Efavirenz

6 ADVERSE REACTIONS The most significant adverse reactions observed in patients treated with efavirenz tablets are: • psychiatric symptoms [see Warnings and Precautions ( 5.5)], • nervous system symptoms [see Warnings and Precautions (5.6)], • rash [see Warnings and Precautions (5.8)]. • hepatotoxicity [see Warnings and Precautions ( 5.9)] Most common adverse reactions (>5%, moderate-severe) are impaired concentration, abnormal dreams, rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. (6) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 tablets in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of efavirenz tablets-treated patients in two controlled clinical trials are presented in Table 2. Table 2: Selected Treatment-Emergent a Adverse Reactions of Moderate or Severe Intensity Reported in ≥2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364 Adverse Reactions Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients Efavirenz tablets b + ZDV/LAM (n=412) 180 weeks c Efavirenz tablets b + Indinavir (n=415) 102 weeks c Indinavir + ZDV/LAM (n=401) 76 weeks c Efavirenz tablets b + Nelfinavir + NRTIs (n=64) 71.1 weeks c Efavirenz tablets b + NRTIs (n=65) 70.9 weeks c Nelfinavir + NRTIs (n=66) 62.7 weeks c Body as a Whole Fatigue 8% 5% 9% 0 2% 3% Pain 1% 2% 8% 13% 6% 17% Central and Peripheral Nervous System Dizziness 9% 9% 2% 2% 6% 6% Headache 8% 5% 3% 5% 2% 3% Insomnia 7% 7% 2% 0 0 2% Concentration impaired 5% 3% <1% 0 0 0 Abnormal dreams 3% 1% 0 — — — Somnolence 2% 2% <1% 0 0 0 Anorexia 1% <1% <1% 0 2% 2% Gastrointestinal Nausea 10% 6% 24% 3% 2% 2% Vomiting 6% 3% 14% — — — Diarrhea 3% 5% 6% 14% 3% 9% Dyspepsia 4% 4% 6% 0 0 2% Abdominal pain 2% 2% 5% 3% 3% 3% Psychiatric Anxiety 2% 4% <1% — — — Depression 5% 4% <1% 3% 0 5% Nervousness 2% 2% 0 2% 0 2% Skin & Appendages Rash d 11% 16% 5% 9% 5% 9% Pruritus <1% 1% 1% 9% 5% 9% a Includes adverse events at least possibly related to study drug or of unknown relationship for Study 006. Includes all adverse events regardless of relationship to study drug for Study ACTG 364. b Efavirenz tablets provided as 600 mg once daily. c Median duration of treatment. d Includes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for Study 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and pruritus for ACTG 364. — = Not Specified. ZDV = zidovudine, LAM=lamivudine. Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients (see Laboratory Abnormalities ). Nervous System Symptoms For 1,008 patients treated with regimens containing efavirenz tablets and 635 patients treated with a control regimen in controlled trials, Table 3 lists the frequency of symptoms of different degrees of severity and gives the discontinuation rates for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking, and depersonalization [see Warnings and Precautions (5.6)]. The frequencies of specific central and peripheral nervous system symptoms are provided in Table 2. Table 3: Percent of Patients with One or More Selected Nervous System Symptoms a,b Percent of Patients with: Efavirenz Tablets 600 mg Once Daily (n=1,008) % Control Groups (n=635) % Symptoms of any severity 52.7 24.6 Mild symptoms c 33.3 15.6 Moderate symptoms d 17.4 7.7 Severe symptoms e 2 1.3 Treatment discontinuation as a result of symptoms 2.1 1.1 a Includes events reported regardless of causality. b Data from Study 006 and three Phase 2/3 studies. c “Mild” = Symptoms which do not interfere with patient’s daily activities. d “Moderate” = Symptoms which may interfere with daily activities. e “Severe” = Events which interrupt patient’s usual daily activities. Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with efavirenz tablets. In controlled trials, psychiatric symptoms observed at a frequency greater than 2% among patients treated with efavirenz tablets or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%). Rash In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1,008 adults treated with regimens containing efavirenz tablets and 17% for 635 adults treated with a control regimen. Most reports of rash were mild or moderate in severity. The frequency of Grade 3 rash was 0.8% for efavirenz tablets-treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz tablets and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz tablets-treated patients and 0.3% for control groups [see Warnings and Precautions (5.8)]. Experience with efavirenz tablets in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with efavirenz tablets. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz tablets, and two of these patients discontinued because of rash. Laboratory Abnormalities Selected Grade 3 to 4 laboratory abnormalities reported in ≥2% of efavirenz tablets-treated patients in two clinical trials are presented in Table 4. Table 4: Selected Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364 Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients Variable Limit Efavirenz tablets a +ZDV/LAM(n=412) 180 weeks b Efavirenz tablets a +Indinavir (n=415) 102 weeks b Indinavir +ZDV/LAM (n=401) 76 weeks b Efavirenz tablets a +Nelfinavir + NRTIs (n=64) 71.1 weeks b Efavirenz tablets a + NRTIs (n=65) 70.9 weeks b Nelfinavir + NRTIs (n=66) 62.7 weeks b Chemistry ALT >5 x ULN 5% 8% 5% 2% 6% 3% AST >5 x ULN 5% 6% 5% 6% 8% 8% GGT c >5 x ULN 8% 7% 3% 5% 0 5% Amylase >2 x ULN 4% 4% 1% 0 6% 2% Glucose >250 mg/dL 3% 3% 3% 5% 2% 3% Triglycerides d ³751mg/dL 9% 6% 6% 11% 8% 17% Hematology Neutrophils <750/mm 3 10% 3% 5% 2% 3% 2% a Efavirenz tablets provided as 600 mg once daily. b Median duration of treatment. c Isolated elevations of GGT in patients receiving efavirenz tablets may reflect enzyme induction not associated with liver toxicity. d Nonfasting. ZDV = zidovudine, LAM = lamivudine, ULN = upper limit of normal, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyltransferase. Patients Coinfected with Hepatitis B or C Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with efavirenz tablets-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a 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 tablets 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 tablets arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz tablets-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 tablets + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz tablets + 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 tablets + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with efavirenz tablets + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of efavirenz tablets 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 tablets 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 (ie, 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 tablets. 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, 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 tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. • Coadministration of efavirenz with elbasvir and grazoprevir is contraindicated [see Warnings and Precautions (5.1) and Drug Interactions ( 7.1)]. • Patients with previously demonstrated hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. (4) • Coadministration of efavirenz with elbasvir/grazoprevir.

