Efavirenz

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

2 DOSAGE AND ADMINISTRATION Efavirenz capsules should be taken orally once daily on an empty stomach, preferably at bedtime. ( 2 ) Recommended adult dose: 600 mg. ( 2.2 ) With voriconazole, increase voriconazole maintenance dose to 400 mg every 12 hours and decrease efavirenz dose to 300 mg once daily using the capsule formulation. (2.2) With rifampin, increase efavirenz capsules dose to 800 mg once daily for patients weighing 50 kg or more. (2.2) Pediatric dosing is based on weight. (2.3) 2.1 Hepatic Function Monitor hepatic function prior to and during treatment with efavirenz capsules [see Warnings and Precautions (5.9) ] . Efavirenz capsules are not recommended in patients with moderate or severe hepatic impairment (Child Pugh B or C) [see Warnings and Precautions (5.9) and Use in Specific Populations (8.6) ] . 2.2 Adults The recommended dosage of efavirenz capsules is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz capsules be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz capsules with food may lead to an increase in frequency of adverse reactions [see Clinical Pharmacology (12.3) ]. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Warnings and Precautions (5.6) , Adverse Reactions (6.1) , and Patient Counseling Information (17) ]. Efavirenz capsules should be swallowed intact with liquid. For patients who cannot swallow capsules, the capsule sprinkle method of administration is recommended [see Dosage and Administration (2.4) ]. Concomitant Antiretroviral Therapy Efavirenz capsules must be given in combination with other antiretroviral medications [see Indications and Usage (1) , Warnings and Precautions (5.3) , Drug Interactions (7.1) , and Clinical Pharmacology (12.3) ] . Dosage Adjustment If efavirenz capsules are coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz dose should be decreased to 300 mg once daily using the capsule formulation (one 200 mg and two 50 mg capsules or six 50 mg capsules). If efavirenz capsules are coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of efavirenz capsules to 800 mg once daily is recommended [see Drug Interactions (7.1, Table 5 ) and Clinical Pharmacology (12.3, Table 8) ]. 2.3 Pediatric Patients It is recommended that efavirenz capsules be taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended dose of efavirenz capsules for pediatric patients 3 months of age or older and weighing between 3.5 kg and 40 kg [see Clinical Pharmacology (12.3) ] . The recommended dosage of efavirenz capsules for pediatric patients weighing 40 kg or greater is 600 mg once daily. For pediatric patients who cannot swallow capsules, the capsule contents can be administered with a small amount of food or infant formula using the capsule sprinkle method of administration [see Dosage and Administration (2.4) ]. Table 1: Efavirenz Capsules Dosing in Pediatric Patients Patient Body Weight Efavirenz Capsules Daily Dose Number of Capsules a and Strength to Administer 3.5 kg to less than 5 kg 100 mg two 50 mg capsules 5 kg to less than 7.5 kg 150 mg three 50 mg capsules 7.5 kg to less than 15 kg 200 mg one 200 mg capsule 15 kg to less than 20 kg 250 mg one 200 mg + one 50 mg capsule 20 kg to less than 25 kg 300 mg one 200 mg + two 50 mg capsules 25 kg to less than 32.5 kg 350 mg one 200 mg + three 50 mg capsules 32.5 kg to less than 40 kg 400 mg two 200 mg capsules at least 40 kg 600 mg three 200 mg capsules a Capsules can be administered intact or as sprinkles [see Dosage and Administration (2.4) ]. 2.4 Capsule Sprinkle Method of Administration For pediatric patients at least 3 months old and weighing at least 3.5 kg and adults who …

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

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

6 ADVERSE REACTIONS The most significant adverse reactions observed in patients treated with efavirenz are: psychiatric symptoms [see Warnings and Precautions (5.5) ] nervous system symptoms [see Warnings and Precautions (5.6) ] rash [see Warnings and Precautions (5.8) ] hepatotoxicity [see Warnings and Precautions (5.9) ] Most common adverse reactions (>5%, moderate-severe) are impaired concentration, abnormal dreams, rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice. Adverse Reactions in Adults The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with efavirenz in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting. Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of efavirenz-treated patients in two controlled clinical trials are presented in Table 2. Table 2: Selected Treatment-Emergent a Adverse Reactions of Moderate or Severe Intensity Reported in ≥2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364 Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients Adverse Reactions Efavirenz b + ZDV/LAM (n=412) 180 weeks c Efavirenz b + Indinavir (n=415) 102 weeks c Indinavir + ZDV/LAM (n=401) 76 weeks c Efavirenz b + Nelfinavir + NRTIs (n=64) 71.1 weeks c Efavirenz b + NRTIs (n=65) 70.9 weeks c Nelfinavir + NRTIs (n=66) 62.7 weeks c Body as a Whole Fatigue 8% 5% 9% 0 2% 3% Pain 1% 2% 8% 13% 6% 17% Central and Peripheral Nervous System Dizziness 9% 9% 2% 2% 6% 6% Headache 8% 5% 3% 5% 2% 3% Insomnia 7% 7% 2% 0 0 2% Concentration impaired 5% 3% 5 x ULN 5% 8% 5% 2% 6% 3% AST >5 x ULN 5% 6% 5% 6% 8% 8% GGT c >5 x ULN 8% 7% 3% 5% 0 5% Amylase >2 x ULN 4% 4% 1% 0 6% 2% Glucose >250 mg/dL 3% 3% 3% 5% 2% 3% Triglycerides d ≥751 mg/dL 9% 6% 6% 11% 8% 17% Hematology Neutrophils <750/mm 3 10% 3% 5% 2% 3% 2% a Efavirenz provided as 600 mg once daily. b Median duration of treatment. c Isolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity. d Nonfasting. ZDV = zidovudine, LAM = lamivudine, ULN = upper limit of normal, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyltransferase. Patients Coinfected with Hepatitis B or C Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with efavirenz-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among these coinfected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the efavirenz arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the efavirenz arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders [see Warnings and Precautions (5.9) ] . Lipids Increases from baseline in total cholesterol of 10 to 20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz + zidovudine + lamivudi …

