant clinical viral isolates with NNRTI resistance-associated substitutions (A98G, L100I, K101E/P, K103N/S, V106A, Y181X, Y188X, G190X, P225H, F227L, or M230L) showed reduced susceptibility to efavirenz in cell culture. Greater than 90% of NRTI-resistant clinical isolates tested in cell culture retained susceptibility to efavirenz.

12.1 Mechanism of Action Efavirenz is an antiviral drug [see Microbiology (12.4) ].

12.2 Pharmacodynamics Cardiac Electrophysiology The effect of efavirenz on the QTc interval was evaluated in an open-label, positive and placebo controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean Cmax of efavirenz in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between efavirenz concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 ms and 11.3 ms in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days [ see Warnings and Precautions (5.2) ].

12.3 Pharmacokinetics Absorption Peak efavirenz plasma concentrations of 1.6 to 9.1 µM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in C max and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. In HIV-1-infected patients at steady state, mean C max , mean C min , and mean AUC were dose proportional following 200 mg, 400 mg, and 600 mg daily doses. Time-to-peak plasma concentrations were approximately 3 to 5 hours and steady-state plasma concentrations were reached in 6 to 10 days. In 35 patients receiving efavirenz 600 mg once daily, steady-state C max was 12.9 ± 3.7 µM (mean ± SD), steady-state C min was 5.6 ± 3.2 µM, and AUC was 184 ± 73 µM•h. Effect of Food on Oral Absorption: Capsules : Administration of a single 600 mg dose of efavirenz capsules with a high-fat/high­-caloric meal (894 kcal, 54 g fat, 54% calories from fat) or a reduced-fat/normal-caloric meal (440 kcal, 2 g fat, 4% calories from fat) was associated with a mean increase of 22% and 17% in efavirenz AUC ∞ and a mean increase of 39% and 51% in efavirenz C max , respectively, relative to the exposures achieved when given under fasted conditions [see Dosage and Administration (2) and Patient Counseling Information (17) ]. Bioavailability of capsule contents mixed with food vehicles: In healthy adult subjects, the efavirenz AUC when administered as the contents of three 200 mg capsules mixed with 2 teaspoons of certain food vehicles (applesauce, grape jelly or yogurt, or infant formula) met bioequivalency criteria for the AUC of the intact capsule formulation administered under fasted conditions. Distribution Efavirenz is highly bound (approximately 99.5 to 99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received efavirenz 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma. Metabolism Studies in humans and in vitro studies using human liver microsomes have demonstrated that 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. The in vitro studies suggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200 to 400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22 to 42% lower) and a shorter terminal half-life of 40 to 55 hours (single dose half-life 52 to 76 hours). Elimination Efavirenz has a terminal half-life of 52 to 76 hours after single doses and 40 to 55 hours after multiple doses. A one-month mass balance/excretion study was conducted using 400 mg per day with a 14 C-labeled dose administered on Day 8. Approximately 14 to 34% of the radiolabel was recovered in the urine and 16 to 61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces. Special Populations Pediatric: The pharmacokinetic parameters for efavirenz at