11 DESCRIPTION Efavirenz is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI). Efavirenz USP is chemically described as (S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its empirical formula is C 14 H 9 ClF 3 NO 2 and its structural formula is: Efavirenz USP is a white to slightly pink crystalline powder with a molecular mass of 315.68. It is practically insoluble in water (<10 microgram/mL). Tablets: Efavirenz are available as film-coated tablets for oral administration containing 600 mg of efavirenz USP and the following inactive ingredients: microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate. The film coating contains Opadry® Yellow (hypromellose, titanium dioxide, iron oxide yellow and polyethylene glycol). Efavirenzstructure

2 DOSAGE & ADMINISTRATION • Efavirenz tablets should be taken orally once daily on an empty stomach, preferably at bedtime. (2) • Recommended adult dose: 600 mg. (2.2) • Pediatric dosing is based on weight. (2.3) 2.1 Hepatic Function Monitor hepatic function prior to and during treatment with efavirenz tablets [see Warnings and Precautions ( 5.9)]. Efavirenz tablets 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 Populationns ( 8.6)]. 2.2 Adults The recommended dosage of efavirenz tablets are 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz tablets be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz tablets 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 tablets should be swallowed intact with liquid. Concomitant Antiretroviral Therapy Efavirenz tablets 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)]. 2.3 Pediatric Patients It is recommended that efavirenz tablets be taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended dose of efavirenz tablets 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 tablets for pediatric patients weighing 40 kg or greater is 600 mg once daily. Table 1: Efavirenz Tablets Dosing in Pediatric Patients Patient Body Weight Efavirenz Tablets Daily Dose Number of Tablets b and Strength to Administer at least 40 kg 600 mg one 600 mg tablet b Tablets must not be crushed.

1 INDICATIONS & USAGE Efavirenz tablets in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and in pediatric patients at least 3 months old and weighing at least 3.5 kg. Efavirenz is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 infection in adults and in pediatric patients at least 3 months old and weighing at least 3.5 kg. (1)

