1 INDICATIONS AND USAGE HIV-1 Treatment ( 1.1 ) Emtricitabine and tenofovir disoproxil fumarate tablets are a two-drug combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated: in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg.

HIV-1 PrEP ( 1.2 ): Emtricitabine and tenofovir disoproxil fumarate tablets are indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection.

Individuals must have a negative HIV-1 test immediately prior to initiating emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP.

1.1 Treatment of HIV-1 Infection Emtricitabine and tenofovir disoproxil fumarate tablets are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg [see Clinical Studies (14) ] .

1.2 HIV-1 Pre-Exposure Prophylaxis (PrEP) Emtricitabine and tenofovir disoproxil fumarate tablets are indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection.

Individuals must have a negative HIV-1 test immediately prior to initiating emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP [see Dosage and Administration (2.2) , Warnings and Precautions (5.2 )] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B in Patients with HBV Infection [see Warnings and Precautions (5.1) ] .

New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3) ] .

Immune Reconstitution Syndrome [see Warnings and Precautions (5.4) ] .

Bone Loss and Mineralization Defects [see Warnings and Precautions (5.5) ] .

Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.6) ] .

In HIV-1 infected patients, the most common adverse reactions (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.

( 6.1 ) In HIV-1 uninfected adults in PrEP trials, adverse reactions that were reported by more than 2% of emtricitabine and tenofovir disoproxil fumarate participants and more frequently than by placebo participants were headache, abdominal pain, and weight decreased.

( 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.

Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Subjects Clinical Trials in Adult Subjects In Study 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either FTC+TDF (N=257) or zidovudine (AZT)/lamivudine (3TC) (N=254) for 144 weeks.

The most common adverse reactions (incidence greater than or equal to 10%, all grades) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.

Table 3 provides the treatment-emergent adverse reactions (Grades 2 to 4) occurring in greater than or equal to 5% of subjects treated in any treatment group.

Skin discoloration, manifested by hyperpigmentation, occurred in 3% of subjects taking FTC+TDF, and was generally mild and asymptomatic.

The mechanism and clinical significance are unknown.

Table 3 Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥5% in Any 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 emtricitabine and tenofovir disoproxil fumarate tablets with efavirenz in place of FTC+TDF with efavirenz.

c.

Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, 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% Nasopharyngitis 5% 3% Vomiting 2% 5% Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of TDF and/or FTC (Table 4).

Table 4 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Study 934 (0 to 144 Weeks) a.

From Weeks 96 to 144 of the trial, subjects received emtricitabine and tenofovir disoproxil fumarate tablets with efavirenz in place of FTC+TDF with efavirenz.

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% Clinical Trials in Pediatric Subjects Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with FTC in the larger of two open-label, uncontrolled pediatric trials (N=116).

Tenofovir Disoproxil Fumarate: In pediatric clinical trials (Studies 352 and 321) conducted in 184 HIV-1 infected subjects 2 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with TDF were consistent with those observed in clinical trials of TDF in adults.

In Study 352 (2 to less than 12 years of age), 89 pediatric subjects received TDF for a median exposure of 104 weeks.

Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy.

Three of these 4 subjects presented with hypophosphatemia and had decreases in total body or spine BMD Z-score [see Warnings and Precautions (5.5) ].

Total body BMD gain at Week 48 was less in the TDF group compared to the stavudine (d4T) or zidovudine (AZT) treatment groups.

The mean rate of BMD gain in lumbar spine was similar between treatment groups.

One TDF-treated subject and none of the d4T- or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48.

Changes from baseline in BMD Z-scores were −0.012 for lumbar spine and −0.338 for total body in the 64 subjects who were treated with TDF for 96 weeks.

In Study 321 (12 to less than 18 years of age), the mean rate of BMD gain at Week 48 was less in the TDF compared to the placebo treatment group.

Six TDF-treated subjects and one placebo-treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48.

Changes from baseline BMD Z-scores were −0.341 for lumbar spine and −0.458 for total body in the 28 subjects who were treated with TDF for 96 weeks.

In both trials, skeletal growth (height) appeared to be unaffected.

Adverse Reactions from Clinical Trial Experience in Uninfected Subjects Taking Emtricitabine and Tenofovir Disoproxil Fumarate for HIV-1 PrEP Clinical Trials in Adult Subjects The safety profile of emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP was comparable to that observed in clinical trials of HIV-infected subjects based on two randomized placebo-controlled clinical trials (iPrEx, Partners PrEP) in which 2,830 HIV-1 uninfected adults received emtricitabine and tenofovir disoproxil fumarate once daily for HIV-1 PrEP.