steady state in pediatric patients were predicted by a population pharmacokinetic model and are summarized in Table 6 by weight ranges that correspond to the recommended doses. Table 6: Predicted Steady-State Pharmacokinetics of Recommended Doses of Efavirenz (Capsules/Capsule Sprinkles) in HIV-Infected Pediatric Patients Body Weight Dose Mean AUC (0-24) µM·h Mean C max mcg/mL Mean C min mcg/mL 3.5 to 5 kg 100 mg 220.52 5.81 2.43 5 to 7.5 kg 150 mg 262.62 7.07 2.71 7.5 to 10 kg 200 mg 284.28 7.75 2.87 10 to 15 kg 200 mg 238.14 6.54 2.32 15 to 20 kg 250 mg 233.98 6.47 2.3 20 to 25 kg 300 mg 257.56 7.04 2.55 25 to 32.5 kg 350 mg 262.37 7.12 2.68 32.5 to 40 kg 400 mg 259.79 6.96 2.69 >40 kg 600 mg 254.78 6.57 2.82 Gender and race: The pharmacokinetics of efavirenz in patients appear to be similar between men and women and among the racial groups studied. Renal impairment: The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal. Hepatic impairment: A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics. Drug Interaction Studies Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have shown that efavirenz inhibited CYP isozymes 2C9 and 2C19 with K i values (8.5 to 17 μM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (K i values 82 to 160 μM) only at concentrations well above those achieved clinically. Coadministration of efavirenz with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A, or CYP2B6 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A and CYP2B6 activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. Drug interaction studies were performed with efavirenz and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. The effects of coadministration of efavirenz on the C max , AUC, and C min are summarized in Table 7 (effect of efavirenz on other drugs) and Table 8 (effect of other drugs on efavirenz). For information regarding clinical recommendations see Drug Interactions (7.1). Table 7: Effect of Efavirenz on Coadministered Drug Plasma C max, AUC, and C min Coadministered Drug Dose Efavirenz Dose Number of Subjects Coadministered Drug (mean % change) C max (90% CI) AUC (90% CI) C min (90% CI) Atazanavir 400 mg qd with a light meal d 1-20 600 mg qd with a light meal d 7-20 27 ↓ 59% (49-67%) ↓ 74% (68-78%) ↓ 93% (90-95%) 400 mg qd d 1-6, then 300 mg qd d 7-20 with ritonavir 100 mg qd and a light meal 600 mg qd 2 h after atazanavir and ritonavir d 7-20 13 ↑ 14% a (↓ 17-↑ 58%) ↑ 39% a (2-88%) ↑ 48% a (24-76%) 300 mg qd/ritonavir 100 mg qd d 1-10 (pm), then 400 mg qd/ritonavir 100 mg qd d 11-24 (pm) (simultaneous with efavirenz) 600 mg qd with a light snack d 11-24 (pm) 14 ↑ 17% (8-27%) ↔ ↓ 42% (31-51%) Indinavir 1000 mg q 8 h x 10 days 600 mg qd x 10 days 20 After morning dose ↔ b ↓ 33% b (26-39%) ↓ 39% b (24-51%) After afternoon dose ↔ b ↓ 37% b (26-46%) ↓ 52% b (47-57%) After evening dose ↓ 29% b (11-43%) ↓ 46% b (37-54%) ↓ 57% b (50-63%) Lopinavir/ ritonavir 400/100 mg capsule q12h × 9 days 500/125 mg tablet q12h x 10 days with efavirenz compared to 400/100 mg q12h alone 600/150 mg tablet q12h x 10 days with efavirenz compared to 400/100 mg q12h alone 600 mg qd x 9 days 600 mg qd x 9 days 600 mg qd x 9 days 11,7 c 19 23 ↔ d ↑ 12% d (2-23%) ↑ 36% d (28-44%) ↓ 19% d (↓ 36-↑3%) ↔ d ↑ 36% d (28-44%) ↓ 39% d (3-62%) ↓ 10% d (↓ 22-↑ 4%) ↑ 32% d (21-44%) Nelfinavir 750 mg q8h x 7 days 600 mg qd x 7 days 10 ↑ 21% (10-33%) ↑ 20% (8-34%) ↔ Metabolite AG-1402 ↓ 40% (30-48%) ↓ 37% (25-48%) ↓ 43% (21-59%) Ritonavir 500 mg q12h x 8 days 600 mg qd x 10 days 11 After AM dose ↑ 24% (12-38%) ↑ 