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 tablets 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 tablets. 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 tablets. 7.2 Potential for Other Drugs to Affect Efavirenz Drugs that induce CYP3A activity (eg, phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations [see Dosage and Administration (2.2)]. 7.3 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 tablets are summarized in Tables 5. For pharmacokinetics data, [see Clinical Pharmacology (12.3)] Tables 7 and 8. This table includes potentially significant interactions, but is not all inclusive. Table 5: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class: Drug Name Effect Clinical Comment HIV antiviral agents Protease inhibitor: Fosamprenavir calcium ↓amprenavir Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz tablets are administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz tablets are administered with fosamprenavir plus ritonavir twice daily. Protease inhibitor: Atazanavir ↓atazanavir * Treatment-naive patients: When coadministered with efavirenz tablets, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and efavirenz tablets 600 mg (once daily on an empty stomach, preferably at bedtime). Treatment-experienced patients: Coadministration of efavirenz tablets and atazanavir is not recommended. Protease inhibitor: Indinavir ↓indinavir * The optimal dose of indinavir, when given in combination with efavirenz tablets, is not known. Increasing the indinavir dose to 1,000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz tablets. Protease inhibitor: Lopinavir/ritonavir ↓lopinavir * Lopinavir/ritonavir once daily dosing is not recommended when coadministered with efavirenz tablets. The dose of lopinavir/ritonavir must be increased when coadministered with efavirenz tablets. See the lopinavir/ritonavir prescribing information for dose adjustments of lopinavir/ritonavir when coadministered with efavirenz in adult and pediatric patients. Protease inhibitor: Ritonavir ↑ritonavir * ­ ↑efavirenz * Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz tablet is coadministered with ritonavir. Protease inhibitor: Saquinavir ↓saquinavir * Appropriate doses of the combination of efavirenz tablets and saquinavir/ritonavir with respect to safety and efficacy have not been established. NNRTI: Other NNRTIs ­ ↑ or ↓efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. ↑Efavirenz tablets should not be coadministered with other NNRTIs. CCR5 co-receptor antagonist: Maraviroc ↓maraviroc * Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz. Hepatitis C antiviral agents Boceprevir ↓ boceprevir * Concomitant administration of boceprevir with efavirenz tablet is not recommended because it may result in loss of therapeutic effect of boceprevir. Elbasvir/Grazoprevir ↓ elbasvir ↓ grazoprevir Coadministration of clopidogrel with elbasvir/grazoprevir is contraindicated [ see Contraindications (4) ] because it may lead to loss of virologic response to elbasvir/grazoprevir. Pibrentasvir/Glecaprevir ↓ pibrentasvir ↓ glecaprevir Coadministration of clopidogrel is not recommended because it may lead to reduced therapeutic effect of pibrentasvir/glecaprevir. Simeprevir ↓ simeprevir * ↔efavirenz * Concomitant administration of simprevir with efavirenz tablet is not recommended because it may result in loss of therapeutic effect of simeprevir. Velpatasvir/ Sofosbuvir ↓ velpatasvir Coadministration of efavirenz and sofosbuvir/velpatasvir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir. Velpatasvir /Sofosbuvir /Voxilaprevir velpatasvir sofosbuvir Coadministration of efavirenz and sofosbuvir/velpatasvir/voxilaprevir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir. Other agents Anticoagulant: Warfarin ­ ↑ or ↓warfarin Monitor INR and adjust warfarin dosage if necessary. Anticonvulsants: Carbamazepine ↓carbamazepine * ↓efavirenz * There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used. Phenytoin Phenobarbital ↓anticonvulsant ↓efavirenz Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. Antidepressants: Bupropion Sertraline ↓bupropion * ↓sertraline * Increases in bupropion dosage should be guided by clinical response. Bupropion dose should not exceed the maximum recommended dose. Increases in sertraline dosage should be guided by clinical response. Antifungals: Voriconazole ↓voriconazole * ­ ↑efavirenz * Efavirenz tablets and voriconazole should not be coadministered at standard doses. When voriconazole is coadministered with efavirenz tablets, voriconazole maintenance dose should be increased to 400 mg every 12 hours and efavirenz tablets dose should be decreased to 300 mg once daily using the capsule formulation. Efavirenz tablets must not be broken. [ See Dosage and Administration (2.2) and Clinical Pharmacology (12.3, Tables 7 and 8) .] Itraconazole ↓itraconazole * ↓hydroxyitraconazole * Consider alternative antifungal treatment because no dose recommendation for itraconazole can be made. Ketoconazole ↓ketoconazole Consider alternative antifungal treatment because no dose recommendation for ketoconazole can be made. Posaconazole ↓posaconazole * Avoid concomitant use unless the benefit outweighs the risks. Anti-infective: Clarithromycin ↓ clarithromycin * ­ ↑14-OH metabolite * Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation. Antimycobacterials: Rifabutin ↓ rifabutin * Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. Rifampin ↓efavirenz * Increase efavirenz tablets to 800 mg once daily when coadministered with rifampin to patients weighing 50 kg or more. Antimalarials: Artemether/ lumefantrine Atovaquone/ proguanil ↓ artemether* ↓ dihydroartemisinin* ↓ lumefantrine* ↓ atovaquone ↓ proguanil Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation. Concomitant administration is not recommended. Calcium channel blockers: Diltiazem ↓diltiazem * ↓desacetyl diltiazem * ↓N-monodesmethyl diltiazem * Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem. Others (eg, felodipine, nicardipine, nifedipine, verapamil) ↓ calcium channel blocker When coadministered with efavirenz tablets, 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 tablets 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 C max 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 C max 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 1,600 mg administered to uninfected volunteers. Dose-related increases in C max and AUC were seen for doses up to 1,600 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 tablets 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: Tablets: Administration of a single 600 mg efavirenz tablet with a high-fat/high-caloric meal (approximately 1,000 kcal, 500 to 600 kcal from fat) was associated with a 28% increase in mean AUC ∞ of efavirenz and a 79% increase in mean C max of efavirenz relative to the exposures achieved under fasted conditions. [ See Dosage and Administration (2) and Patient Counseling Information (17 .] 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 tablets 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. 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 ↑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. 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 1-20 400 mg qd d 1-6, then 300 mg qd d 7-20 with ritonavir 100 mg qd and a light meal 300 mg qd/ritonavir 100 mg qd d 1-10 (pm), then 400 mg qd d 11-24 (pm) (simultaneous with efavirenz) 600 mg qd qd with a light meal d 7-20 600 mg qd 2 h after atazanavir and ritonavir d 7-20 600 mg qd withn a light snack d 11-24 (pm) 27 13 14 ↓59% (49-67%) ↑ 14% a (↓17- ↑58%) ↑17% (8-27%) ↓74% (68-78%) ↑39% a (2-88%) ↔ ↓93% (90-95%) ↑48% a (24-76%) ↓42% (31-51%) Indinavir 1000 mg q8h x 10 days After morning Dose After afternoon dose After evening dose 600 mg qd × 10 days 20 ↔ b ↔ b ↓ 29% b (11-43%) ↓33% b (26-39%) ↓ 37% b (26-46%) ↓ 46% b (37-54%) ↓ 39% b (24-51%) ↓52% b (47-57%) ↓ 57% b (50-63%) Lopinavir/ ritonavir 400/ 100 mg Capsules q 12 x 9 days 500/ 125 mg tablet q 12 x 10 days with efavirenz compared to 400/100 mg q 12 h Alone 600/150 mg tablet Q 12 x 10 days with efavirenz compared to 400/100 mg q 12 h 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 Metabolite AG-1402 750 mg q8h x 7 days 600 mg qd x 7 days 10 ↑ 21% (10-33) ↓ 40% (30-48) ↑ 20% (8-34%) ↓ 37% (25-48%) ↔ ↓ 43% (21-59%) Ritonavir 500 mg q 12 × 8 days After AM dose After PM dose 600 mg qd x 10 days 11 ↑ 24% (12-38%) ↔ ↑ 18% (6-33%) ↔ ↑ 42% (9-86%) e ↑ 24% ( 3-50) e Saquinavir SGC f 1200 mg q8h X 10 days 600 mg qd x 10 days 12 ↓ 50% (28-66%) ↓ 62% (45-74%) ↓ 56% (16-77%) e Lamivudine 150 mg q 12 h x 14 days 600 14 days 9 ↔ ↔ ↑ 265% (37-873%) Tenofovir g 300 mg qd 600 mg qd x 14 days 29 ↔ ↔ ↔ zidovudine 300 mg q 12h 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 14-OH metabolite 500 mg q12h X 7 days 400 mg qd x 7 days 11 ↓ 26% (15-35%) ↑ 49% (32-69%) ↓ 39% (30-46%) ↑ 34% (18-53%) ↓ 53% (42-63%) ↑ 26% (9-45%) Fluconazole 200 mg x 7 days 400 mg qd x 7 days 10 ↔ ↔ ↔ Itraconazole Hydroxyl- itraconazole 200 mg q 12h x 28 days 600 mg qd x 14 days 18 ↓ 37% (20-51%) ↓ 35% (12-52%) ↓ 39% (21-53%) ↓ 37% (14-55%) ↓ 44% (27-58%) ↓ 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 q 12h x 1 day, then 200 mg Po q 12h x 8 days 300 mg po q 12h Days 2-7 400 mg po q 12h days 2-7 400 mg qd x 9 days 300 mg qd x 7 days 300 mg qd x 7 days NA NA NA ↓ 61% h ↓ 36% i (21-49%) ↑ 23% i (↓ 1 –↑53%) ↓ 77% h ↓ 55% i (45-62%) ↓ 7% i (↓23 -↑ 13%) NA NA NA Artemether/ lumefantrine Arthemether dihydroartemisinin lamefantrine Artemether 20 mg / lumefantrine 120 mg tablets (6 4- tablet doses over 3 days) 600 mg qd x 26 days 12 ↓ 21% ↓ 38% ↔ ↓ 51% ↓ 46% ↓ 21% NA NA NA Atorvastatin Total active (including metabolites 10 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 14% (1-26%) ↓ 15% (2-26%) ↓ 43% (34-50%) ↓ 32% (21-41%) ↓ 69% (49-81%) ↓ 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%) Simavastatin Total active (including Metabolites) 40 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 72% (63-79%) ↓ 68 % (55-78 %) ↓ 68% (62-73%) ↓ 60 % (52-68 %) ↓ 45% (20-62%) 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 Desacetyl diltiazem N- monodes- Methyl diltiazem 240 mg x 21 days 600 mg qd x 14 days 13 ↓ 60% (50-68%) ↓ 64% (57-69%) ↓ 28% (7-44%) ↓ 69% (55-79%) ↓ 75% (59-84%) ↓ 37% (17-52%) ↓63% (44-75%) ↓ 62% (44-75%) ↓ 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 35-100 mg daily 600 mg qd x 14-21 days 11 ↓ 45% (25-59%) ↓ 52% (33-66%) NA Bupropion Hydroxyl- 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%) Table 8: Effect of Coadministered Drug on Efavirenz Plasma C max , AUC, and C min Coadministered Drug Dose Efavirenz Dose Number of subjects Efavirenz (mean % change) 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 q12h x 8 days 300 mg po q12h days 2-7 400 mg po q12h days 2-7 400 mg qd x 9 days 300 mg qd x 7 days 300 mg qd