Subjects were followed for a median of 71 weeks and 87 weeks, respectively.

Table 5 provides a list of selected adverse events that occurred in 2% or more of subjects in any treatment group in the iPrEx trial, with an incidence greater than placebo.

Table 5 Selected Adverse Events (All Grades) Reported in ≥2% in Any Treatment Group in the iPrEx Trial and Greater than Placebo FTC/TDF (N=1,251) Placebo (N=1,248) Headache Abdominal pain Weight decreased 7% 4% 3% 6% 2% 2% In the Partners PrEP trial, the frequency of adverse events in the emtricitabine and tenofovir disoproxil fumarate treatment group was generally either less than or the same as in the placebo group.

Laboratory Abnormalities : Table 6 provides a list of Grade 2 to 4 laboratory abnormalities observed in the iPrEx and Partners PrEP trials.

Six subjects in the TDF-containing arms of the Partners PrEP trial discontinued from the trial due to an increase in serum creatinine compared with no discontinuations in the placebo group.

One subject in the emtricitabine and tenofovir disoproxil fumarate arm of the iPrEx trial discontinued from the trial due to an increase in serum creatinine and another subject discontinued due to low serum phosphorus.

Grades 2 to 3 proteinuria (2 to 4+) and/or glycosuria (3+) occurred in less than 1% of subjects treated with emtricitabine and tenofovir disoproxil fumarate in the iPrEx trial and Partners PrEP trial.

Table 6 Laboratory Abnormalities (Highest Toxicity Grade Reported for Each Subject) in the iPrEx Trial and Partners PrEP Trial Grading is per DAIDS criteria.

Grade 2 to 4 a iPrEx Trial Partners PrEP Trial FTC/TDF (N=1,251) Placebo (N=1,248) FTC/TDF (N=1,579) Placebo (N=1,584) Creatinine (>1.4 x ULN) <1% <1% <1% <1% Phosphorus(<2.0 mg/dL) 10% 8% 9% 9% AST (>2.6 x ULN) 5% 5% <1% <1% ALT (>2.6 x ULN) 7% 7% <1% <1% Hemoglobin (<9.4 mg/dL) 1% 2% 2% 2% Neutrophils (<750/mm 3 ) <1% <1% 5% 3% Changes in Bone Mineral Density: In clinical trials of HIV-1 uninfected individuals, decreases in BMD were observed.

In the iPrEx trial, a substudy of 503 subjects found mean changes from baseline in BMD ranging from –0.4% to –1.0% across total hip, spine, femoral neck, and trochanter in the emtricitabine and tenofovir disoproxil fumarate group compared with the placebo group, which returned toward baseline after discontinuation of treatment.

Thirteen percent of emtricitabine and tenofovir disoproxil fumarate-treated subjects versus 6% of placebo-treated subjects lost at least 5% of BMD at the spine during treatment.

Bone fractures were reported in 1.7% of the emtricitabine and tenofovir disoproxil fumarate group compared with 1.4% in the placebo group.

No correlation between BMD and fractures was noted [see Clinical Studies (14.3) ] .

The Partners PrEP trial found similar fracture rates between the treatment and placebo groups (0.8% and 0.6%,respectively); no BMD evaluations were performed in this trial [see Clinical Studies (14.4) ] .

Clinical Trials in Adolescent Subjects In a single-arm, open-label clinical trial (ATN113), in which 67 HIV-1 uninfected adolescent (15 to 18 years of age) men who have sex with men received emtricitabine and tenofovir disoproxil fumarate once daily for HIV-1 PrEP, the safety profile of emtricitabine and tenofovir disoproxil fumarate was similar to that observed in adults.

Median duration to exposure of emtricitabine and tenofovir disoproxil fumarate was 47 weeks [see Use in Specific Populations (8.4) ].

In the ATN113 trial, median BMD increased from baseline to Week 48, +2.58% for lumbar spine and +0.72% for total body.

One subject had significant (greater than or equal to 4%) total body BMD loss at Week 24.

Median changes from baseline BMD Z-scores were 0.0 for lumbar spine and −0.2 for total body at Week 48.

Three subjects showed a worsening (change from > −2 to ≤ −2) from baseline in their lumbar spine or total body BMD Z-scores at Week 24 or 48.

Interpretation of these data, however, may be limited by the low rate of adherence to emtricitabine and tenofovir disoproxil fumarate by Week 48.

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

No additional adverse reactions have been identified during postapproval use of FTC.

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.

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.