18% (6-33%) ↑ 42% (9-86%) e After PM dose ↔ ↔ ↑ 24% (3-50%) e Saquinavir 1200 mg q8h x 10 days 600 mg qd x 10 days 12 ↓ 50% (28-66%) ↓ 62% (45-74%) ↓ 56% (16-77%) e SGC f Lamivudine 150 mg q12h x 14 days 600 mg qd x 14 days 9 ↔ ↔ ↑ 265% (37-873%) Tenofovir g 300 mg qd 600 mg qd x 14 days 29 ↔ ↔ ↔ Zidovudine 300 mg q12h x 14 days 600 mg qd x 14 days 9 ↔ ↔ ↑ 225% (43-640%) Maraviroc 100 mg bid 600 mg qd 12 ↓ 51% (37-62%) ↓ 45% (38-51%) ↓ 45% (28-57%) Raltegravir 400 mg single dose 600 mg qd 9 ↓ 36% (2-59%) ↓ 36% (20-48%) ↓ 21% (↓ 51-↑ 28%) Boceprevir 800 mg tid x 6 days 600 mg qd x 16 days NA ↓ 8% (↓22-↑8%) ↓ 19% (11-25%) ↓ 44% (26-58%) Simeprevir 150 mg qd x 14 days 600 mg qd x 14 days 23 ↓ 51% (↓46-↓56%) ↓ 71% (↓67-↓ 74%) ↓ 91% (↓ 88-↓ 92%) Azithromycin 600 mg single dose 400 mg qd x 7 days 14 ↑ 22% (4-42%) ↔ NA Clarithromycin 500 mg q12h x 7 days 400 mg qd x 7 days 11 ↓ 26% (15-35%) ↓ 39% (30-46%) ↓ 53% (42-63%) 14-OH metabolite ↑ 49% (32-69%) ↑ 34% (18-53%) ↑ 26% (9-45%) Fluconazole 200 mg x 7 days 400 mg qd x 7 days 10 ↔ ↔ ↔ Itraconazole 200 mg q12h x 28 days 600 mg qd x 14 days 18 ↓ 37% (20-51%) ↓ 39% (21-53%) ↓ 44% (27-58%) Hydroxy-itraconazole ↓ 35% (12-52%) ↓ 37% (14-55%) ↓ 43% (18-60%) Posaconazole 400 mg (oral suspension) bid x 10 and 20 days 400 mg qd x 10 and 20 days 11 ↓ 45% (34-53%) ↓ 50% (40-57%) NA Rifabutin 300 mg qd x 14 days 600 mg qd x 14 days 9 ↓ 32% (15-46%) ↓ 38% (28-47%) ↓ 45% (31-56%) Voriconazole 400 mg po q12h x 1 day, then 200 mg po q12h x 8 days 400 mg qd x 9 days NA ↓ 61% h ↓ 77% h NA 300 mg po q12h days 2-7 300 mg qd x 7 days NA ↓ 36% i (21-49%) ↓ 55% i (45-62%) NA 400 mg po q12h days 2-7 300 mg qd x 7 days NA ↑ 23% i (↓ 1-↑ 53%) ↓ 7% i (↓ 23-↑ 13%) NA Artemether/ lumefantrine Artemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over 3 days) 600 mg qd × 26 days 12 Artemether ↓ 21% ↓ 51% NA dihydroartemisinin ↓ 38% ↓ 46% NA Lumefantrine ↔ ↓ 21% NA Atorvastatin 10 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 14% (1-26%) ↓ 43% (34-50%) ↓ 69% (49-81%) Total active (including metabolites) ↓ 15% (2-26%) ↓ 32% (21-41%) ↓ 48% (23-64%) Pravastatin 40 mg qd x 4 days 600 mg qd x 15 days 13 ↓ 32% (↓ 59 -↑ 12%) ↓ 44% (26-57%) ↓ 19% (0-35%) Simvastatin 40 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 72% (63-79%) ↓ 68% (62-73%) ↓ 45% (20-62%) Total active (including metabolites) ↓ 68% (55-78%) ↓ 60% (52-68%) NA j Carbamazepine Epoxide metabolite 200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 29 days 600 mg qd x 14 days 12 ↓ 20% (15-24%) ↓ 27% (20-33%) ↓ 35% (24-44%) ↔ ↔ ↓ 13% (↓ 30 -↑ 7%) Cetirizine 10 mg single dose 600 mg qd x 10 days 11 ↓ 24% (18-30%) ↔ NA Diltiazem 240 mg x 21 days 600 mg qd x 14 days 13 ↓ 60% (50-68%) ↓ 69% (55-79%) ↓ 63% (44-75%) Desacetyl diltiazem ↓ 64% (57-69%) ↓ 75% (59-84%) ↓ 62% (44-75%) N‑monodes-methyl diltiazem ↓ 28% (7-44%) ↓ 37% (17-52%) ↓ 37% (17-52%) Ethinyl estradiol/ Norgestimate Ethinyl estradiol Norelgestromin Levonorgestrel 0.035 mg/0.25 mg x 14 days 600 mg qd x 14 days 21 21 6 ↔ ↓ 46% (39-52%) ↓ 80% (77-83%) ↔ ↓ 64% (62-67%) ↓ 83% (79-87%) ↔ ↓ 82% (79-85%) ↓ 86% (80-90%) Lorazepam 2 mg single dose 600 mg qd x 10 days 12 ↑ 16% (2-32%) ↔ NA Methadone Stable maintenance 35 to 100 mg daily 600 mg qd x 14-21 days 11 ↓ 45% (25-59%) ↓ 52% (33-66%) NA Bupropion Hydroxy-bupropion 150 mg single dose (sustained-release) 600 mg qd x 14 days 13 ↓34% (21-47%) ↑50% (20-80%) ↓ 55% (48-62%) ↔ NA NA Paroxetine 20 mg qd x 14 days 600 mg qd x 14 days 16 ↔ ↔ ↔ Sertraline 50 mg qd x 14 days 600 mg qd x 14 days 13 ↓ 