x 7 days NA NA NA ↑ 38% e ↓ 14% f (7-21%) ↔ f ↔ ↑ 44% e ↔ f ↑ 17% f (6-29%) NA NA NA Artemether/ Lumefantrine Artemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over 3 days) 600 mg qd x 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 x15 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 to 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 delaviridine and nevirapine compared to baseline. Delaviridine- 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 C max 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 C max 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 1,600 mg administered to uninfected volunteers. Dose-related increases in C max and AUC were seen for doses up to 1,600 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 tablets 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: Tablets: Administration of a single 600 mg efavirenz tablet with a high-fat/high-caloric meal (approximately 1,000 kcal, 500 to 600 kcal from fat) was associated with a 28% increase in mean AUC ∞ of efavirenz and a 79% increase in mean C max of efavirenz relative to the exposures achieved under fasted conditions. [ See Dosage and Administration (2) and Patient Counseling Information (17 .] 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 tablets 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. 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 ↑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. 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 1-20 400 mg qd d 1-6, then 300 mg qd d 7-20 with ritonavir 100 mg qd and a light meal 300 mg qd/ritonavir 100 mg qd d 1-10 (pm), then 400 mg qd d 11-24 (pm) (simultaneous with efavirenz) 600 mg qd qd with a light meal d 7-20 600 mg qd 2 h after atazanavir and ritonavir d 7-20 600 mg qd withn a light snack d 11-24 (pm) 27 13 14 ↓59% (49-67%) ↑ 14% a (↓17- ↑58%) ↑17% (8-27%) ↓74% (68-78%) ↑39% a (2-88%) ↔ ↓93% (90-95%) ↑48% a (24-76%) ↓42% (31-51%) Indinavir 1000 mg q8h x 10 days After morning Dose After afternoon dose After evening dose 600 mg qd × 10 days 20 ↔ b ↔ b ↓ 29% b (11-43%) ↓33% b (26-39%) ↓ 37% b (26-46%) ↓ 46% b (37-54%) ↓ 39% b (24-51%) ↓52% b (47-57%) ↓ 57% b (50-63%) Lopinavir/ ritonavir 400/ 100 mg Capsules q 12 x 9 days 500/ 125 mg tablet q 12 x 10 days with efavirenz compared to 400/100 mg q 12 h Alone 600/150 mg tablet Q 12 x 10 days with efavirenz compared to 400/100 mg q 12 h 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 Metabolite AG-1402 750 mg q8h x 7 days 600 mg qd x 7 days 10 ↑ 21% (10-33) ↓ 40% (30-48) ↑ 20% (8-34%) ↓ 37% (25-48%) ↔ ↓ 43% (21-59%) Ritonavir 500 mg q 12 × 8 days After AM dose After PM dose 600 mg qd x 10 days 11 ↑ 24% (12-38%) ↔ ↑ 18% (6-33%) ↔ ↑ 42% (9-86%) e ↑ 24% ( 3-50) e Saquinavir SGC f 1200 mg q8h X 10 days 600 mg qd x 10 days 12 ↓ 50% (28-66%) ↓ 62% (45-74%) ↓ 56% (16-77%) e Lamivudine 150 mg q 12 h x 14 days 600 14 days 9 ↔ ↔ ↑ 265% (37-873%) Tenofovir g 300 mg qd 600 mg qd x 14 days 29 ↔ ↔ ↔ zidovudine 300 mg q 12h 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 14-OH metabolite 500 mg q12h X 7 days 400 mg qd x 7 days 11 ↓ 26% (15-35%) ↑ 49% (32-69%) ↓ 39% (30-46%) ↑ 34% (18-53%) ↓ 53% (42-63%) ↑ 26% (9-45%) Fluconazole 200 mg x 7 days 400 mg qd x 7 days 10 ↔ ↔ ↔ Itraconazole Hydroxyl- itraconazole 200 mg q 12h x 28 days 600 mg qd x 14 days 18 ↓ 37% (20-51%) ↓ 35% (12-52%) ↓ 39% (21-53%) ↓ 37% (14-55%) ↓ 44% (27-58%) ↓ 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 q 12h x 1 day, then 200 mg Po q 12h x 8 days 300 mg po q 12h Days 2-7 400 mg po q 12h days 2-7 400 mg qd x 9 days 300 mg qd x 7 days 300 mg qd x 7 days NA NA NA ↓ 61% h ↓ 36% i (21-49%) ↑ 23% i (↓ 1 –↑53%) ↓ 77% h ↓ 55% i (45-62%) ↓ 7% i (↓23 -↑ 13%) NA NA NA Artemether/ lumefantrine Arthemether dihydroartemisinin lamefantrine Artemether 20 mg / lumefantrine 120 mg tablets (6 4- tablet doses over 3 days) 600 mg qd x 26 days 12 ↓ 21% ↓ 38% ↔ ↓ 51% ↓ 46% ↓ 21% NA NA NA Atorvastatin Total active (including metabolites 10 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 14% (1-26%) ↓ 15% (2-26%) ↓ 43% (34-50%) ↓ 32% (21-41%) ↓ 69% (49-81%) ↓ 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%) Simavastatin Total active (including Metabolites) 40 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 72% (63-79%) ↓ 68 % (55-78 %) ↓ 68% (62-73%) ↓ 60 % (52-68 %) ↓ 45% (20-62%) 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 Desacetyl diltiazem N- monodes- Methyl diltiazem 240 mg x 21 days 600 mg qd x 14 days 13 ↓ 60% (50-68%) ↓ 64% (57-69%) ↓ 28% (7-44%) ↓ 69% (55-79%) ↓ 75% (59-84%) ↓ 37% (17-52%) ↓63% (44-75%) ↓ 62% (44-75%) ↓ 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 35-100 mg daily 600 mg qd x 14-21 days 11 ↓ 45% (25-59%) ↓ 52% (33-66%) NA Bupropion Hydroxyl- 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%) Table 8: Effect of Coadministered Drug on Efavirenz Plasma C max , AUC, and C min Coadministered Drug Dose Efavirenz Dose Number of subjects Efavirenz (mean % change) 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 q12h x 8 days 300 mg po q12h days 2-7 400 mg po q12h days 2-7 400 mg qd x 9 days 300 mg qd x 7 days 300 mg qd x 7 days NA NA NA ↑ 38% e ↓ 14% f (7-21%) ↔ f ↔ ↑ 44% e ↔ f ↑ 17% f (6-29%) NA NA NA Artemether/ Lumefantrine Artemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over 3 days) 600 mg qd x 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 x15 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.

