Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate

RECENT MAJOR CHANGES Warnings and Precautions Nervous System Symptoms ( 5.6 ) 10/2019 Immune Reconstitution Syndrome ( 5.12 ) 10/2019

1 INDICATIONS AND USAGE Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are indicated as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 40 kg. Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are a three-drug combination of efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 40 kg. ( 1 )

2 DOSAGE AND ADMINISTRATION Testing: Consult Full Prescribing Information for important testing recommendations prior to initiation and during treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. ( 2.1 ) Recommended dosage in adults and pediatric patients weighing at least 40 kg: One tablet once daily taken orally on an empty stomach, preferably at bedtime. ( 2.2 ) Renal impairment: Not recommended in patients with estimated creatinine clearance below 50 mL/min. ( 2.3 ) Hepatic impairment: Not recommended in patients with moderate to severe hepatic impairment. ( 2.4 ) Dosage adjustment with rifampin coadministration: An additional 200 mg/day of efavirenz is recommended for patients weighing 50 kg or more. ( 2.5 ) 2.1 Testing Prior to Initiation and During Treatment with Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate Tablets Prior to or when initiating efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, test patients for hepatitis B virus infection [see Warnings and Precautions ( 5.1 )]. Prior to initiation and during use of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions ( 5.7 )]. Monitor hepatic function prior to and during treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets [see Warnings and Precautions ( 5.3) ] . Perform pregnancy testing before initiation of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in adolescents and adults of childbearing potential [see Warnings and Precautions ( 5.8 ), Use in Specific Populations ( 8.1 , 8.3 )]. 2.2 Recommended Dosage for Adults and Pediatric Patients Weighing at Least 40 kg Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are a three-drug fixed-dose combination product containing 600 mg of efavirenz (EFV), 200 mg of emtricitabine (FTC), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in adults and pediatric patients weighing at least 40 kg is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Clinical Pharmacology ( 12.3 )] . 2.3 Not Recommended in Patients with Moderate or Severe Renal Impairment Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min) [see Warnings and Precautions ( 5.7 ), Use in Specific Populations ( 8.6 )] . 2.4 Not Recommended in Patients with Moderate to Severe Hepatic Impairment Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C) [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.7 )] . 2.5 Dosage Adjustment with Rifampin If efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are coadministered with rifampin in patients weighing 50 kg or more, take one tablet of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets once daily followed by one additional 200 mg per day of efavirenz [see Drug Interactions ( 7.3 ) and Clinical Pharmacology ( 12.3 )] .

3 DOSAGE FORMS AND STRENGTHS Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate is available as tablets. Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (tenofovir DF, which is equivalent to 245 mg of tenofovir disoproxil). The tablets are pink coloured, capsule-shaped, biconvex film-coated tablet, debossed with 'C210'on one side and plain on other side. Tablets: 600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate. ( 3 )

4 CONTRAINDICATIONS • Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to efavirenz, a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets [see Warnings and Precautions ( 5.2 )]. • Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are contraindicated to be coadministered with voriconazole or elbasvir/grazoprevir [see Drug Interactions ( 7.3 ) and Clinical Pharmacology ( 12.3 )]. • Previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to efavirenz, a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. ( 4 ) • Coadministration with voriconazole. ( 4 ) • Coadministration with elbasvir/grazoprevir. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions (5.1) ] . Rash [see Warnings and Precautions (5.2) ] . Hepatotoxicity [see Warnings and Precautions (5.3) ] . Psychiatric Symptoms [see Warnings and Precautions (5.5) ] . Nervous System Symptoms [see Warnings and Precautions (5.6) ] . New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.7) ] . Embryo-Fetal Toxicity [see Warnings and Precautions (5.8) ] . Bone Loss and Mineralization Defects [see Warnings and Precautions (5.9) ] . Convulsions [see Warnings and Precautions (5.10) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.11) ] . Immune Reconstitution Syndrome [see Warnings and Precautions (5.12) ] . Fat Redistribution [see Warnings and Precautions (5.13) ] . Most common adverse reactions (incidence greater than or equal to 10%) observed in an active-controlled clinical trial of EFV, FTC, and TDF are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-8787) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Adult Subjects Study 934 was an open-label active-controlled trial in which 511 antiretroviral-naïve subjects received either FTC + TDF administered in combination with EFV (N=257) or zidovudine (AZT)/lamivudine (3TC) administered in combination with EFV (N=254). The most common adverse reactions (incidence greater than or equal to 10%, any severity) occurring in Study 934 include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions observed in Study 934 were generally consistent with those seen in previous trials of the individual components (Table 1). Table 1 Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥5% in Either Treatment Group in Study 934 (0 to 144 Weeks) a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. From Weeks 96 to 144 of the trial, subjects received FTC/TDF administered in combination with EFV in place of FTC + TDF with EFV. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular. FTC+TDF+EFV b AZT/3TC+EFV N=257 N=254 Fatigue 9% 8% Depression 9% 7% Nausea 9% 7% Diarrhea 9% 5% Dizziness 8% 7% Upper respiratory tract infections 8% 5% Sinusitis 8% 4% Rash Event c 7% 9% Headache 6% 5% Insomnia 5% 7% Anxiety 5% 4% Nasopharyngitis 5% 3% Vomiting 2% 5% In Study 073, subjects with stable, virologic suppression on antiretroviral therapy and no history of virologic failure were randomized to receive efavirenz, emtricitabine and tenofovir disoproxil fumarate or to stay on their baseline regimen. The adverse reactions observed in Study 073 were generally consistent with those seen in Study 934 and those seen with the individual components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets when each was administered in combination with other antiretroviral agents. Efavirenz, Emtricitabine, or TDF In addition to the adverse reactions in Study 934 and Study 073, the following adverse reactions were observed in clinical trials of EFV, FTC, or TDF in combination with other antiretroviral agents. Efavirenz: The most significant adverse reactions observed in subjects treated with EFV were nervous system symptoms [see Warnings and Precautions (5.6) ], …