29% (15-40%) ↓ 39% (27-50%) ↓ 46% (31-58%) ↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of <10%. a Compared with atazanavir 400 mg qd alone. b Comparator dose of indinavir was 800 mg q8h x 10 days. c Parallel-group design; n for efavirenz + lopinavir/ritonavir, n for lopinavir/ritonavir alone. d Values are for lopinavir; the pharmacokinetics of ritonavir in this study were unaffected by concurrent efavirenz. e 95% CI. f Soft Gelatin Capsule. g Tenofovir disoproxil fumarate. h 90% CI not available. i Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days). j Not available because of insufficient data. NA = not available. Table 8: Effect of Coadministered Drug on Efavirenz Plasma C max, AUC, and C min Efavirenz (mean % change) Coadministered Drug Dose Efavirenz Dose Number of Subjects C max (90% CI) AUC (90% CI) C min (90% CI) Indinavir 800 mg q8h x 14 days 200 mg qd x 14 days 11 ↔ ↔ ↔ Lopinavir/ ritonavir 400/100 mg q12h x 9 days 600 mg qd x 9 days 11,12 a ↔ ↓ 16% (↓ 38-↑ 15%) ↓ 16% (↓ 42-↑ 20%) Nelfinavir 750 mg q8h x 7 days 600 mg qd x 7 days 10 ↓ 12% (↓ 32-↑ 13%) b ↓ 12% (↓ 35-↑ 18%) b ↓ 21% (↓ 53-↑ 33%) Ritonavir 500 mg q12h x 8 days 600 mg qd x 10 days 9 ↑ 14% (4-26%) ↑ 21% (10-34%) ↑ 25% (7-46%) b Saquinavir SGC c 1200 mg q8h x 10 days 600 mg qd x 10 days 13 ↓ 13% (5-20%) ↓ 12% (4-19%) ↓ 14% (2-24%) b Tenofovir d 300 mg qd 600 mg qd x 14 days 30 ↔ ↔ ↔ Boceprevir 800 mg tid x 6 days 600 mg qd x 16 days NA ↑11% (2-20%) ↑ 20% (15-26%) NA Simeprevir 150 mg qd x 14 days 600 mg qd x 14 days 23 ↔ ↓ 10% (5-15%) ↓ 13% (7-19%) Azithromycin 600 mg single dose 400 mg qd x 7 days 14 ↔ ↔ ↔ Clarithromycin 500 mg q12h x 7 days 400 mg qd x 7 days 12 ↑ 11% (3-19%) ↔ ↔ Fluconazole 200 mg x 7 days 400 mg qd x 7 days 10 ↔ ↑ 16% (6-26%) ↑ 22% (5-41%) Itraconazole 200 mg q12h x 14 days 600 mg qd x 28 days 16 ↔ ↔ ↔ Rifabutin 300 mg qd x 14 days 600 mg qd x 14 days 11 ↔ ↔ ↓ 12% (↓ 24-↑ 1%) Rifampin 600 mg x 7 days 600 mg qd x 7 days 12 ↓ 20% (11-28%) ↓ 26% (15-36%) ↓ 32% (15-46%) Voriconazole 400 mg po q12h x 1 day, then 200 mg po q l2 h x 8 days 400 mg qd x 9 days NA ↑ 38% e ↑ 44% e NA 300 mg po q12h days 2-7 300 mg qd x 7 days NA ↓ 14% f (7-21%) ↔ f NA 400 mg po q12h days 2-7 300 mg qd x 7 days NA ↔ f ↑ 17% f (6-29%) NA Artemether/ Lumefantrine Artemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over 3 days) 600 mg qd × 26 days 12 ↔ ↓ 17% NA Atorvastatin 10 mg qd x 4 days 600 mg qd x 15 days 14 ↔ ↔ ↔ Pravastatin 40 mg qd x 4 days 600 mg qd x 15 days 11 ↔ ↔ ↔ Simvastatin 40 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 12% (↓ 28-↑ 8%) ↔ ↓ 12% (↓ 25-↑ 3%) Aluminum hydroxide 400 mg, magnesium hydroxide 400 mg, plus simethicone 40 mg 30 mL single dose 400 mg single dose 17 ↔ ↔ NA Carbamazepine 200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 15 days 600 mg qd x 35 days 14 ↓ 21% (15-26%) ↓ 36% (32-40%) ↓ 47% (41-53%) Cetirizine 10 mg single dose 600 mg qd x 10 days 11 ↔ ↔ ↔ Diltiazem 240 mg x 14 days 600 mg qd x 28 days 12 ↑ 16% (6-26%) ↑ 11% (5-18%) ↑ 13% (1-26%) Famotidine 40 mg single dose 400 mg single dose 17 ↔ ↔ NA Paroxetine 20 mg qd x 14 days 600 mg qd x 14 days 12 ↔ ↔ ↔ Sertraline 50 mg qd x 14 days 600 mg qd x 14 days 13 ↑ 11% (6-16%) ↔ ↔ ↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of <10%. a Parallel-group design; n for efavirenz + lopinavir/ritonavir, n for efavirenz alone. b 95% CI. c Soft Gelatin Capsule. d Tenofovir disoproxil fumarate. e 90% CI not available. f Relative to steady-state administration of efavirenz (600 mg once daily for 9 days). NA = not available.