20230515

3

3 DOSAGE FORMS & STRENGTHS • Tablets 600 mg tablets are yellow, capsular-shaped, film-coated tablets, with ‘H’ on one side and ‘4’ on the other side. • Tablets: 600 mg (3)

Efavirenz Efavirenz CELLULOSE, MICROCRYSTALLINE SODIUM LAURYL SULFATE CROSCARMELLOSE SODIUM HYDROXYPROPYL CELLULOSE LACTOSE MONOHYDRATE MAGNESIUM STEARATE HYPROMELLOSES TITANIUM DIOXIDE POLYETHYLENE GLYCOL, UNSPECIFIED FERRIC OXIDE YELLOW EFAVIRENZ EFAVIRENZ Capsular H;4

13.2 Animal Pharmacology & OR 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 Pharmacology & OR 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)].

ANDA078886

Efavirenz

Efavirenz

31722-504

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Efavirenz Tablets 600 mg container Label 30s count Efavirenz Tablets 600 mg container Label 250s count Efavirenztabcontlabel30s Efavirenztabcontlabel250s

Dosage and Administration, Hepatic Function (2.1) 10/2017 Contraindications, Antiviral Agents (4) 10/2017 Warnings and Precautions, Psychiatric Symptoms (5.5) 01/2017 Warnings and Precautions, Hepatotoxicity (5.9) 10/2017

Patient Information Efavirenz (EF-a-VIR-enz) tablets Important: Ask your doctor or pharmacist about medicines that should not be taken with efavirenz tablets. For more information, see the section “What should I tell my doctor before taking efavirenz tablets?” Read this Patient Information before you start taking efavirenz tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. What are efavirenz tablets? Efavirenz tablets are a prescription HIV-1 (Human Immunodeficiency Virus type 1) medicine used with other antiretroviral medicines to treat HIV-1 infection in adults and in children who are at least 3 months old and who weigh at least 7 pounds 12 ounces (3.5 kg). HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). It is not known if efavirenz tablets are safe and effective in children younger than 3 months of age or who weigh less than 7 pounds 12 ounces (3.5 kg). When used with other antiretroviral medicines to treat HIV-1 infection, efavirenz tablets may help: • reduce the amount of HIV-1 in your blood. This is called viral load. • increase the number of CD4+ (T) cells in your blood that help fight off other infections. Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections). Efavirenz tablets does not cure HIV-1 infection or AIDS. You should keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses. 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 any body fluids such as semen, vaginal secretions, or blood. Ask your doctor if you have any questions about how to prevent passing HIV to other people. Who should not take efavirenz tablets? Do not take efavirenz tablets if you are allergic to efavirenz or any of the ingredients in efavirenz tablets. See the end of this leaflet for a complete list of ingredients in efavirenz tablets. Do not take efavirenz if you are currently taking elbasvir and grazoprevir (zepatier ® ). What should I tell my doctor before taking efavirenz tablets? Before taking efavirenz tablets, tell your doctor if you have any medical conditions and in particular, if you: • have a heart condition • have ever had a mental health problem • have ever used street drugs or large amounts of alcohol • have liver problems, including hepatitis B or C virus infection • have a history of seizures • are pregnant or plan to become pregnant. Efavirenz tablets may harm your unborn baby. If you are able to become pregnant your healthcare provider should do a pregnancy test before you start efavirenz tablets. You should not become pregnant while taking efavirenz tablets and for 12 weeks after stopping treatment with efavirenz tablets. Females who are able to become pregnant should use 2 effective forms of birth control during treatment and for 12 weeks after stopping treatment with efavirenz tablets. A barrier form of birth control should always be used along with another type of birth control. • Barrier forms of birth control may include latex or polyurethane condom, contraceptive sponge, diaphragm with spermicide, and cervical cap. • Hormonal forms of birth control, such as birth control pills, injections, vaginal rings, or implants may not work during treatment with efavirenz tablets. • Talk to your doctor about forms of birth control that may be used during treatment with efavirenz tablets. • Pregnancy Registry. There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry. • Do not breastfeed if you take efavirenz tablets. • You should not breastfeed if you have HIV because of the risk of passing HIV to your baby. Tell your doctor and pharmacist about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Efavirenz tablets may affect the way other medicines work, and other medicines may affect how efavirenz tablets works, and may cause serious side effects. If you take certain medicines with efavirenz tablets, the amount of efavirenz tablets in your body may be too low and it may not work to help control your HIV infection. The HIV virus in your body may become resistant to efavirenz tablets or other HIV medicines that are like it. You should not take efavirenz tablets if you take ATRIPLA (efavirenz, emtricitabine, tenofovir disoproxil fumarate) unless your doctor tells you to. Tell your doctor and pharmacist about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with efavirenz tablets. Keep a list of your medicines to show your doctor and pharmacist. • You can ask your doctor or pharmacist for a list of medicines that interact with efavirenz tablets. • Do not start taking a new medicine without telling your doctor. Your doctor can tell you if it is safe to take efavirenz tablets with other medicines. How should I take efavirenz tablets? • Take efavirenz tablets exactly as your doctor tells you to. • Do not change your dose or stop taking efavirenz tablets unless your doctor tells you to. • Stay under the care of your doctor during treatment with efavirenz tablets. • Efavirenz tablets must be used with other antiretroviral medicines. • Take efavirenz tablets 1 time each day. • Efavirenz comes as tablets. • Efavirenz tablets must not be broken. • Swallow efavirenz tablets whole with liquid. How and when to take efavirenz tablets. • You should take efavirenz tablets on an empty stomach at bedtime. Taking efavirenz tablets with food increases the amount of medicine in your body. Some side effects may bother you less if you take efavirenz tablets on an empty stomach and at bedtime. • Your child’s doctor will prescribe the right dose of efavirenz tablets based on your child’s weight. • If you have difficulty swallowing tablets, tell your doctor. • Do not miss a dose of efavirenz tablets. If you forget to take efavirenz tablets, take the missed dose right away, unless it is almost time for your next dose. Do not take 2 doses at one time. Just take your next dose at your regularly scheduled time. If you need help in planning the best times to take your medicine, ask your doctor or pharmacist. • If you take too much efavirenz tablets, call your doctor or go to the nearest hospital emergency room right away. • When your efavirenz tablets supply starts to run low, get more from your doctor or pharmacy. It is important not to run out of efavirenz tablets. The amount of HIV-1 in your blood may increase if the medicine is stopped for even a short time. The virus may become resistant to efavirenz tablets and harder to treat. What are the possible side effects of efavirenz tablets? Efavirenz tablets may cause serious side effects, including: • Serious mental health problems can happen in people who take efavirenz tablets. Tell your doctor right away if you have any of the following symptoms: • feel sad or hopeless • do not trust other people • feel anxious or restless • hear or see things that are not real • have thoughts of hurting yourself (suicide) or have tried to hurt yourself or others • are not able to move or speak normally. • are not able to tell the difference between what is true or real and what is false or unreal • Nervous system symptoms are common in people who take efavirenz tablets and can be severe. These symptoms usually begin during the first or second day of treatment with efavirenz tablets and usually go away after 2 to 4 weeks of treatment. These symptoms may become worse if you drink alcohol, take a medicine for mental health problems, or use certain street drugs during treatment with efavirenz tablets. Symptoms may include: • dizziness • trouble sleeping • trouble concentrating • unusual dreams • drowsiness If you have dizziness, trouble concentrating or drowsiness, do not drive a car, use machinery, or do anything that needs you to be alert. • Skin rash is common with efavirenz tablets but can sometimes be severe. Skin rash usually goes away without any change in treatment. If you develop a rash with any of the following symptoms, tell your doctor right away: • skin rash, with or without itching • peeling skin • fever • mouth sores • swelling of your face • red or inflamed eyes, like “pink eye” (conjunctivitis) • blisters or skin lesions Liver problems, including liver failure and death can happen in people who take efavirenz liver problems can also happen in people without a history of liver problems. Your doctor will do blood tests to check your liver before you start efavirenz and during treatment. Tell your doctor right away if you get any of the following symptoms: • your skin or the white part of your eyes turns yellow (jaundice) • you don’t feel like eating food for several days or longer • your urine turns dark • you feel sick to your stomach (nausea) • your bowel movements (stools) turn light in color • you have lower stomach area (abdominal) pain • Seizures can happen in people who take efavirenz tablets. Seizures are more likely to happen if you have had seizures in the past. Tell your doctor if you have had a seizure or if you take a medicine to help prevent seizures. • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your doctor if you start having new symptoms after starting your HIV-1 medicine. • Changes in body fat can happen in people who take HIV-1 medicine. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known. The most common side effects of efavirenz tablets include: • rash • abnormal dreams • dizziness • tiredness • nausea • trouble sleeping • headache • vomiting • difficulty concentrating Some patients taking efavirenz tablets have experienced increased levels of lipids (cholesterol and triglycerides) in the blood. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of efavirenz tablets. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store efavirenz tablets? • Store efavirenz tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep efavirenz tablets and all medicines out of the reach of children. General information about efavirenz tablets Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use efavirenz tablets for a condition for which it was not prescribed. Do not give efavirenz tablets to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about efavirenz tablets that is written for health professionals. For more information call 1-886-495-1995. What are the ingredients in efavirenz tablets? Active Ingredient: efavirenz, USP Inactive ingredients: Efavirenz tablets: microcrystalline cellulose, sodium lauryl sulfate, croscarmellose sodium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate. The film coating contains Opadry ® Yellow (hypromellose, titanium dioxide, iron oxide yellow and polyethylene glycol) This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854 Manufactured by HETERO TM HETERO LABS LIMITED 22-110, I.D.A., Jeedimetla, Hyderabad – 500 055, India. Revised: February 2018 All brand names listed are the registered trademarks of their respective owners and are not trademarks of Hetero Labs Limited. Efavirenztabcamberlogo2