7 DRUG INTERACTIONS Consult Full Prescribing Information prior to and during treatment for important potential drug interactions. (4 , 5.4 , 7 ) HIV-1 protease inhibitors: Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with either lopinavir/ritonavir or darunavir and ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with either atazanavir or atazanavir and ritonavir is not recommended. (7.3) 7.1 Efavirenz 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 EFV. Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of EFV, resulting in lowered plasma concentrations [see Dosage and Administration (2.2) ]. There is limited information available on the potential for a pharmacodynamic interaction between EFV and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of EFV [see Clinical Pharmacology (12.2) ]. Consider alternatives to efavirenz emtricitabine and tenofovir disoproxil fumarate when coadministered with a drug with a known risk of Torsade de Pointes. 7.2 Drugs Affecting Renal Function FTC and tenofovir are primarily eliminated by the kidneys [see Clinical Pharmacology (12.3) ] . Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.7) ] . Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir. 7.3 Established and Potentially Significant Interactions Other important drug interaction information for efavirenz, emtricitabine and tenofovir disoproxil fumarate is summarized in Table 3. The drug interactions described are based on trials conducted with either efavirenz, emtricitabine and tenofovir disoproxil fumarate, the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate (EFV, FTC, or TDF) as individual agents, or are potential drug interactions [see Clinical Pharmacology (12.3) ]. Table 3 Established and Potentially Significant a Drug Interactions Concomitant Drug Class: Drug Name Effect Clinical Comment HIV antiviral agents Protease inhibitor: atazanavir ↓ atazanavir ­ ↑ tenofovir Coadministration of atazanavir with efavirenz, emtricitabine and tenofovir disoproxil fumarate is not recommended. The combined effect of EFV plus TDF on atazanavir plasma concentrations is not known. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with efavirenz, emtricitabine and tenofovir disoproxil fumarate. Protease inhibitor: fosamprenavir calcium ↓ amprenavir Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and efavirenz, emtricitabine and tenofovir disoproxil fumarate 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, emtricitabine and tenofovir disoproxil fumarate is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz, emtricitabine and tenofovir disoproxil fumarate is administered with fosamprenavir plus ritonavir twice daily. Protease inhibitor: indinavir ↓ indinavir The optimal dose of indinavir, when given in combination with EFV, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to …