20220421

5

3 DOSAGE FORMS AND STRENGTHS Efavirenz capsules USP 50 mg are Yellow/White size ‘4’ hard gelatin capsules imprinted with ‘D’ on yellow cap and ‘72’ on white body with black edible ink filled with white to off-white colored powder. Efavirenz capsules USP 100 mg are White/White size ‘2’ hard gelatin capsules imprinted with ‘D’ on white cap and ‘71’ on white body with black edible ink filled with white to off-white colored powder. Efavirenz capsules USP 200 mg are Yellow/Yellow size ‘0EL’ hard gelatin capsules imprinted with ‘D’ on yellow cap and ‘36’ on yellow body with black edible ink filled with white to off-white colored powder. Capsules: 50 mg, 100 mg, and 200 mg. (3)

Efavirenz Efavirenz EFAVIRENZ EFAVIRENZ LACTOSE MONOHYDRATE MAGNESIUM STEARATE SODIUM LAURYL SULFATE SODIUM STARCH GLYCOLATE TYPE A POTATO GELATIN, UNSPECIFIED SILICON DIOXIDE TITANIUM DIOXIDE FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE SHELLAC D;72 Efavirenz Efavirenz EFAVIRENZ EFAVIRENZ LACTOSE MONOHYDRATE MAGNESIUM STEARATE SODIUM LAURYL SULFATE SODIUM STARCH GLYCOLATE TYPE A POTATO GELATIN, UNSPECIFIED SILICON DIOXIDE TITANIUM DIOXIDE FERROSOFERRIC OXIDE SHELLAC D;71 Efavirenz Efavirenz EFAVIRENZ EFAVIRENZ LACTOSE MONOHYDRATE MAGNESIUM STEARATE SODIUM LAURYL SULFATE SODIUM STARCH GLYCOLATE TYPE A POTATO GELATIN, UNSPECIFIED SILICON DIOXIDE FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE SHELLAC D;36

13.2 Animal Toxicology Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose [see Warnings and Precautions (5.10) ] .

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. There was no NOAEL in females established for this study because tumor findings occurred at all doses. AUC at the NOAEL (150 mg/kg) in the males was approximately 0.9 times that in humans at the recommended clinical dose. In the rat study, no increases in tumor incidence were observed at doses up to 100 mg/kg/day, for which AUCs were 0.1 (males) or 0.2 (females) times those in humans at the recommended clinical dose. Mutagenesis Efavirenz tested negative in a battery of in vitro and in vivo genotoxicity assays. These included bacterial mutation assays in S. typhimurium and E. coli , mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay. Impairment of Fertility Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. The AUCs at the NOAEL values in male (200 mg/kg) and female (100 mg/kg) rats were approximately ≤0.15 times that in humans at the recommended clinical dose.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. There was no NOAEL in females established for this study because tumor findings occurred at all doses. AUC at the NOAEL (150 mg/kg) in the males was approximately 0.9 times that in humans at the recommended clinical dose. In the rat study, no increases in tumor incidence were observed at doses up to 100 mg/kg/day, for which AUCs were 0.1 (males) or 0.2 (females) times those in humans at the recommended clinical dose. Mutagenesis Efavirenz tested negative in a battery of in vitro and in vivo genotoxicity assays. These included bacterial mutation assays in S. typhimurium and E. coli , mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay. Impairment of Fertility Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. The AUCs at the NOAEL values in male (200 mg/kg) and female (100 mg/kg) rats were approximately ≤0.15 times that in humans at the recommended clinical dose. 13.2 Animal Toxicology Nonsustained convulsions were observed in 6 of 20 monkeys receiving efavirenz at doses yielding plasma AUC values 4- to 13-fold greater than those in humans given the recommended dose [see Warnings and Precautions (5.10) ] .

ANDA078064

Efavirenz

Efavirenz

65862-105

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 50 mg (30 Capsules Bottle) NDC 65862-104-30 Rx only Efavirenz Capsules USP 50 mg ALERT: Find out about medicines that should NOT be taken with Efavirenz Capsules USP. AUROBINDO 30 Capsules PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 50 mg (30 Capsule Bottle)