7 DRUG INTERACTIONS Coadministration of efavirenz can alter the concentrations of other drugs and other drugs may alter the concentrations of efavirenz. The potential for drug-drug interactions should be considered before and during therapy. ( 7 ) 7.1 Potential for Efavirenz to Affect other Drugs Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with efavirenz. 7.2 Potential for Other Drugs to Affect Efavirenz Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations [see Dosage and Administration (2.2) ]. 7.3 QT Prolonging Drugs There is limited information available on the potential for a pharmacodynamic interaction between efavirenz and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of efavirenz [see Clinical Pharmacology (12.2) ] . Consider alternatives to efavirenz when coadministered with a drug with a known risk of Torsade de Pointes. 7.4 Established and Other Potentially Significant Drug Interactions Drug interactions with efavirenz are summarized in Table 5. For pharmacokinetics data, [see Clinical Pharmacology (12.3) ] Tables 7 and 8. This table includes potentially significant interactions, but is not all inclusive. Table 5: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction * The interaction between efavirenz and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. This table is not all-inclusive. Concomitant Drug Class: Drug Name Effect Clinical Comment HIV antiviral agents Protease inhibitor: Fosamprenavir Calcium ↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with fosamprenavir plus ritonavir twice daily. Protease inhibitor: Atazanavir ↓ atazanavir* Treatment-naive patients: When coadministered with efavirenz, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and efavirenz 600 mg (once daily on an empty stomach, preferably at bedtime). Treatment-experienced patients: Coadministration of efavirenz and atazanavir is not recommended. Protease inhibitor: Indinavir ↓ indinavir* The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. Protease inhibitor: Lopinavir/ritonavir ↓ lopinavir* Lopinavir/ritonavir once daily dosing is not recommended when coadministered with efavirenz. The dose of lopinavir/ritonavir must be increased when coadministered with efavirenz. See the lopinavir/ritonavir prescribing information for dose adjustments of lopinavir/ritonavir when coadministered with efavirenz in adult and pediatric patients. Protease inhibitor: Ritonavir ↑ ritonavir* ↑ efavirenz* Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Protease inhibitor: Saquinavir ↓ saquinavir* Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established. NNRTI: Other NNRTIs ↑ or ↓ efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. Efavirenz should not be coadministered with other NNRTIs. CCR5 co-receptor antagonist: Maraviroc ↓ maraviroc* Refer to the fu …

8 USE IN SPECIFIC POPULATIONS Lactation : Breastfeeding not recommended. ( 8.2 ) Females and Males of Reproductive Potential: Pregnancy testing and contraception are recommended. ( 8.3 ) Hepatic impairment: Efavirenz is not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. ( 8.6 ) Pediatric patients: The incidence of rash was higher than in adults. ( 5.8 , 6.2 , 8.4 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to efavirenz during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Risk Summary There are retrospective case reports of neural tube defects in infants whose mothers were exposed to efavirenz-containing regimens in the first trimester of pregnancy. Prospective pregnancy data from the Antiretroviral Pregnancy Registry are not sufficient to adequately assess this risk. Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Although a causal relationship has not been established between exposure to efavirenz in the first trimester and neural tube defects, similar malformations have been observed in studies conducted in monkeys at doses similar to the human dose. In addition, fetal and embryonic toxicities occurred in rats, at a dose ten times less than the human exposure at recommended clinical dose. Because of the potential risk of neural tube defects, efavirenz should not be used in the first trimester of pregnancy. Advise pregnant women of the potential risk to a fetus. Data Human Data There are retrospective postmarketing reports of findings consistent with neural tube defects, including meningomyelocele, all in infants of mothers exposed to efavirenz-containing regimens in the first trimester. Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of approximately 1000 live births following exposure to efavirenz-containing regimens (including over 800 live births exposed in the first trimester), there was no difference between efavirenz and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. As of the interim APR report issued December 2014, the prevalence of birth defects following first-trimester exposure was 2.3% (95% CI: 1.4% to 3.6%). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported. This case also included severe oblique facial clefts and amniotic banding, which have a known association with anophthalmia. Animal Data Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in a second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, efavirenz was administered either d …

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

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

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

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