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 tablets. Efavirenz may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication. General Information for Patients Patients should be informed that efavirenz tablets are 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 tablets. Patients should be advised 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 Patients should be advised to take efavirenz tablets every day as prescribed. If a patient forgets to take efavirenz tablets, 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 tablets must always be used in combination with other antiretroviral drugs. Patients should be advised to take efavirenz tablets on an empty stomach, preferably at bedtime. Taking efavirenz tablets 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 tablets dosing schedule for infants and young children. Patients should call their healthcare provider or pharmacist if they have any questions. Nervous System Symptoms Patients should be informed 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 tablets [see Warnings and Precautions (5.6)]. Dosing at bedtime may improve the tolerability of these symptoms, which are likely to improve with continued therapy. Patients should be alerted to the potential for additive effects when efavirenz tablets are used concomitantly with alcohol or psychoactive drugs. Patients should be instructed that if they experience NSS they should avoid potentially hazardous tasks such as driving or operating machinery. Psychiatric Symptoms Patients should be informed 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 tablets [see Warnings and Precautions (5.5)]. If they experience severe psychiatric adverse experiences they should seek immediate medical evaluation. Patients should be advised to inform their physician of any history of mental illness or substance abuse. Rash Patients should be informed 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, patients should be advised 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 tablets and for 12 weeks after discontinuing efavirenz tablets. Advise patients to contact their healthcare provider if they plan to become pregnant, become pregnant, or if pregnancy is suspected during treatment with efavirenz tablets [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 tablets during pregnancy [see Use in Specific Populations (8.1)]. Fat Redistribution Patients should be informed 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)]. All brand names listed are the registered trademarks of their respective owners and are not trademarks of Hetero Labs Limited. Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854. Manufactured by: HETERO TM HETERO LABS LIMITED 22-110, I.D.A., Jeedimetla, Hyderabad – 500 055, India. Barcode Revised: February 2018 Efavirenztabcamberlogo1