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ). Drug Interactions A statement to patients and healthcare providers is included on the product’s bottle labels: ALERT: Find out about medicines that should NOT be taken with Efavirenz Capsules. Efavirenz may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription or nonprescription medication. General Information for Patients Inform patients that efavirenz is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician while taking efavirenz. Advise patients to avoid doing things that can spread HIV-1 infection to others. Do not share or reuse needles or other injection equipment. Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. Do not breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk. Dosing Instructions Advise patients to take efavirenz every day as prescribed. If a patient forgets to take efavirenz, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not to take 2 doses at one time and to take the next dose at the regularly scheduled time. Advise the patient to ask a healthcare provider if he/she needs help in planning the best times to take his/her medicine. Efavirenz must always be used in combination with other antiretroviral drugs. Advise patients to take efavirenz on an empty stomach, preferably at bedtime. Taking efavirenz with food increases efavirenz concentrations and may increase the frequency of adverse reactions. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Dosage and Administration (2) and Adverse Reactions (6.1) ]. Healthcare providers should assist parents or caregivers in determining the best efavirenz dosing schedule for infants and young children. For adult and pediatric patients who cannot swallow capsules, patients or their caregivers should be advised to read and carefully follow the instructions for administering the capsule contents in a small amount of food or infant formula [see Dosage and Administration (2.3) and FDA-approved patient labeling (Patient Information and Instructions for Use )] . Patients should call their healthcare provider or pharmacist if they have any questions. Nervous System Symptoms Inform patients that central nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams are commonly reported during the first weeks of therapy with efavirenz [see Warnings and Precautions (5.6) ]. Dosing at bedtime may improve the tolerability of these symptoms, which are likely to improve with continued therapy. Alert patients to the potential for additive effects when efavirenz is used concomitantly with alcohol or psychoactive drugs. Instruct patients that if they experience NSS they should avoid potentially hazardous tasks such as driving or operating machinery. Inform patients that there is a risk of developing late-onset neurotoxicity, including ataxia and encephalopathy which may occur months to years after beginning efavirenz therapy [see Warnings and Precautions (5.6) ] . Psychiatric Symptoms Inform patients that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms and catatonia have been reported in patients receiving efavirenz [see Warnings and Precautions (5.5) ]. If they experience severe psychiatric adverse experiences they should seek immediate medical evaluation. Advise patients to inform their physician of any history of mental illness or substance abuse. Rash Inform patients that a common side effect is rash [see Warnings and Precautions (5.8) ]. Rashes usually go away without any change in treatment. However, since rash may be serious, advise patients to contact their physician promptly if rash occurs. Hepatotoxicity Inform patients to watch for early warning signs of liver inflammation or failure, such as fatigue, weakness, lack of appetite, nausea and vomiting, as well as later signs such as jaundice, confusion, abdominal swelling, and discolored feces, and to consult their health care professional without delay if such symptoms occur [see Warnings and Precautions (5.9) and Adverse Reactions (6.1) ] . Females of Reproductive Potential Advise females of reproductive potential to use effective contraception as well as a barrier method during treatment with efavirenz and for 12 weeks after discontinuing efavirenz. Advise patients to contact their healthcare provider if they plan to become pregnant, become pregnant, or if pregnancy is suspected during treatment with efavirenz [see Warnings and Precautions (5.7) and Use in Specific Populations (8.1 , 8.3 )] . Pregnancy Exposure Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz during pregnancy [see Use in Specific Populations (8.1) ] . Fat Redistribution Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known [see Warnings and Precautions (5.13) ]. Dispense with Patient Information available at: www.aurobindousa.com/medication-guides

