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 )

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 Annora Pharma Private Limited at 1-866-495-1995 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) 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% 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.

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 )] , psychiatric symptoms [see Warnings and Precautions ( 5.5 )], and rash [see Warnings and Precautions ( 5.2 )].

Selected adverse reactions of moderate-to-severe intensity observed in greater than or equal to 2% of EFV-treated subjects in two controlled clinical trials included pain, impaired concentration, abnormal dreams, somnolence, anorexia, dyspepsia, abdominal pain, nervousness, and pruritus.

Pancreatitis has also been reported, although a causal relationship with EFV has not been established.

Asymptomatic increases in serum amylase levels were observed in a significantly higher number of subjects treated with EFV 600 mg than in control subjects.

Skin discoloration has been reported with higher frequency among FTC-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic.

The mechanism and clinical significance are unknown.

Clinical Trials in Pediatric Subjects Efavirenz : Assessment of adverse reactions is based on three pediatric clinical trials in 182 HIV-1 infected pediatric subjects who received EFV in combination with other antiretroviral agents for a median of 123 weeks.

The type and frequency of adverse reactions in the three trials were generally similar to that of adult subjects with the exception of a higher incidence of rash, which was reported in 32% (59/182) of pediatric subjects compared to 26% of adults, and a higher frequency of Grade 3 or 4 rash reported in 3% (6/182) of pediatric subjects compared to 0.9% of adults [see Warnings and Precautions ( 5.2 )].

Emtricitabine : In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects who received treatment with FTC in the larger of two open-label, uncontrolled pediatric trials (N=116).

Tenofovir DF : In a pediatric clinical trial conducted in subjects 12 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with TDF (N=81) were consistent with those observed in clinical trials of TDF in adults [see Warnings and Precautions ( 5.9 )].

Laboratory Abnormalities Efavirenz, Emtricitabine and Tenofovir DF : Laboratory abnormalities observed in Study 934 were generally consistent with those seen in previous trials (Table 2).

Table 2 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Either Treatment Group in Study 934 (0 to 144 Weeks) FTC + TDF + EFV a AZT/3TC + EFV N=257 N=254 Any ≥ Grade 3 Laboratory Abnormality 30% 26% Fasting Cholesterol (>240 mg/dL) 22% 24% Creatine Kinase (M: >990 U/L) (F: >845 U/L) 9% 7% Serum Amylase (>175 U/L) 8% 4% Alkaline Phosphatase (>550 U/L) 1% 0% AST (M: >180 U/L) (F: >170 U/L) 3% 3% ALT (M: >215 U/L) (F: >170 U/L) 2% 3% Hemoglobin (<8.0 mg/dL) 0% 4% Hyperglycemia (>250 mg/dL) 2% 1% Hematuria (>75 RBC/HPF) 3% 2% Glycosuria (≥3+) <1% 1% Neutrophils (<750/mm 3 ) 3% 5% Fasting Triglycerides (>750 mg/dL) 4% 2% a .

From Weeks 96 to 144 of the trial, subjects received FTC/TDF administered in combination with EFV in place of FTC + TDF with EFV.

Laboratory abnormalities observed in Study 073 were generally consistent with those in Study 934.

Hepatic Events : In Study 934, 19 subjects treated with EFV, FTC, and TDF and 20 subjects treated with EFV and fixed-dose zidovudine/lamivudine were hepatitis B surface antigen or hepatitis C antibody positive.

Among these coinfected subjects, one subject (1/19) in the EFV, FTC, and TDF arm had elevations in transaminases to greater than five times ULN through 144 weeks.

In the fixed-dose zidovudine/lamivudine arm, two subjects (2/20) had elevations in transaminases to greater than five times ULN through 144 weeks.

No HBV and/or HCV coinfected subject discontinued from the trial due to hepatobiliary disorders [see Warnings and Precautions ( 5.3 )].

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of EFV, FTC, or TDF.

Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Efavirenz: Cardiac Disorders Palpitations Ear and Labyrinth Disorders Tinnitus, vertigo Endocrine Disorders Gynecomastia Eye Disorders Abnormal vision Gastrointestinal Disorders Constipation, malabsorption General Disorders and Administration Site Conditions Asthenia Hepatobiliary Disorders Hepatic enzyme increase, hepatic failure, hepatitis Immune System Disorders Allergic reactions Metabolism and Nutrition Disorders Redistribution/accumulation of body fat [see Warnings and Precautions ( 5.13 )], hypercholesterolemia, hypertriglyceridemia Musculoskeletal and Connective Tissue Disorders Arthralgia, myalgia, myopathy Nervous System Disorders Abnormal coordination, ataxia, encephalopathy, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor Psychiatric Disorders Aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia Respiratory, Thoracic and Mediastinal Disorders Dyspnea Skin and Subcutaneous Tissue Disorders Flushing, erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome Emtricitabine: No postmarketing adverse reactions have been identified for inclusion in this section.

Tenofovir DF : Immune System Disorders Allergic reaction, including angioedema Metabolism and Nutrition Disorders Lactic acidosis, hypokalemia, hypophosphatemia Respiratory, Thoracic, and Mediastinal Disorders Dyspnea Gastrointestinal Disorders Pancreatitis, increased amylase, abdominal pain Hepatobiliary Disorders Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT) Skin and Subcutaneous Tissue Disorders Rash Musculoskeletal and Connective Tissue Disorders Rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy Renal and Urinary Disorders Acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria General Disorders and Administration Site Conditions Asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.