14 CLINICAL STUDIES 14.1 Adults Study 006, a randomized, open-label trial, compared efavirenz tablets (600 mg once daily) + zidovudine (ZDV, 300 mg q12h) + lamivudine (LAM, 150 mg q12h) or efavirenz tablets (600 mg once daily) + indinavir (IDV, 1,000 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 Efaverinz tablets + ZDV + LAM (n=422) Efavirenz tablets + IDV (n=429) IDV + ZDV + LAM (n=415) Outcome 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 tablets + zidovudine + lamivudine, efavirenz tablets + 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 tablets (600 mg once daily), or nelfinavir (NFV, 750 mg three times daily), or efavirenz tablets (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 8,130 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 tablets + NFV + NRTIs (n=65) Efavirenz tablets + NRTIs (n=65) NFV + NRTIs (n=66) HIV-1 RNA <500 copies/mL a 71% 63% 41% HIV-1 RNA ≥500 copies/mL b CDC category C Event 17% 2% 34% 0% 54% 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 tablets-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 1,144 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 1,021 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 tablets. At baseline, median plasma HIV-1 RNA was 4.8 log10 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 tablets. Eighty-seven percent of patients had received prior antiretroviral therapy. At baseline, median plasma HIV-1 RNA was 4.57 log10 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 tablets 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 tablets. [See Use in Specific Populations (8.1).] Pregnancy Testing Females of reproductive potential should undergo pregnancy testing before initiation of efavirenz tablets. Contraception Females of reproductive potential should use effective contraception during treatment with efavirenz tablets and for 12 weeks after discontinuing efavirenz tablets 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 tablets 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 tablets 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 tablets have not been evaluated in this age group and there is a risk of developing HIV resistance if efavirenz tablets are underdosed. [See Dosage and Administration (2.2)] for dosing recommendations for pediatric patients.

8.1 Pregnancy Tetratogenic Effects Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz tablets during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Risk Summary There are retrospective case reports of neural tube defects in infants whose mothers were exposed to efavirenz-containing regimens in the first trimester of pregnancy. Prospective pregnancy data from the Antiretroviral Pregnancy Registry are not sufficient to adequately assess this risk. Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Although a causal relationship has not been established between exposure to efavirenz in the first trimester and neural tube defects, similar malformations have been observed in studies conducted in monkeys at doses similar to the human dose. In addition, fetal and embryonic toxicities occurred in rats, at a dose ten times less than the human exposure at recommended clinical dose. Because of the potential risk of neural tube defects, efavirenz should not be used in the first trimester of pregnancy. Advise pregnant women of the potential risk to a fetus. Data Human Data There are retrospective postmarketing reports of findings consistent with neural tube defects, including meningomyelocele, all in infants of mothers exposed to efavirenz-containing regimens in the first trimester. Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of approximately 1,000 live births following exposure to efavirenz-containing regimens (including over 800 live births exposed in the first-trimester), there was no difference between efavirenz and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. As of the interim APR report issued December 2014, the prevalence of birth defects following first-trimester exposure was 2.3% (95% CI: 1.4% to 3.6%). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported. This case also included severe oblique facial clefts and amniotic banding, which have a known association with anophthalmia. Animal Data Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in a second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, efavirenz was administered either during organogenesis (gestation days 7 to 18) or from gestation day 7 through lactation day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with increase in the incidence of early resorptions; and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose. Drug concentrations in the milk on lactation day 10 were approximately 8 times higher than those in maternal plasma. In pregnant rabbits, efavirenz was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation days 6 through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose.

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 tablets are 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 Tetratogenic Effects Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz tablets during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Risk Summary There are retrospective case reports of neural tube defects in infants whose mothers were exposed to efavirenz-containing regimens in the first trimester of pregnancy. Prospective pregnancy data from the Antiretroviral Pregnancy Registry are not sufficient to adequately assess this risk. Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Although a causal relationship has not been established between exposure to efavirenz in the first trimester and neural tube defects, similar malformations have been observed in studies conducted in monkeys at doses similar to the human dose. In addition, fetal and embryonic toxicities occurred in rats, at a dose ten times less than the human exposure at recommended clinical dose. Because of the potential risk of neural tube defects, efavirenz should not be used in the first trimester of pregnancy. Advise pregnant women of the potential risk to a fetus. Data Human Data There are retrospective postmarketing reports of findings consistent with neural tube defects, including meningomyelocele, all in infants of mothers exposed to efavirenz-containing regimens in the first trimester. Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of approximately 1,000 live births following exposure to efavirenz-containing regimens (including over 800 live births exposed in the first-trimester), there was no difference between efavirenz and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. As of the interim APR report issued December 2014, the prevalence of birth defects following first-trimester exposure was 2.3% (95% CI: 1.4% to 3.6%). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported. This case also included severe oblique facial clefts and amniotic banding, which have a known association with anophthalmia. Animal Data Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in a second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, efavirenz was administered either during organogenesis (gestation days 7 to 18) or from gestation day 7 through lactation day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with increase in the incidence of early resorptions; and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose. Drug concentrations in the milk on lactation day 10 were approximately 8 times higher than those in maternal plasma. In pregnant rabbits, efavirenz was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation days 6 through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose. 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 tablets. [See Use in Specific Populations (8.1).] Pregnancy Testing Females of reproductive potential should undergo pregnancy testing before initiation of efavirenz tablets. Contraception Females of reproductive potential should use effective contraception during treatment with efavirenz tablets and for 12 weeks after discontinuing efavirenz tablets 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 tablets 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 tablets 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 tablets have not been evaluated in this age group and there is a risk of developing HIV resistance if efavirenz tablets are underdosed. [See Dosage and Administration (2.2)] for dosing recommendations for pediatric patients. 8.5 Geriatric Use Clinical studies of efavirenz tablets 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 tablets are 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 tablets to these patients [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3)].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.2 Tablets Efavirenz tablets, USP are available as follows: Tablets 600 mg are yellow, capsular-shaped, film-coated tablets debossed with ‘H’ on one side and ‘4’ on the other side. Bottles of 30 NDC 31722-504-30 Bottles of 250 NDC 31722-504-25 16.3 Storage Efavirenz tablets, USP should be stored at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].