14 CLINICAL STUDIES 14.1 Adults Study 006 , a randomized, open-label trial, compared efavirenz (600 mg once daily) + zidovudine (ZDV, 300 mg q12h) + lamivudine (LAM, 150 mg q12h) or efavirenz (600 mg once daily) + indinavir (IDV, 1000 mg q8h) with indinavir (800 mg q8h) + zidovudine (300 mg q12h) + lamivudine (150 mg q12h). Twelve hundred sixty-six patients (mean age 36.5 years [range 18 to 81], 60% Caucasian, 83% male) were enrolled. All patients were efavirenz-, lamivudine-, NNRTI-, and PI-naive at study entry. The median baseline CD4+ cell count was 320 cells/mm 3 and the median baseline HIV-1 RNA level was 4.8 log 10 copies/mL. Treatment outcomes with standard assay (assay limit 400 copies/mL) through 48 and 168 weeks are shown in Table 9. Plasma HIV RNA levels were quantified with standard (assay limit 400 copies/mL) and ultrasensitive (assay limit 50 copies/mL) versions of the AMPLICOR HIV-1 MONITOR assay. During the study, version 1.5 of the assay was introduced in Europe to enhance detection of non-clade B virus. Table 9: Outcomes of Randomized Treatment Through 48 and 168 Weeks, Study 006 Outcome Efavirenz + ZDV + LAM (n=422) Efavirenz + IDV (n=429) IDV + ZDV + LAM (n=415) Week 48 Week 168 Week 48 Week 168 Week 48 Week 168 Responder a 69% 48% 57% 40% 50% 29% Virologic failure b 6% 12% 15% 20% 13% 19% Discontinued for adverse events 7% 8% 6% 8% 16% 20% Discontinued for other reasons c 17% 31% 22% 32% 21% 32% CD4+ cell count (cells/mm 3 ) Observed subjects (n) (279) (205) (256) (158) (228) (129) Mean change from baseline 190 329 191 319 180 329 a Patients achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Week 48 or Week 168. b Includes patients who rebounded, patients who were on study at Week 48 and failed to achieve confirmed HIV-1 RNA <400 copies/mL at time of discontinuation, and patients who discontinued due to lack of efficacy. c Includes consent withdrawn, lost to follow-up, noncompliance, never treated, missing data, protocol violation, death, and other reasons. Patients with HIV-1 RNA levels <400 copies/mL who chose not to continue in the voluntary extension phases of the study were censored at date of last dose of study medication. For patients treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, or indinavir + zidovudine + lamivudine, the percentage of responders with HIV-1 RNA <50 copies/mL was 65%, 50%, and 45%, respectively, through 48 weeks, and 43%, 31%, and 23%, respectively, through 168 weeks. A Kaplan-Meier analysis of time to loss of virologic response (HIV RNA <400 copies/mL) suggests that both the trends of virologic response and differences in response continue through 4 years. ACTG 364 is a randomized, double-blind, placebo-controlled, 48-week study in NRTI-experienced patients who had completed two prior ACTG studies. One-hundred ninety-six patients (mean age 41 years [range 18 to 76], 74% Caucasian, 88% male) received NRTIs in combination with efavirenz (600 mg once daily), or nelfinavir (NFV, 750 mg three times daily), or efavirenz (600 mg once daily) + nelfinavir in a randomized, double-blinded manner. The mean baseline CD4+ cell count was 389 cells/mm 3 and mean baseline HIV-1 RNA level was 8130 copies/mL. Upon entry into the study, all patients were assigned a new open-label NRTI regimen, which was dependent on their previous NRTI treatment experience. There was no significant difference in the mean CD4+ cell count among treatment groups; the overall mean increase was approximately 100 cells at 48 weeks among patients who continued on study regimens. Treatment outcomes are shown in Table 10. Plasma HIV RNA levels were quantified with the AMPLICOR HIV-1 MONITOR assay using a lower limit of quantification of 500 copies/mL. Table 10: Outcomes of Randomized Treatment Through 48 Weeks, Study ACTG 364* Outcome Efavirenz + NFV + NRTIs (n=65) Efavirenz + NRTIs (n=65) NFV + NRTIs (n=66) HIV-1 RNA <500 copies/mL a 71% 63% 41% HIV-1 RNA ≥500 copies/mL b 17% 34% 54% CDC Category C Event 2% 0% 0% Discontinuations for adverse events c 3% 3% 5% Discontinuations for other reasons d 8% 0% 0% * For some patients, Week 56 data were used to confirm the status at Week 48. a Subjects achieved virologic response (two consecutive viral loads <500 copies/mL) and maintained it through Week 48. b Includes viral rebound and failure to achieve confirmed <500 copies/mL by Week 48. c See Adverse Reactions (6.1) for a safety profile of these regimens. d Includes loss to follow-up, consent withdrawn, noncompliance. A Kaplan-Meier analysis of time to treatment failure through 72 weeks demonstrates a longer duration of virologic suppression (HIV RNA <500 copies/mL) in the efavirenz-containing treatment arms. 14.2 Pediatric Patients Study AI266922 is an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of efavirenz in combination with didanosine and emtricitabine in antiretroviral-naive and -experienced pediatric patients. Thirty-seven patients 3 months to 6 years of age (median 0.7 years) were treated with efavirenz. At baseline, median plasma HIV-1 RNA was 5.88 log 10 copies/mL, median CD4+ cell count was 1144 cells/mm 3 , and median CD4+ percentage was 25%. The median time on study therapy was 60 weeks; 27% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 57% (21/37) and 46% (17/37), respectively. The median increase from baseline in CD4+ count at 48 weeks was 196 cells/mm 3 and the median increase in CD4+ percentage was 6%. Study PACTG 1021 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of efavirenz in combination with didanosine and emtricitabine in pediatric patients who were antiretroviral therapy naive. Forty-three patients 3 months to 21 years of age (median 9.6 years) were dosed with efavirenz. At baseline, median plasma HIV-1 RNA was 4.8 log 10 copies/mL, median CD4+ cell count was 367 cells/mm 3 , and median CD4+ percentage was 18%. The median time on study therapy was 181 weeks; 16% of patients discontinued before Week 48. Using an ITT analysis, the overall proportions of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 77% (33/43) and 70% (30/43), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 238 cells/mm 3 and the median increase in CD4+ percentage was 13%. Study PACTG 382 was an open-label study to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of efavirenz in combination with nelfinavir and an NRTI in antiretroviral-naive and NRTI-experienced pediatric patients. One hundred two patients 3 months to 16 years of age (median 5.7 years) were treated with efavirenz. Eighty-seven percent of patients had received prior antiretroviral therapy. At baseline, median plasma HIV-1 RNA was 4.57 log 10 copies/mL, median CD4+ cell count was 755 cells/mm 3 , and median CD4+ percentage was 30%. The median time on study therapy was 118 weeks; 25% of patients discontinued before Week 48. Using an ITT analysis, the overall proportion of patients with HIV RNA <400 copies/mL and <50 copies/mL at Week 48 were 57% (58/102) and 43% (44/102), respectively. The median increase from baseline in CD4+ count at 48 weeks of therapy was 128 cells/mm 3 and the median increase in CD4+ percentage was 5%.

8.5 Geriatric Use Clinical studies of efavirenz did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy.

8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of the potential for HIV transmission in breastfed infants, advise women not to breastfeed.