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Avoid pregnancy while receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate and for 12 weeks after discontinuation. ( 5.8 , 8.3 ) • Lactation: Breastfeeding is not recommended. ( 8.2 ) • Females and Males of Reproductive Potential: Pregnancy testing and contraception are recommended. ( 8.3 ) • Pediatrics: The incidence of rash was higher than in adults. ( 5.2 , 6.1 ) 8.1 Pregnancy Antiretroviral Pregnancy Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in adults and adolescents exposed to efavirenz, emtricitabine and tenofovir disoproxil fumarate during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at (800) 258-4263. Risk Summary There are retrospective case reports of neural tube defects in infants whose mothers were exposed to EFV-containing regimens in the first trimester of pregnancy. Prospective pregnancy data from the APR are not sufficient to adequately assess this risk. Although a causal relationship has not been established between exposure to EFV 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 (see Data). In addition, fetal and embryonic toxicities occurred in rats at a dose 10 times less than the human exposure at the recommended clinical human dose (RHD) of EFV. Because of the potential risk of neural tube defects, EFV is not recommended for use in the first trimester of pregnancy. Avoid pregnancy while receiving efavirenz, emtricitabine and tenofovir disoproxil fumarate and for 12 weeks after discontinuation. Advise pregnant patients of the potential risk to a fetus. Available data from the APR show no increase in the overall risk of major birth defects for EFV, FTC, or TDF compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15 to 20%. The background risk of major birth defects and miscarriage for the indicated population is unknown. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates mothers and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. In animal reproduction studies, no adverse developmental effects were observed when FTC and TDF were administered separately at doses/exposures ≥60 (FTC), ≥14 (TDF) and 2.7 (tenofovir) times those at the RHD of efavirenz, emtricitabine and tenofovir disoproxil fumarate (see Data). Data Human Data Efavirenz : There are retrospective postmarketing reports of findings consistent with neural tube defects, including meningomyelocele, all in infants of mothers exposed to EFV-containing regimens in the first trimester. Based on prospective reports to the APR of 1,217 exposures to EFV-containing regimens during pregnancy resulting in live births (including over 1,023 live births exposed in the first trimester and 194 exposed in the second/third trimester), there was no increase in overall birth defects with EFV compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.5% to 3.5%) with first trimester exposure to EFV-containing regimens, and 1.5% (95% CI: 0.3% to 4.5%) with the second/third trimester exposure to EFV-containing regimens. 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 EFV has also been prospectively reported. This case also included severe oblique …

12.1 Mechanism of Action Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are a fixed-dose combination of antiviral drugs EFV, FTC, and TDF [see Microbiology ( 12.4 )].

11 DESCRIPTION Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablet is a fixed-dose combination tablet containing EFV, FTC, and TDF. EFV is a non-nucleoside reverse transcriptase inhibitor (NNRTI). FTC is a synthetic nucleoside analog of cytidine. TDF, which is converted in vivo to tenofovir, is an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'‐monophosphate. Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablets are for oral administration. Each tablet contains 600 mg of EFV, 200 mg of FTC, and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients: Croscarmellose sodium, hydroxypropyl cellulose, hypromellose, isopropyl alcohol, microcrystalline cellulose, magnesium stearate, red iron oxide, sodium lauryl sulfate. The tablets are film-coated with a coating material opadry AMB 80W54485 pink containing polyvinyl alcohol-part, hydrolyzed, titanium dioxide, talc, lecithin (soya), xanthan gum, iron oxide yellow, iron oxide red and opadry AMB 80W56843 brown containing polyvinyl alcohol-part, hydrolyzed, titanium dioxide, talc, lecithin (soya), xanthan gum, iron oxide red. Efavirenz: EFV is chemically described as ( S )-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2 H -3,1-benzoxazin-2-one. Its molecular formula is C 14 H 9 ClF 3 NO 2 and its structural formula is: Efavirenz is a white to slightly pink crystalline powder with a molecular mass of 315.68. It is practically insoluble in water (less than 10 μg/mL). Emtricitabine: The chemical name of FTC is 5-fluoro-1-(2 R ,5 S )-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. FTC is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position. It has a molecular formula of C 8 H 10 FN 3 O 3 S and a molecular weight of 247.24. It has the following structural formula: Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25°C. Tenofovir DF: TDF is a fumaric acid salt of the bis -isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of TDF is 9-[( R )-2[[bis[[(isopropoxycarbonyl)oxy]-methoxy] phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C 19 H 30 N 5 O 10 P • C 4 H 4 O 4 and a molecular weight of 635.52. It has the following structural formula: TDF is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25°C. Image Image Image

10 OVERDOSAGE If overdose occurs, the patient should be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. Administration of activated charcoal may be used to aid removal of unabsorbed EFV. Hemodialysis can remove both FTC and TDF (refer to detailed information below) but is unlikely to significantly remove EFV from the blood. Efavirenz : Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions. Emtricitabine : Hemodialysis treatment removes approximately 30% of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether FTC can be removed by peritoneal dialysis. Tenofovir DF : Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of TDF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

16 HOW SUPPLIED/STORAGE AND HANDLING Efavirenz, Emtricitabine and Tenofovir disoproxil fumarate tablets are pink colored, capsule-shaped, biconvex, film-coated tablets debossed with 'C210' on one side and plain on other side. Each bottle contains: 30 tablets (NDC 69097-210-02) and silica gel desiccant, and is closed with a child-resistant closure. Store at 25°C (77°F); excursions permitted to 15°C –30°C (59°F –86°F) [See USP Controlled Room Temperature] . Keep container tightly closed. Dispense only in original container. Do not use if seal over bottle opening is broken or missing.