Efavirenz

1 INDICATIONS & USAGE Efavirenz 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 )

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

2 DOSAGE & ADMINISTRATION • Efavirenz should be taken orally once daily on an empty stomach, preferably at bedtime. ( 2 ) • Recommended adult dose: 600 mg. ( 2.2 ) • With rifampin, increase efavirenz 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 [ see Warnings and Precautions ( 5.9 ) ]. Efavirenz is 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 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 be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz 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 or tablets should be swallowed intact with liquid. Concomitant Antiretroviral Therapy Efavirenz 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 is 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). Efavirenz tablets must not be broken. [See Drug Interactions ( 7.1 , Table 5) and Clinical Pharmacology ( 12.3 , Tables 7 and 8] . If efavirenz is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of efavirenz 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 be taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended dose of efavirenz 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 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 . Table 1: Efavirenz Dosing in Pediatric Patients Patient Body Weight Efavirenz Daily Dose Number of Capsules a or Tablets b 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 capsule 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 one 600 mg tablet OR three 200 mg capsules a Capsules can be administered intact or as sprinkles [see Dosage and Administration (2.4)]. b Tablets must not be crushed

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 Macleods Pharmaceutical Ltd at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice. Adverse Reactions in Adults. The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with efavirenz in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of efavirenz-treated patients in two controlled clinical trials are presented in Table 2 Table 2: Selected Treatment-Emergent a Adverse Reactions of Moderate or Severe Intensity Reported in ≥2% of EFAVIRENZ TABLETS-Treated Patients in Studies 006 and ACTG 364 Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI- and Protease Inhibitor-Naive Patients Adverse Reactions Efavirenz b + ZDV/LAM (n=412) Efavirenz b + Indinavir (n=415) Indinavir + ZDV/LAM (n=401) Efavirenz b + Nelfinavir + NRTIs (n=64) Efavirenz b + NRTIs (n=65) Nelfinavir + NRTIs (n=66) 180 weeks c 102 weeks c 76 weeks c 71.1 weeks c 70.9 weeks c 62.7 weeks c Psychiatric Body as a Whole Fatigue 8% 5% 9% 0 2% 3% Pain 1% 2% 8% 13% 6% 17% Central and Peripheral Nervous System Dizziness 9% 9% 2% 2% 6% 6% Headache 8% 5% 3% 5% 2% 3% Insomnia 7% 7% 2% 0 0 2% Concentration impaired 5% 3% <1% 0 0 0 Abnormal dreams 3% 1% 0 — — — Somnolence 2% 2% <1% 0 0 0 Anorexia 1% <1% <1% 0 2% 2% Gastrointestinal Nausea 10% 6% 24% 3% 2% 2% Vomiting 6% 3% 14% — — — Diarrhea 3% 5% 6% 14% 3% 9% Dyspepsia 4% 4% 6% 0 0 2% Abdominal pain 2% 2% 5% 3% 3% 3% Anxiety 2% 4% <1% — — — Depression 5% 4% <1% 3% 0 5% Nervousness 2% 2% 0 2% 0 2% Skin & Appendages Rash d 11% 16% 5% 9% 5% 9% Pruritis <1% 1% 1% 9% 5% 9% a Includes adverse events at least possibly related to study drug or of unknown relationship for Study 006. Includes all adverse events regardless of relationship to study drug for Study ACTG 364. b Efavirenz tablets provided as 600 mg once daily. c Median duration of treatment. d Includes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for Study 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and pruritus for ACTG 364. — = Not Specified. ZDV = zidovudine, LAM=lamivudine. Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients ( see Laboratory Abnormalities ). Nervous System Symptoms For 1008 patients treated with regimens containing efavirenz and 635 patients treated with a control regimen in controlled trials, Table 3 lists the frequency of symptoms of different degrees of severity and gives the discontinuation rates for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, halluci

5 WARNINGS AND PRECAUTIONS • QTc prolongation : Consider alternatives to efavirenz in patients taking other medications with a known risk of Torsade de Pointes or in patients at higher risk of Torsade de Pointes. ( 5.2 ) • Do not use as a single agent or add on as a sole agent to a failing regimen. Consider potential for cross resistance when choosing other agents. ( 5.3 ) •Not recommended with ATRIPLA, which contains efavirenz, emtricitabine, and tenofovir disoproxil fumarate, unless needed for dose adjustment when coadministered with rifampin. ( 5.4 ) • Serious psychiatric symptoms : Immediate medical evaluation is recommended for serious psychiatric symptoms such as severe depression or suicidal ideation. ( 5.5 , 17 ) • Nervous system symptoms (NSS): NSS are frequent and usually begin 1-2 days after initiating therapy and resolve in 2-4 weeks. Dosing at bedtime may improve tolerability. NSS are not predictive of onset of psychiatric symptoms. ( 5.6 , 6.1 , 17 ) • Embryo-Fetal Toxicity : Avoid administration in the first trimester of pregnancy as fetal harm may occur. ( 5.7 , 8.1 ) • Hepatotoxicity : Monitor liver function tests before and during treatment in patients with underlying hepatic disease, including hepatitis B or C coinfection, marked transaminase elevations, or who are taking medications associated with liver toxicity. Among reported cases of hepatic failure, a few occurred in patients with no pre-existing hepatic disease. ( 5.9 , 6.1 , 8.6 ) • Rash : Rash usually begins within 1-2 weeks after initiating therapy and resolves within 4 weeks. Discontinue if severe rash develops. ( 5.8 , 6.1 , 17 ) • Convulsions : Use caution in patients with a history of seizures. ( 5.10 ) • Lipids : Total cholesterol and triglyceride elevations. Monitor before therapy and periodically thereafter. ( 5.11 ) • Immune reconstitution syndrome : May necessitate further evaluation and treatment. ( 5.12 ) • Redistribution/accumulation of body fat : Observed in patients receiving antiretroviral therapy. ( 5.13 , 17 ) 5.1 Drug Interactions Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A. Likewise, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A or CYP2B6. The most prominent effect of efavirenz at steady-state is induction of CYP3A and CYP2B6 [see Dosage and Administration ( 2.2 ) and Drug Interactions ( 7.1 )]. 5.2 QTc Prolongation QTc prolongation has been observed with the use of efavirenz [ see Drug Interactions ( 7.3 , 7.4 ) and Clinical Pharmacology ( 12.2 )]. Consider alternatives to efavirenz when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes. 5.3 Resistance Efavirenz must not be used as a single agent to treat HIV-1 infection or added on as a sole agent to a failing regimen. Resistant virus emerges rapidly when efavirenz is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with efavirenz should take into consideration the potential for viral cross-resistance. 5.4 Coadministration with Related Products Coadministration of efavirenz with ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) is not recommended unless needed for dose adjustment (e.g., with rifampin), since efavirenz is one of its active ingredients. 5.5 Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1008 patients treated with regimens containing efavirenz for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among patients who received efavirenz or control regimens, respectively, were severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0), aggressive behavior (0.4%, 0.5%), paranoid

4 CONTRAINDICATIONS • Efavirenz is 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

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.