8.3 Females and Males of Reproductive Potential Because of potential teratogenic effects, pregnancy should be avoided in women receiving efavirenz [see Use in Specific Populations (8.1) ]. Pregnancy Testing Females of reproductive potential should undergo pregnancy testing before initiation of efavirenz. Contraception Females of reproductive potential should use effective contraception during treatment with efavirenz and for 12 weeks after discontinuing efavirenz due to the long half-life of efavirenz. Barrier contraception should always be used in combination with other methods of contraception. Hormonal methods that contain progesterone may have decreased effectiveness [see Drug Interactions (7.1) ] .

8.4 Pediatric Use The safety, pharmacokinetic profile, and virologic and immunologic responses of efavirenz were evaluated in antiretroviral-naive and -experienced HIV-1 infected pediatric patients 3 months to 21 years of age in three open-label clinical trials [see Adverse Reactions (6.2) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ]. The type and frequency of adverse reactions in these trials were generally similar to those of adult patients with the exception of a higher frequency of rash, including a higher frequency of Grade 3 or 4 rash, in pediatric patients compared to adults [see Warnings and Precautions (5.8) and Adverse Reactions (6.2) ]. Use of efavirenz in patients younger than 3 months of age OR less than 3.5 kg body weight is not recommended because the safety, pharmacokinetics, and antiviral activity of efavirenz have not been evaluated in this age group and there is a risk of developing HIV resistance if efavirenz is underdosed. See Dosage and Administration (2.2) for dosing recommendations for pediatric patients.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz 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 1000 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.

8 USE IN SPECIFIC POPULATIONS Lactation : Breastfeeding not recommended. ( 8.2 ) Females and Males of Reproductive Potential: Pregnancy testing and contraception are recommended. ( 8.3 ) Hepatic impairment: Efavirenz is not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. ( 8.6 ) Pediatric patients: The incidence of rash was higher than in adults. ( 5.8 , 6.2 , 8.4 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz 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 1000 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. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Because of the potential for HIV transmission in breastfed infants, advise women not to breastfeed. 8.3 Females and Males of Reproductive Potential Because of potential teratogenic effects, pregnancy should be avoided in women receiving efavirenz [see Use in Specific Populations (8.1) ]. Pregnancy Testing Females of reproductive potential should undergo pregnancy testing before initiation of efavirenz. Contraception Females of reproductive potential should use effective contraception during treatment with efavirenz and for 12 weeks after discontinuing efavirenz due to the long half-life of efavirenz. Barrier contraception should always be used in combination with other methods of contraception. Hormonal methods that contain progesterone may have decreased effectiveness [see Drug Interactions (7.1) ] . 8.4 Pediatric Use The safety, pharmacokinetic profile, and virologic and immunologic responses of efavirenz were evaluated in antiretroviral-naive and -experienced HIV-1 infected pediatric patients 3 months to 21 years of age in three open-label clinical trials [see Adverse Reactions (6.2) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ]. The type and frequency of adverse reactions in these trials were generally similar to those of adult patients with the exception of a higher frequency of rash, including a higher frequency of Grade 3 or 4 rash, in pediatric patients compared to adults [see Warnings and Precautions (5.8) and Adverse Reactions (6.2) ]. Use of efavirenz in patients younger than 3 months of age OR less than 3.5 kg body weight is not recommended because the safety, pharmacokinetics, and antiviral activity of efavirenz have not been evaluated in this age group and there is a risk of developing HIV resistance if efavirenz is underdosed. See Dosage and Administration (2.2) for dosing recommendations for pediatric patients. 8.5 Geriatric Use Clinical studies of efavirenz did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other therapy. 8.6 Hepatic Impairment Efavirenz is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine whether dose adjustment is necessary. Patients with mild hepatic impairment may be treated with efavirenz without any adjustment in dose. Because of the extensive cytochrome P450-mediated metabolism of efavirenz and limited clinical experience in patients with hepatic impairment, caution should be exercised in administering efavirenz to these patients [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Capsules Efavirenz capsules USP are available as follows: Efavirenz capsules USP 50 mg are Yellow/White size ‘4’ hard gelatin capsules imprinted with ‘D’ on yellow cap and ‘72’ on white body with black edible ink filled with white to off-white colored powder. Bottles of 30 NDC 65862-104-30 3 x 10 Unit-dose Capsules NDC 65862-104-10 Efavirenz capsules USP 100 mg are White/White size ‘2’ hard gelatin capsules imprinted with ‘D’ on white cap and ‘71’ on white body with black edible ink filled with white to off-white colored powder. Bottles of 30 NDC 65862-105-30 3 x 10 Unit-dose Capsules NDC 65862-105-10 Efavirenz capsules USP 200 mg are Yellow/Yellow size ‘0EL’ hard gelatin capsules imprinted with ‘D’ on yellow cap and ‘36’ on yellow body with black edible ink filled with white to off-white colored powder. Bottles of 30 NDC 65862-106-30 Bottles of 90 NDC 65862-106-90 3 x 10 Unit-dose Capsules NDC 65862-106-10 9 x 10 Unit-dose Capsules NDC 65862-106-09 16.3 Storage Efavirenz capsules should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].